Next Article in Journal
Chloramidine/Bisindolylmaleimide-I-Mediated Inhibition of Exosome and Microvesicle Release and Enhanced Efficacy of Cancer Chemotherapy
Next Article in Special Issue
The Regulatory Capacity of Bivalent Genes—A Theoretical Approach
Previous Article in Journal
Diverging Concepts and Novel Perspectives in Regenerative Medicine
Previous Article in Special Issue
Epigenetic Bases of Aberrant Glycosylation in Cancer
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Exploiting Epigenetic Alterations in Prostate Cancer

Drug Discovery, Bayer AG, Müllerstr. 178, 13353 Berlin, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2017, 18(5), 1017; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18051017
Submission received: 21 April 2017 / Revised: 4 May 2017 / Accepted: 4 May 2017 / Published: 9 May 2017
(This article belongs to the Special Issue Cancer Epigenetics)

Abstract

:
Prostate cancer affects an increasing number of men worldwide and is a leading cause of cancer-associated deaths. Beside genetic mutations, many epigenetic alterations including DNA and histone modifications have been identified in clinical prostate tumor samples. They have been linked to aberrant activity of enzymes and reader proteins involved in these epigenetic processes, leading to the search for dedicated inhibitory compounds. In the wake of encouraging anti-tumor efficacy results in preclinical models, epigenetic modulators addressing different targets are now being tested in prostate cancer patients. In addition, the assessment of microRNAs as stratification biomarkers, and early clinical trials evaluating suppressor microRNAs as potential prostate cancer treatment are being discussed.

Graphical Abstract

1. Introduction

Prostate adenocarcinoma is one of the most frequent male malignancies in developed countries and is a leading cause of cancer-related deaths. Its increasing rate is linked in part to the overall ageing of the population, particularly in the Western world [1]. It remains indolent in most cases but can later advance to aggressive prostate cancer. Despite initial good response to androgen deprivation therapy, most men with metastatic disease will eventually progress to castration-resistant prostate cancer (CRPC), where the androgen receptor (AR) axis still plays an essential role [2,3,4].
The disease is characterized by a high genetic heterogeneity which results in variable progression rates and difficult choices when it comes to treatment [3,4,5,6]. This heterogeneity is due to the multifocal origin of the disease [7] and the incremental accumulation of mutations during tumor progression. This was evidenced by extensive genomic profiling analyses performed on primary tumors [8] and on metastatic samples [2]. Importantly, these studies confirmed the essential role of the AR axis in early and late stages of the disease, thus vindicating ongoing efforts towards the identification of more efficacious AR antagonists and androgen synthesis inhibitors [9,10]. They furthermore show that genetic alterations with impact on the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway and the DNA repair process are overrepresented [5,11], and indeed a number of studies document that these pathways interact with AR signaling [12,13]. Nonetheless, the precise molecular mechanisms involved in the progression of prostate cancer are still insufficiently understood [14,15,16].
Beside genetic mutations, diverse epigenetic changes are also likely to significantly contribute to prostate cancer progression [17,18,19]. Importantly, signaling downstream of AR activation is closely regulated by epigenetic modifications, suggesting that interfering with local chromatin modulation may represent a promising novel strategy to block androgen-mediated gene transcription. This area has attracted much attention due to the anticipated reversibility of epigenetic alterations and the recent identification of potent and selective inhibitors of epigenetic tumor drivers [20,21].
An epigenetic aberration which is often observed in prostate cancer is the global reduction of DNA methylation, but the existence of a causal link awaits further confirmation [22]. On the other hand, local DNA hypermethylation leading to the silencing of tumor suppressor genes occurs frequently [23]. In addition, multiple changes in the distribution of post-translational modifications (PTMs) of histones have been reported in prostate cancer. Increased and decreased histone acetylation levels have both been observed in prostate adenocarcinomas [24,25,26]. Modifiers and readers of histone acetylation were evaluated in detail for their oncogenic role in prostate cancer and potential targets for treatment identified [17,27]. Also, aberrant histone methylation, both at lysine and arginine residues, has been documented at different stages of prostate cancer, as well as expression changes and mutations in enzymes that add or remove these histone marks [17]. Finally, the investigation of microRNA dysregulation in prostate cancer is coming of age and accumulating data suggest that they may represent useful biomarkers for disease progression and treatment response [28]. Also, first studies with suppressor microRNAs show some anti-tumor efficacy in preclinical prostate cancer models [29].

2. Epigenetic Events in Prostate Cancer and Preclinical Efficacy of Inhibitors of Epigenetic Targets

2.1. DNA Methylation

DNA methylation is performed by dedicated DNA methyltransferases (DNMTs) that use S-adenosyl methionine as donor and predominantly modify CpG dinucleotides [23]. DNMT expression and activity are elevated in prostate tumor models [30], and also in androgen-resistant prostate cancer cell lines [31]. The expression of several genes, including GSTP1 and HOX family members, is recurrently down-regulated in prostate cancer due to promoter hypermethylation [23]. This and other studies led to the proposal of panels of DNA methylation markers for the diagnosis of cancerous prostate tissue [32]. Interestingly, in CRPC, androgen target genes are more prone to changes in DNA methylation, in line with the continuous implication of the AR axis in late-stage disease [33]. Recently, a stratification of prostate cancer subtypes based on DNA methylation patterns has been proposed [8], but the clinical usefulness is still unclear.
The DNMT inhibitors azacitidine and decitabine have been evaluated in vivo in prostate cancer xenografts and showed some efficacy [34,35,36]. With the help of an improved formulation, a strong anti-tumor effect was observed for decitabine in two different prostate cancer xenografts [37]. Decitabine also prevents tumor growth in the transgenic adenocarcinoma of the mouse model [38].
One eraser of DNA methylation is the DNA hydroxymethylase ten–eleven translocation 1 which can revert cytosine methylation and was described as tumor suppressor [39]. Its expression is often reduced in prostate cancer tissue and associated with decreased survival [40].

2.2. Histone Acetylation

Global and local acetylation results from the balanced activity of cellular histone acetyltransferases (HATs) and histone deacetylases (HDACs). Site-specific reductions of acetylated histone H3 have been measured in clinical samples of prostate cancer in comparison to normal tissue, and in tumor cell lines, in parallel to increased HDAC activity [26]. Concordantly, another study reports significantly decreased histone H3 and H4 acetylation levels in prostate cancer [41]. On the other hand, high levels of global H3K18 acetylation are linked to a higher risk of recurrence [25], implying a deregulation of HATs and HDACs in prostate cancer.
Chromatin immunoprecipitation studies show that acetylated histone H3 peaks are found in the vicinity of AR binding regions and are characteristic of androgen-responsive genes [42]. Importantly, local hyper-acetylation and chromatin opening contribute to reduced androgen dependency in resistant prostate cancer models [43]. Recently, the role of hyper-acetylated super-enhancer regions as multi-molecular cooperative units that drive the expression of oncogenes has been outlined [44,45,46]. First studies related to the implication of such super-enhancers in prostate cancer are emerging and the enrichment of the acetyl mark binder bromodomain-containing protein 4 (BRD4) at genetic risk loci has recently been reported [47].
The AR interacts with numerous cofactors possessing HAT activity, which will impact the local histone acetylation status and downstream androgen-controlled gene expression [48]. In addition, several AR PTMs including lysine acetylation are probably catalyzed by the very same HATs [49,50,51]. Further, global expression profiling shows that EP300/KAT3B is an essential player involved in androgen target gene regulation [52]. It cooperates with GATA2 to open up chromatin at AR-targeted enhancers and facilitates gene expression [53]. The transcript levels of E1A-associated protein p300 (EP300) and the related cAMP-response element-binding protein (CREB) binding protein (CREBBP)/KAT3A are reduced by androgen but stimulated upon androgen ablation [54]. The dual, allosteric activator of EP300 and CREBBP I-CBP112 increases histone acetylation, mainly at H3K18, and impairs prostate cancer cell proliferation when applied at a low micromolar concentration [55]. MYST1/KAT8 also controls the activity of androgen target genes and its knockdown reduces prostate tumor cell proliferation [56,57]. TIP60/KAT5 is up-regulated in prostate cancer [58] and its impact on nuclear translocation following AR acetylation has been reported [59].
Up to now, only few selective and potent HAT inhibitors are available. They address either the enzymatic activity or bromodomain function [60]. In some cases, their impact on prostate cancer models has been determined (Figure 1). The EP300 inhibitor C646 reduces AR function and induces apoptosis, but only at high doses [61]. The two related EP300 inhibitors NK13650A and NK13650B impair the viability of prostate cancer cells when given at high concentrations [62]. For TIP60 also, first inhibitory compounds have been identified [63]. Anti-proliferative effects and apoptosis induction were reported following in vitro treatment of prostate cancer cells with the TIP60 inhibitor NU9056 [64].
In line with site-specific reduction of histone acetylation marks, HDAC levels are elevated in prostate cancer, especially in high-grade tumors, and the levels of HDAC1 and HDAC2 are positively correlated with Gleason score [65,66]. The role of HDACs in androgen-driven gene expression via changes in local histone acetylation has been reported [67,68].
Inhibitors directed at the zinc-dependent HDAC family members have been around for many years (Figure 1), and their impact on the acetylation status of histone and non-histone proteins were described by numerous groups (see overview in [69]). Their efficacy was evidenced in several prostate tumor models. In vivo activity was, for instance, reported for the pan-HDAC inhibitors panobinostat and belinostat [70,71], and for the more selective inhibitors entinostat and mocetinostat [72,73]. Panobinostat was also shown to block growth of castration-resistant models [74]. Importantly, a stronger impact of HDAC inhibitors was observed in models harboring the ERG gene fusion, which is detected in about 50% of prostate tumors [75]. Concerning NAD+–dependent HDACs, it was described that sirtuin 1 directly interacts with the AR to locally reduce histone acetylation and repress its activity [76].
Bromodomain proteins are readers of histone acetylation marks that translate epigenetic modifications in their cellular context into a transcriptional response. The bromodomain and extra-terminal protein (BET) subgroup is probably the best studied one, due to the availability of highly potent and selective inhibitors (Figure 1) [77,78,79,80]. The role of BET proteins, mainly BRD4, in prostate cancer has been reported by several groups. Inhibitors of BET bromodomains with various chemical scaffolds such as JQ1, OTX015/MK-8628, I-BET762 or ABVV-075 exhibit strong anti-proliferative effects in different tumor xenografts, including models that respond poorly to anti-androgens [81,82,83,84,85]. A reduction of the expression and binding of AR full-length and of a splice variant found in resistant tumors was reported [84]. Another study shows that a model bearing an AR mutation responsible for enzalutamide resistance is still responsive to a combination treatment with JQ1 [86]. Also, BRD4 interacts with ERG to control the expression of common target genes which are up-regulated in CRPC. BET bromodomain inhibitors such as JQ1 and I-BET762 can partially prevent this interaction, implying an additional mechanism by which they reduce prostate tumor growth [87]. A newly described approach is the proteolysis targeting chimera (PROTAC) technology [88] where a BET bromodomain inhibitor linked to a ligand that recruits the E3 ubiquitin ligase von Hippel-Lindau was used for promoting degradation of the targeted BET proteins. A strong efficacy including tumor regression was observed in a CRPC model [89]. The marked effects observed for BET bromodomain inhibitors in several studies can be in part explained by the disruption of transcriptional networks as a consequence of the targeting of enhancers and super-enhancers which are required for proliferation and cellular identity [44].
Several other bromodomain proteins have been linked to prostate cancer. Examples include ATAD2, an AR cofactor up-regulated in a subset of prostate tumors [90], but no direct experiments probing its functional impact in vivo have been reported. Further, the transcriptional activator tripartite motif-containing 24 (TRIM24) is stabilized by speckle-type POZ protein (SPOP) mutations, which are often detected in recurrent prostate cancer [91,92]. TRIM24 and the AR have many common target genes and a direct cooperation between both regulators leading to enhanced downstream gene expression has been reported [92]. The levels of transcription initiation factor TFIID subunit 1 (TAF1), which is part of the basal multiprotein transcription complex TFIID, are linked with prostate cancer progression. This bromodomain protein stimulates the transcriptional activity of the AR, as shown by gene silencing experiments, probably by affecting AR ubiquitylation levels [93]. No data concerning the specific role of the respective bromodomains of TRIM24 or TAF1 are yet available, so that the recent discovery of inhibitors addressing these regions should greatly help to clarify this [94,95,96].

2.3. Histone Methylation

Dynamic changes in histone lysine methylation patterns during prostate cancer progression have been reported. For instance, elevated H3K4 dimethylation correlates with Gleason score and is associated with increased relapse risk [25,97]. Interestingly, the levels of this histone mark have recently been found to be stimulated by androgen treatment [98]. Also, H3K4 monomethylation, as well as H3K9 di- and trimethylation are diminished in prostate tumors compared to non-tumor tissues [41]. Another report shows that H4K20 methylation is much reduced in CRPC [99]. Far less is known about arginine methylation but H4R3 dimethylation is positively correlated with the Gleason score [97].
The AR interacts with several factors that govern histone methylation, most notably the polycomb repressive complex 2 (PRC2) [100]. A prominent member of this complex is an enhancer of zeste homolog 2 (EZH2), which is overexpressed in various cancer types, including prostate cancer where its elevated levels correlate with disease progression and higher Gleason score [101,102]. EZH2 catalyzes di- and trimethylation of H3K27, an essential mark associated with condensed and transcriptionally silent chromatin, thereby repressing gene transcription and disrupting differentiation processes, which may promote cancer stem cell development [103,104,105]. Beside its repressive role, EZH2 also acts independently of the PRC2 complex and co-activates gene transcription by interacting with transcription factors such as the AR [106], making it a promising target for prostate cancer treatment. Indeed, several recent in vitro and in vivo studies document that inhibition of EZH2 with compounds such as DZNeP and GSK126 alone (Figure 1), or in combination with other drugs, decreases prostate tumor size and proliferation [107,108]. Another essential component of the PRC2 complex is the embryonic ectoderm development protein (EED), for which selective inhibitors phenocopying EZH2 inhibitors have very recently been described [109,110,111,112]. EED inhibitors display potent in vitro and in vivo efficacy in different tumor types, also in models harboring an EZH2 mutation leading to resistance to inhibitors [109,110,111]. It will be interesting to find out whether tumors respond differently to inhibitors of EED or EZH2 inhibitors, and this will help to understand the respective roles of the H3K27me3 mark and of EZH2, as EED inhibition effectively reduces H3K27me3 levels but probably does not affect EZH2.
SET and MYND domain-containing protein 3 (SMYD3) methylates specific lysine residues in histones H3 and H4 but also in other proteins involved in cell proliferation pathways [113]. An elevated expression is predictive of prostate cancer aggressiveness and selective SMYD3 gene silencing reduces tumor growth in vitro and in vivo [114,115]. A SMYD3 inhibitor named BCI-121 (Figure 1) with anti-proliferative effects on tumor cell lines including prostate cancer models has been described, and its activity was linked to SMYD3 levels [116].
Protein arginine methyltransferase 5 (PRMT5) has an oncogenic function in prostate tumor and other cancer types [117]. Apart from histones, it also methylates several additional proteins including the AR, thus regulating its activity on downstream target genes [118]. It furthermore controls AR levels upon interaction with the transcription factor Sp1 [119]. This was shown both by PRMT5 knockdown studies and with the inhibitor BLL3.3 (Figure 1) which reduces AR gene transcription and H4R3 methylation [119].
Concerning histone demethylases (HDMs), overexpression has been observed for several of them in clinical prostate cancer samples. Examples include lysine-specific demethylase 1 (LSD1)/KDM1A, jumonji D2 (JMJD2)/JHDM3/KDM4, jumonji AT-rich interactive domain 1B (JARID1B)/KDM5B and PHD finger protein 8 (PHF8)/KDM7B [120,121,122,123,124]. A functional impact of HDMs on AR signaling has been reported by different groups and reviewed in detail [18,125]. This is the case for LSD1 which co-localizes with the AR and stimulates androgen-dependent gene transcription [126]. In addition, LSD1 cooperates with JMJD2C to control AR activity and regulates target gene expression via demethylation of H3K9 [127]. More recently it was found that LSD1 directly represses AR gene expression by removing H3K4 methylation marks in the second intron. This is not observed when androgen concentrations are low, which may explain the increased AR levels observed in patients relapsing during deprivation therapy [128]. NCL1 (Figure 1) is a recently described, low micromolar inhibitor of LSD1, which reduces growth of a CRPC model in vivo, while inducing apoptosis and autophagy [129]. Along with JMJD2C, JMJD2B also controls AR transcriptional activity as well as AR stability, by blocking its ubiquitylation [122]. PHF8 demethylates H4K20 and acts as an AR cofactor. Its expression is induced by hypoxia, which promotes late-stage prostate cancer progression, including neuroendocrine differentiation [130,131]. The ongoing efforts to identify better, highly potent and selective compounds that selectively inhibit individual HDMs will be of great help to further delineate the individual roles of members of this enzyme family in AR signaling and prostate cancer [132].
Chromodomain helicase DNA-binding protein 1 (CHD1) is a reader of H3K4 di- and trimethylation marks which is often mutated in ETS fusion-negative late-stage prostate cancer [133]. Its loss promotes prostate cancer aggressiveness [134,135] but also sensitizes tumor cells to inhibitors of the poly-ADP ribose polymerase, due to its role in the DNA damage response [136]. Interestingly, in PTEN-deficient prostate cancer, the inactivation of CHD1 dramatically reduces proliferation and survival, due to its regulatory role on the tumor necrosis factor/nuclear factor kappa-light-chain-enhancer of activated B cells pathway [137].

2.4. Histone Ubiquitylation

Histone ubiquitylation is a chromatin mark associated mainly with the transcribed region of genes and involved in cellular differentiation as well as in DNA damage response [138,139,140]. The role of histone ubiquitylation in controlling AR function has only been analyzed in a few studies. The E3 ubiquitin ligases RNF20 and RNF40 stimulate H2B ubiquitylation and AR activity at target genes, and their depletion leads to impaired prostate cancer cell proliferation [141]. Ubiquitylation of the histone variant H2A.Z reduces AR activity and is controlled by USP10 [142]. Other studies show that direct ubiquitylation of the AR affects its stability and function [143,144,145,146]. Interestingly, the E3 ubiquitin ligase SPOP is a frequently inactivated tumor suppressor in prostate cancer [147]. It represses PI3K/mTOR signaling and its mutation promotes tumorigenesis, as evidenced in a mouse model [148]. The respective impacts of histone and AR ubiquitylation on downstream gene regulation remain to be exactly delineated [149,150].

2.5. Histone Phosphorylation

There are few published data on the impact of histone phosphorylation on AR signaling. H3T11 is phosphorylated by protein kinase N1 (PKN1), leading to androgen-mediated recruitment of the chromatin-associated protein WD repeat-containing protein 5 (WDR5) to AR target genes [151]. In line with this, inhibition of PKN1 with Ro318220 (Figure 1), and knockdown of WDR5, reduces androgen target gene expression and prostate cancer cell proliferation, respectively [151,152].

3. Clinical Studies in Prostate Cancer Addressing Epigenetic Targets

An overview of clinical trials performed with DNMT inhibitors and including prostate cancer patients is given in Table 1. Early studies with the demethylating compound decitabine showed only a limited efficacy in metastatic CRPC patients [153]. Presently, azacitidine is being evaluated in three clinical studies for prostate cancer treatment. In the most advanced one, it is tested in combination with docetaxel in chemotherapy-resistant metastatic CRPC patients to determine whether their response to docetaxel can be restored [154]. Phase 2 results show an objective response in three out of ten patients but more studies are needed to confirm this. Two additional trials are still ongoing but no concluding results are available yet.
Different HDAC inhibitors have been or are currently being assessed in clinical phase 1 or 2 for prostate cancer (Table 1). Early studies with vorinostat or romidepsin were disappointing as only limited responses were observed, probably due to the insufficient therapeutic window [155,156]. Similarly, a recently completed study with pracinostat showed only limited efficacy [157]. Panobinostat given as single agent leads to prostate-specific antigen decrease in a small number of patients only [158]. Combination treatments using different HDAC inhibitors and docetaxel or androgen deprivation are currently being evaluated but only few data are available until now [159,160]. To date, no phase 3 clinical trial has been performed, so the jury remains open as to whether HDAC inhibition is a valuable approach to treat prostate cancer patients [161].
BET bromodomain inhibitors with different chemical scaffolds are presently being tested in various tumor types, including prostate cancer in a few instances (Table 2). Two phase 1 trials focusing on metastatic CRPC evaluate ZEN003694 as single agent or in combination with the AR antagonist enzalutamide [162]. They started in 2016 and dose escalation is currently ongoing.
Several EZH2 inhibitors have entered clinical trials, but not for the indication of prostate cancer. However, the EED inhibitor MAK683 which targets the PRC2 complex just entered clinical phase 1 for different tumor types including prostate cancer (Table 2).
A clinical study with the PRMT5 inhibitor GSK3326595 (Figure 1) was recently initiated in patients with different malignancies, including prostate cancer (Table 2).

4. MicroRNAs as Potential Biomarkers for Prostate Cancer

Another way to take advantage of epigenetic alterations occurring in prostate cancer is to determine whether changes in microRNA profiles represent diagnosis biomarkers or are associated with natural disease progression and therapy response [163]. Following the discovery that miR-141 is elevated in prostate cancer and correlates with the serum PSA levels [164], a number of other microRNAs were found to be up-regulated (e.g., miR-20a, miR-21, miR-195 and miR-375) or down-regulated (e.g., miR-34a, miR-143/145, miR-205 and miR-488) in prostate cancer (for recent reviews see [28,165]. Importantly, several microRNAs including miR-34a and miR-34c directly control AR levels by targeting the 3′-untranslated region of the corresponding transcript [166]. This was also reported for miR-130b, which was furthermore shown to increase invasion and therapy resistance. In patients, miR-130b levels correlate with tumor stage and Gleason score [167]. On the other hand, the AR modulates the expression of some microRNAs which are involved in prostate cancer cell proliferation [28,165]. A few clinical trials are currently ongoing to evaluate circulating microRNAs as potential biomarkers for prostate cancer (Table 3). Their aim is either to identify risks for prostate cancer early on or to predict therapy response, but no final data are available yet.

5. Suppressor MicroRNAs as Potential Treatment for Prostate Cancer

Some preclinical studies suggest that treatment with suppressor microRNAs may represent a novel strategy for prostate cancer treatment, provided efficient delivery can be achieved. First experiments in which miR-15a, miR-16-1 [168], miR-34a [169], miR-124 [170] or miR-145 [171] were delivered into prostate tumor cells showed a reduction of proliferation. Importantly, intravenous miR-124 treatment of mice bearing a CWR22 xenograft results in significant tumor growth inhibition. This effect is further enhanced by additional enzalutamide treatment and linked to reduction of AR splice variant expression [170]. The levels of miR-455-3p are down-regulated in clinical prostate cancer samples and forced overexpression reduces prostate cancer cell growth in vivo [172]. Mechanistically, a reduction of cap-dependent translation due to destabilization of EIF4E transcripts by miR-455-3p has been evidenced [172].
Conversely, microRNAs with an oncogenic role in prostate cancer have also been described. One recent example is miR-4534 which controls the expression of PTEN. Reducing miR-4534 levels in a prostate tumor xenograft strongly impairs in vivo growth [173].
The respective impacts of these microRNAs on prostate cancer growth still need to be compared and more work will be necessary before the findings can be translated into the clinic. The miR-34a mimic MRX34 was evaluated in a clinical phase 1 study addressing solid tumors, but no mention was made of prostate cancer patients [174].

6. Conclusions and Perspectives

Complex epigenetic aberrations take place throughout the progression of tumors so that the determination of the global epigenetic landscape of prostate cancer will necessitate large cohorts of samples and concerted research efforts. Impressive progress has nonetheless already been achieved in the identification of epigenetic players involved in prostate cancer. Early findings on the role of DNA methylation and histone acetylation, and the subsequent discovery of bespoke DNMT and HDAC inhibitors ultimately led to extensive clinical testing. Unfortunately, this was not successful up to now, possibly due to the comparatively low proliferation rate of prostate tumor cells, especially in comparison to leukemias. Also, multiple side-effects leading to lack of therapeutic window have been reported in many instances, implying that more selective drugs and stratification strategies to identify prostate cancer subgroups will be essential in defining the patient subpopulation most likely to respond to such treatments. Concerning novel epigenetic targets such as BET proteins, we should soon know whether their specific inhibitors are successful in the clinical setting. Ultimately, combination with an additional agent may prove more beneficial for increased efficacy and also to delay therapy resistance. In this line it will be interesting to find out whether immune checkpoint inhibitors can be successfully combined with epigenetic drugs, especially in the area of prostate cancer where responses have been limited so far [175]. Altogether, the tremendous progress recently made in large-scale analyses of genomic and epigenetic alterations will provide invaluable information for the identification of novel targets, development of novel therapies and stratification of patients.

Acknowledgments

We thank all our colleagues involved in prostate cancer and epigenetic research for many helpful discussions.

Author Contributions

Simon J. Baumgart and Bernard Haendler reviewed the literature and wrote the manuscript. Simon J. Baumgart designed Figure 1.

Conflicts of Interest

The authors are employees and/or own shares of Bayer AG.

References

  1. Dy, G.W.; Gore, J.L.; Forouzanfar, M.H.; Naghavi, M.; Fitzmaurice, C. Global burden of urologic cancers, 1990–2013. Eur. Urol. 2017, 71, 437–446. [Google Scholar] [CrossRef] [PubMed]
  2. Robinson, D.; Van Allen, E.M.; Wu, Y.M.; Schultz, N.; Lonigro, R.J.; Mosquera, J.M.; Montgomery, B.; Taplin, M.E.; Pritchard, C.C.; Attard, G.; et al. Integrative clinical genomics of advanced prostate cancer. Cell 2015, 161, 1215–1228. [Google Scholar] [CrossRef] [PubMed]
  3. Yap, T.A.; Smith, A.D.; Ferraldeschi, R.; Al-Lazikani, B.; Workman, P.; de Bono, J.S. Drug discovery in advanced prostate cancer: Translating biology into therapy. Nat. Rev. Drug Discov. 2016, 15, 699–718. [Google Scholar] [CrossRef] [PubMed]
  4. Attard, G.; Parker, C.; Eeles, R.A.; Schroder, F.; Tomlins, S.A.; Tannock, I.; Drake, C.G.; de Bono, J.S. Prostate cancer. Lancet 2016, 387, 70–82. [Google Scholar] [CrossRef]
  5. Ciccarese, C.; Massari, F.; Iacovelli, R.; Fiorentino, M.; Montironi, R.; di Nunno, V.; Giunchi, F.; Brunelli, M.; Tortora, G. Prostate cancer heterogeneity: Discovering novel molecular targets for therapy. Cancer Treat. Rev. 2017, 54, 68–73. [Google Scholar] [CrossRef] [PubMed]
  6. Rodrigues, D.N.; Boysen, G.; Sumanasuriya, S.; Seed, G.; Marzo, A.M.; de Bono, J. The molecular underpinnings of prostate cancer: Impacts on management and pathology practice. J. Pathol. 2017, 241, 173–182. [Google Scholar] [CrossRef] [PubMed]
  7. Squire, J.A.; Park, P.C.; Yoshimoto, M.; Alami, J.; Williams, J.L.; Evans, A.; Joshua, A.M. Prostate cancer as a model system for genetic diversity in tumors. Adv. Cancer Res. 2011, 112, 183–216. [Google Scholar] [PubMed]
  8. Cancer Genome Atlas Research Network. The molecular taxonomy of primary prostate cancer. Cell 2015, 163, 1011–1025. [Google Scholar]
  9. Dellis, A.; Papatsoris, A.G. Phase I and II therapies targeting the androgen receptor for the treatment of castration resistant prostate cancer. Expert Opin. Investig. Drugs 2016, 25, 697–707. [Google Scholar] [CrossRef] [PubMed]
  10. Bambury, R.M.; Rathkopf, D.E. Novel and next-generation androgen receptor-directed therapies for prostate cancer: Beyond abiraterone and enzalutamide. Urol. Oncol. 2016, 34, 348–355. [Google Scholar] [CrossRef] [PubMed]
  11. Pritchard, C.C.; Offit, K.; Nelson, P.S. DNA-repair gene mutations in metastatic prostate cancer. N. Engl. J. Med. 2016, 375, 1804–1805. [Google Scholar] [CrossRef] [PubMed]
  12. Ta, H.Q.; Gioeli, D. The convergence of DNA damage checkpoint pathways and androgen receptor signaling in prostate cancer. Endocri. Relat. Cancer 2014, 21, R395–407. [Google Scholar] [CrossRef] [PubMed]
  13. Yadav, S.S.; Li, J.; Stockert, J.A.; O’Connor, J.; Herzog, B.; Elaiho, C.; Galsky, M.D.; Tewari, A.K.; Yadav, K.K. Combination effect of therapies targeting the PI3K- and AR-signaling pathways in prostate cancer. Oncotarget 2016, 7, 76181–76196. [Google Scholar] [CrossRef] [PubMed]
  14. Gundem, G.; Van Loo, P.; Kremeyer, B.; Alexandrov, L.B.; Tubio, J.M.; Papaemmanuil, E.; Brewer, D.S.; Kallio, H.M.; Hognas, G.; Annala, M.; et al. The evolutionary history of lethal metastatic prostate cancer. Nature 2015, 520, 353–357. [Google Scholar] [CrossRef] [PubMed]
  15. Spratt, D.E.; Zumsteg, Z.S.; Feng, F.Y.; Tomlins, S.A. Translational and clinical implications of the genetic landscape of prostate cancer. Nat. Rev. Clin. Oncol. 2016, 13, 597–610. [Google Scholar] [CrossRef] [PubMed]
  16. Mitchell, T.; Neal, D.E. The genomic evolution of human prostate cancer. Br. J. Cancer 2015, 113, 193–198. [Google Scholar] [CrossRef] [PubMed]
  17. Ngollo, M.; Dagdemir, A.; Karsli-Ceppioglu, S.; Judes, G.; Pajon, A.; Penault-Llorca, F.; Boiteux, J.P.; Bignon, Y.J.; Guy, L.; Bernard-Gallon, D.J. Epigenetic modifications in prostate cancer. Epigenomics 2014, 6, 415–426. [Google Scholar] [CrossRef] [PubMed]
  18. Cucchiara, V.; Yang, J.C.; Mirone, V.; Gao, A.C.; Rosenfeld, M.G.; Evans, C.P. Epigenomic regulation of androgen receptor signaling: Potential role in prostate cancer therapy. Cancers 2017, 9. [Google Scholar] [CrossRef] [PubMed]
  19. Kgatle, M.M.; Kalla, A.A.; Islam, M.M.; Sathekge, M.; Moorad, R. Prostate cancer: Epigenetic alterations, risk factors, and therapy. Prostate Cancer 2016, 2016, 5653862. [Google Scholar] [CrossRef] [PubMed]
  20. Gelato, K.A.; Shaikhibrahim, Z.; Ocker, M.; Haendler, B. Targeting epigenetic regulators for cancer therapy: Modulation of bromodomain proteins, methyltransferases, demethylases, and microRNAs. Expert Opin. Ther. Targets 2016, 20, 783–799. [Google Scholar] [CrossRef] [PubMed]
  21. Graca, I.; Pereira-Silva, E.; Henrique, R.; Packham, G.; Crabb, S.J.; Jeronimo, C. Epigenetic modulators as therapeutic targets in prostate cancer. Clin. Epigenet. 2016, 8, 98. [Google Scholar] [CrossRef] [PubMed]
  22. Zelic, R.; Fiano, V.; Grasso, C.; Zugna, D.; Pettersson, A.; Gillio-Tos, A.; Merletti, F.; Richiardi, L. Global DNA hypomethylation in prostate cancer development and progression: A systematic review. Prostate Cancer Prostatic Dis. 2015, 18, 1–12. [Google Scholar] [CrossRef] [PubMed]
  23. Massie, C.E.; Mills, I.G.; Lynch, A.G. The importance of DNA methylation in prostate cancer development. J. Steroid Biochem. Mol. Biol. 2017, 166, 1–15. [Google Scholar] [CrossRef] [PubMed]
  24. Attar, N.; Kurdistani, S.K. Exploitation of EP300 and CREBBP lysine acetyltransferases by cancer. Cold Spring Harb. Perspect. Med. 2017, 7. [Google Scholar] [CrossRef] [PubMed]
  25. Bianco-Miotto, T.; Chiam, K.; Buchanan, G.; Jindal, S.; Day, T.K.; Thomas, M.; Pickering, M.A.; O'Loughlin, M.A.; Ryan, N.K.; Raymond, W.A.; et al. Global levels of specific histone modifications and an epigenetic gene signature predict prostate cancer progression and development. Cancer Epidemiol. Biomark. Prev. 2010, 19, 2611–2622. [Google Scholar] [CrossRef] [PubMed]
  26. Cang, S.; Feng, J.; Konno, S.; Han, L.; Liu, K.; Sharma, S.C.; Choudhury, M.; Chiao, J.W. Deficient histone acetylation and excessive deacetylase activity as epigenomic marks of prostate cancer cells. Int. J. Oncol. 2009, 35, 1417–1422. [Google Scholar] [PubMed]
  27. Lochrin, S.E.; Price, D.K.; Figg, W.D. BET bromodomain inhibitors—A novel epigenetic approach in castration-resistant prostate cancer. Cancer Biol. Ther. 2014, 15, 1583–1585. [Google Scholar] [CrossRef] [PubMed]
  28. Shukla, K.K.; Misra, S.; Pareek, P.; Mishra, V.; Singhal, B.; Sharma, P. Recent scenario of microRNA as diagnostic and prognostic biomarkers of prostate cancer. Urol. Oncol. 2017, 35, 92–101. [Google Scholar] [CrossRef] [PubMed]
  29. Ayub, S.G.; Kaul, D.; Ayub, T. Microdissecting the role of microRNAs in the pathogenesis of prostate cancer. Cancer Genet. 2015, 208, 289–302. [Google Scholar] [CrossRef] [PubMed]
  30. Gravina, G.L.; Ranieri, G.; Muzi, P.; Marampon, F.; Mancini, A.; Di Pasquale, B.; di Clemente, L.; Dolo, V.; D'Alessandro, A.M.; Festuccia, C. Increased levels of DNA methyltransferases are associated with the tumorigenic capacity of prostate cancer cells. Oncol. Rep. 2013, 29, 1189–1195. [Google Scholar] [PubMed]
  31. Gravina, G.L.; Marampon, F.; Piccolella, M.; Motta, M.; Ventura, L.; Pomante, R.; Popov, V.M.; Zani, B.M.; Pestell, R.G.; Tombolini, V.; Jannini, E.A.; Festuccia, C. Hormonal therapy promotes hormone-resistant phenotype by increasing DNMT activity and expression in prostate cancer models. Endocrinology 2011, 152, 4550–4561. [Google Scholar] [CrossRef] [PubMed]
  32. Paziewska, A.; Dabrowska, M.; Goryca, K.; Antoniewicz, A.; Dobruch, J.; Mikula, M.; Jarosz, D.; Zapala, L.; Borowka, A.; Ostrowski, J. DNA methylation status is more reliable than gene expression at detecting cancer in prostate biopsy. Br. J. Cancer 2014, 111, 781–789. [Google Scholar] [CrossRef] [PubMed]
  33. Brocks, D.; Assenov, Y.; Minner, S.; Bogatyrova, O.; Simon, R.; Koop, C.; Oakes, C.; Zucknick, M.; Lipka, D.B.; Weischenfeldt, J.; et al. Intratumor DNA methylation heterogeneity reflects clonal evolution in aggressive prostate cancer. Cell Rep. 2014, 8, 798–806. [Google Scholar] [CrossRef] [PubMed]
  34. Festuccia, C.; Gravina, G.L.; D’Alessandro, A.M.; Muzi, P.; Millimaggi, D.; Dolo, V.; Ricevuto, E.; Vicentini, C.; Bologna, M. Azacitidine improves antitumor effects of docetaxel and cisplatin in aggressive prostate cancer models. Endocr. Relat. Cancer 2009, 16, 401–413. [Google Scholar] [CrossRef] [PubMed]
  35. Gravina, G.L.; Marampon, F.; Di Staso, M.; Bonfili, P.; Vitturini, A.; Jannini, E.A.; Pestell, R.G.; Tombolini, V.; Festuccia, C. 5-Azacitidine restores and amplifies the bicalutamide response on preclinical models of androgen receptor expressing or deficient prostate tumors. Prostate 2010, 70, 1166–1178. [Google Scholar] [CrossRef] [PubMed]
  36. Wang, X.; Gao, H.; Ren, L.; Gu, J.; Zhang, Y. Demethylation of the miR-146a promoter by 5-aza-2′-deoxycytidine correlates with delayed progression of castration-resistant prostate cancer. BMC Cancer 2014, 14, 308. [Google Scholar] [CrossRef] [PubMed]
  37. Naldi, I.; Taranta, M.; Gherardini, L.; Pelosi, G.; Viglione, F.; Grimaldi, S.; Pani, L.; Cinti, C. Novel epigenetic target therapy for prostate cancer: A preclinical study. PLoS ONE 2014, 9, e98101. [Google Scholar] [CrossRef] [PubMed]
  38. McCabe, M.T.; Low, J.A.; Daignault, S.; Imperiale, M.J.; Wojno, K.J.; Day, M.L. Inhibition of DNA methyltransferase activity prevents tumorigenesis in a mouse model of prostate cancer. Cancer Res. 2006, 66, 385–392. [Google Scholar] [CrossRef] [PubMed]
  39. Huang, Y.; Rao, A. Connections between TET proteins and aberrant DNA modification in cancer. Trends Genet. 2014, 30, 464–474. [Google Scholar] [CrossRef] [PubMed]
  40. Spans, L.; Van den Broeck, T.; Smeets, E.; Prekovic, S.; Thienpont, B.; Lambrechts, D.; Karnes, R.J.; Erho, N.; Alshalalfa, M.; Davicioni, E.; et al. Genomic and epigenomic analysis of high-risk prostate cancer reveals changes in hydroxymethylation and TET1. Oncotarget 2016, 7, 24326–24338. [Google Scholar] [CrossRef] [PubMed]
  41. Ellinger, J.; Kahl, P.; von der Gathen, J.; Rogenhofer, S.; Heukamp, L.C.; Gutgemann, I.; Walter, B.; Hofstadter, F.; Buttner, R.; Muller, S.C.; et al. Global levels of histone modifications predict prostate cancer recurrence. Prostate 2010, 70, 61–69. [Google Scholar] [CrossRef] [PubMed]
  42. Jia, L.; Berman, B.P.; Jariwala, U.; Yan, X.; Cogan, J.P.; Walters, A.; Chen, T.; Buchanan, G.; Frenkel, B.; Coetzee, G.A. Genomic androgen receptor-occupied regions with different functions, defined by histone acetylation, coregulators and transcriptional capacity. PLoS ONE 2008, 3, e3645. [Google Scholar] [CrossRef] [PubMed]
  43. Jia, L.; Shen, H.C.; Wantroba, M.; Khalid, O.; Liang, G.; Wang, Q.; Gentzschein, E.; Pinski, J.K.; Stanczyk, F.Z.; Jones, P.A.; et al. Locus-wide chromatin remodeling and enhanced androgen receptor-mediated transcription in recurrent prostate tumor cells. Mol. Cell. Biol. 2006, 26, 7331–7341. [Google Scholar] [CrossRef] [PubMed]
  44. Hnisz, D.; Shrinivas, K.; Young, R.A.; Chakraborty, A.K.; Sharp, P.A. A phase separation model for transcriptional control. Cell 2017, 169, 13–23. [Google Scholar] [CrossRef] [PubMed]
  45. Mansour, M.R.; Abraham, B.J.; Anders, L.; Berezovskaya, A.; Gutierrez, A.; Durbin, A.D.; Etchin, J.; Lawton, L.; Sallan, S.E.; Silverman, L.B.; et al. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element. Science 2014, 346, 1373–1377. [Google Scholar] [CrossRef] [PubMed]
  46. Bradner, J.E.; Hnisz, D.; Young, R.A. Transcriptional addiction in cancer. Cell 2017, 168, 629–643. [Google Scholar] [CrossRef] [PubMed]
  47. Zuber, V.; Bettella, F.; Witoelar, A.; Consortium, P.; Cruk, G.; Consortium, B.; Consortium, T.; Andreassen, O.A.; Mills, I.G.; Urbanucci, A. Bromodomain protein 4 discriminates tissue-specific super-enhancers containing disease-specific susceptibility loci in prostate and breast cancer. BMC Genom. 2017, 18, 270. [Google Scholar] [CrossRef] [PubMed]
  48. Culig, Z.; Comuzzi, B.; Steiner, H.; Bartsch, G.; Hobisch, A. Expression and function of androgen receptor coactivators in prostate cancer. J. Steroid Biochem. Mol. Biol. 2004, 92, 265–271. [Google Scholar] [CrossRef] [PubMed]
  49. Coffey, K.; Robson, C.N. Regulation of the androgen receptor by post-translational modifications. J. Endocrinol. 2012, 215, 221–237. [Google Scholar] [CrossRef] [PubMed]
  50. Faus, H.; Haendler, B. Androgen receptor acetylation sites differentially regulate gene control. J. Cell Biochem. 2008, 104, 511–524. [Google Scholar] [CrossRef] [PubMed]
  51. Lavery, D.N.; Bevan, C.L. Androgen receptor signalling in prostate cancer: The functional consequences of acetylation. J. Biomed. Biotechnol. 2011, 2011, 862125. [Google Scholar] [CrossRef] [PubMed]
  52. Ianculescu, I.; Wu, D.Y.; Siegmund, K.D.; Stallcup, M.R. Selective roles for cAMP response element-binding protein binding protein and p300 protein as coregulators for androgen-regulated gene expression in advanced prostate cancer cells. J. Biol. Chem. 2012, 287, 4000–4013. [Google Scholar] [CrossRef] [PubMed]
  53. Wu, D.; Sunkel, B.; Chen, Z.; Liu, X.; Ye, Z.; Li, Q.; Grenade, C.; Ke, J.; Zhang, C.; Chen, H.; et al. Three-tiered role of the pioneer factor GATA2 in promoting androgen-dependent gene expression in prostate cancer. Nucleic Acids Res. 2014, 42, 3607–3622. [Google Scholar] [CrossRef] [PubMed]
  54. Culig, Z. Androgen receptor coactivators in regulation of growth and differentiation in prostate cancer. J. Cell. Physiol. 2016, 231, 270–274. [Google Scholar] [CrossRef] [PubMed]
  55. Zucconi, B.E.; Luef, B.; Xu, W.; Henry, R.A.; Nodelman, I.M.; Bowman, G.D.; Andrews, A.J.; Cole, P.A. Modulation of p300/CBP acetylation of nucleosomes by bromodomain ligand I-CBP112. Biochemistry 2016, 55, 3727–3734. [Google Scholar] [CrossRef] [PubMed]
  56. Jaganathan, A.; Chaurasia, P.; Xiao, G.Q.; Philizaire, M.; Lv, X.; Yao, S.; Burnstein, K.L.; Liu, D.P.; Levine, A.C.; Mujtaba, S. Coactivator MYST1 regulates nuclear factor-κB and androgen receptor functions during proliferation of prostate cancer cells. Mol. Endocrinol. 2014, 28, 872–885. [Google Scholar] [CrossRef] [PubMed]
  57. Kim, J.Y.; Yu, J.; Abdulkadir, S.A.; Chakravarti, D. KAT8 regulates androgen signaling in prostate cancer cells. Mol. Endocrinol. 2016, 30, 925–936. [Google Scholar] [CrossRef] [PubMed]
  58. Halkidou, K.; Gnanapragasam, V.J.; Mehta, P.B.; Logan, I.R.; Brady, M.E.; Cook, S.; Leung, H.Y.; Neal, D.E.; Robson, C.N. Expression of Tip60, an androgen receptor coactivator, and its role in prostate cancer development. Oncogene 2003, 22, 2466–2477. [Google Scholar] [CrossRef] [PubMed]
  59. Shiota, M.; Yokomizo, A.; Masubuchi, D.; Tada, Y.; Inokuchi, J.; Eto, M.; Uchiumi, T.; Fujimoto, N.; Naito, S. Tip60 promotes prostate cancer cell proliferation by translocation of androgen receptor into the nucleus. Prostate 2010, 70, 540–554. [Google Scholar] [CrossRef] [PubMed]
  60. Richters, A.; Koehler, A.N. Epigenetic modulation using small molecules—Targeting histone acetyltransferases in disease. Curr. Med. Chem. 2017. [Google Scholar] [CrossRef] [PubMed]
  61. Santer, F.R.; Hoschele, P.P.; Oh, S.J.; Erb, H.H.; Bouchal, J.; Cavarretta, I.T.; Parson, W.; Meyers, D.J.; Cole, P.A.; Culig, Z. Inhibition of the acetyltransferases p300 and CBP reveals a targetable function for p300 in the survival and invasion pathways of prostate cancer cell lines. Mol. Cancer Ther. 2011, 10, 1644–1655. [Google Scholar] [CrossRef] [PubMed]
  62. Tohyama, S.; Tomura, A.; Ikeda, N.; Hatano, M.; Odanaka, J.; Kubota, Y.; Umekita, M.; Igarashi, M.; Sawa, R.; Morino, T. Discovery and characterization of NK13650s, naturally occurring p300-selective histone acetyltransferase inhibitors. J. Org. Chem. 2012, 77, 9044–9052. [Google Scholar] [CrossRef] [PubMed]
  63. Brown, J.A.; Bourke, E.; Eriksson, L.A.; Kerin, M.J. Targeting cancer using KAT inhibitors to mimic lethal knockouts. Biochem. Soc. Trans. 2016, 44, 979–986. [Google Scholar] [CrossRef] [PubMed]
  64. Coffey, K.; Blackburn, T.J.; Cook, S.; Golding, B.T.; Griffin, R.J.; Hardcastle, I.R.; Hewitt, L.; Huberman, K.; McNeill, H.V.; Newell, D.R.; et al. Characterisation of a Tip60 specific inhibitor, NU9056, in prostate cancer. PLoS ONE 2012, 7, e45539. [Google Scholar] [CrossRef] [PubMed]
  65. Waltregny, D.; North, B.; Van Mellaert, F.; de Leval, J.; Verdin, E.; Castronovo, V. Screening of histone deacetylases (HDAC) expression in human prostate cancer reveals distinct class I HDAC profiles between epithelial and stromal cells. Eur. J. Histochem. 2004, 48, 273–290. [Google Scholar] [PubMed]
  66. Weichert, W.; Roske, A.; Gekeler, V.; Beckers, T.; Stephan, C.; Jung, K.; Fritzsche, F.R.; Niesporek, S.; Denkert, C.; Dietel, M.; et al. Histone deacetylases 1, 2 and 3 are highly expressed in prostate cancer and HDAC2 expression is associated with shorter PSA relapse time after radical prostatectomy. Br. J. Cancer 2008, 98, 604–610. [Google Scholar] [CrossRef] [PubMed]
  67. Gaughan, L.; Logan, I.R.; Neal, D.E.; Robson, C.N. Regulation of androgen receptor and histone deacetylase 1 by Mdm2-mediated ubiquitylation. Nucleic Acids Res. 2005, 33, 13–26. [Google Scholar] [CrossRef] [PubMed]
  68. Welsbie, D.S.; Xu, J.; Chen, Y.; Borsu, L.; Scher, H.I.; Rosen, N.; Sawyers, C.L. Histone deacetylases are required for androgen receptor function in hormone-sensitive and castrate-resistant prostate cancer. Cancer Res. 2009, 69, 958–966. [Google Scholar] [CrossRef] [PubMed]
  69. Olzscha, H.; Bekheet, M.E.; Sheikh, S.; La Thangue, N.B. HDAC inhibitors. Methods Mol. Biol. 2016, 1436, 281–303. [Google Scholar] [PubMed]
  70. Bruzzese, F.; Pucci, B.; Milone, M.R.; Ciardiello, C.; Franco, R.; Chianese, M.I.; Rocco, M.; Di Gennaro, E.; Leone, A.; Luciano, A.; et al. Panobinostat synergizes with zoledronic acid in prostate cancer and multiple myeloma models by increasing ROS and modulating mevalonate and p38-MAPK pathways. Cell Death Dis. 2013, 4, e878. [Google Scholar] [CrossRef] [PubMed]
  71. Gravina, G.L.; Marampon, F.; Giusti, I.; Carosa, E.; Di Sante, S.; Ricevuto, E.; Dolo, V.; Tombolini, V.; Jannini, E.A.; Festuccia, C. Differential effects of PXD101 (belinostat) on androgen-dependent and androgen-independent prostate cancer models. Int. J. Oncol. 2012, 40, 711–720. [Google Scholar] [PubMed]
  72. Qian, D.Z.; Wei, Y.F.; Wang, X.; Kato, Y.; Cheng, L.; Pili, R. Antitumor activity of the histone deacetylase inhibitor MS-275 in prostate cancer models. Prostate 2007, 67, 1182–1193. [Google Scholar] [CrossRef] [PubMed]
  73. Zhang, Q.; Sun, M.; Zhou, S.; Guo, B. Class I HDAC inhibitor mocetinostat induces apoptosis by activation of miR-31 expression and suppression of E2F6. Cell Death Discov. 2016, 2, 16036. [Google Scholar] [CrossRef] [PubMed]
  74. Ruscetti, M.; Dadashian, E.L.; Guo, W.; Quach, B.; Mulholland, D.J.; Park, J.W.; Tran, L.M.; Kobayashi, N.; Bianchi-Frias, D.; Xing, Y.; et al. HDAC inhibition impedes epithelial-mesenchymal plasticity and suppresses metastatic, castration-resistant prostate cancer. Oncogene 2016, 35, 3781–3795. [Google Scholar] [CrossRef] [PubMed]
  75. Bjorkman, M.; Iljin, K.; Halonen, P.; Sara, H.; Kaivanto, E.; Nees, M.; Kallioniemi, O.P. Defining the molecular action of HDAC inhibitors and synergism with androgen deprivation in ERG-positive prostate cancer. Int. J. Cancer 2008, 123, 2774–2781. [Google Scholar] [CrossRef] [PubMed]
  76. Dai, Y.; Ngo, D.; Forman, L.W.; Qin, D.C.; Jacob, J.; Faller, D.V. Sirtuin 1 is required for antagonist-induced transcriptional repression of androgen-responsive genes by the androgen receptor. Mol. Endocrinol. 2007, 21, 1807–1821. [Google Scholar] [CrossRef] [PubMed]
  77. Xu, Y.; Vakoc, C.R. Targeting cancer cells with BET bromodomain inhibitors. Cold Spring Harb. Perspect. Med. 2017. [Google Scholar] [CrossRef] [PubMed]
  78. Sahai, V.; Redig, A.J.; Collier, K.A.; Eckerdt, F.D.; Munshi, H.G. Targeting BET bromodomain proteins in solid tumors. Oncotarget 2016, 7, 53997–54009. [Google Scholar] [CrossRef] [PubMed]
  79. Jung, M.; Gelato, K.A.; Fernandez-Montalvan, A.; Siegel, S.; Haendler, B. Targeting BET bromodomains for cancer treatment. Epigenomics 2015, 7, 487–501. [Google Scholar] [CrossRef] [PubMed]
  80. Taniguchi, Y. The bromodomain and extra-terminal domain (BET) family: Functional anatomy of BET paralogous proteins. Int. J. Mol. Sci. 2016, 17. [Google Scholar] [CrossRef] [PubMed]
  81. Wyce, A.; Degenhardt, Y.; Bai, Y.; Le, B.; Korenchuk, S.; Crouthame, M.C.; McHugh, C.F.; Vessella, R.; Creasy, C.L.; Tummino, P.J.; et al. Inhibition of BET bromodomain proteins as a therapeutic approach in prostate cancer. Oncotarget 2013, 4, 2419–2429. [Google Scholar] [CrossRef] [PubMed]
  82. Asangani, I.A.; Dommeti, V.L.; Wang, X.; Malik, R.; Cieslik, M.; Yang, R.; Escara-Wilke, J.; Wilder-Romans, K.; Dhanireddy, S.; Engelke, C.; et al. Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature 2014, 510, 278–282. [Google Scholar] [CrossRef] [PubMed]
  83. Asangani, I.A.; Wilder-Romans, K.; Dommeti, V.L.; Krishnamurthy, P.M.; Apel, I.J.; Escara-Wilke, J.; Plymate, S.R.; Navone, N.M.; Wang, S.; Feng, F.Y.; et al. BET bromodomain inhibitors enhance efficacy and disrupt resistance to AR antagonists in the treatment of prostate cancer. Mol. Cancer Res. 2016, 14, 324–331. [Google Scholar] [CrossRef] [PubMed]
  84. Chan, S.C.; Selth, L.A.; Li, Y.; Nyquist, M.D.; Miao, L.; Bradner, J.E.; Raj, G.V.; Tilley, W.D.; Dehm, S.M. Targeting chromatin binding regulation of constitutively active AR variants to overcome prostate cancer resistance to endocrine-based therapies. Nucleic Acids Res. 2015, 43, 5880–5897. [Google Scholar] [CrossRef] [PubMed]
  85. Faivre, E.J.; Wilcox, D.; Lin, X.; Hessler, P.; Torrent, M.; He, W.; Uziel, T.; Albert, D.H.; McDaniel, K.; Kati, W.; et al. Exploitation of castration-resistant prostate cancer transcription factor dependencies by the novel BET inhibitor ABBV-075. Mol. Cancer Res. 2017, 15, 35–44. [Google Scholar] [CrossRef] [PubMed]
  86. Coleman, D.J.; Van Hook, K.; King, C.J.; Schwartzman, J.; Lisac, R.; Urrutia, J.; Sehrawat, A.; Woodward, J.; Wang, N.J.; Gulati, R.; et al. Cellular androgen content influences enzalutamide agonism of F877L mutant androgen receptor. Oncotarget 2016, 7, 40690–40703. [Google Scholar] [CrossRef] [PubMed]
  87. Blee, A.M.; Liu, S.; Wang, L.; Huang, H. BET bromodomain-mediated interaction between ERG and BRD4 promotes prostate cancer cell invasion. Oncotarget 2016, 7, 38319–38332. [Google Scholar] [CrossRef] [PubMed]
  88. Neklesa, T.K.; Winkler, J.D.; Crews, C.M. Targeted protein degradation by PROTACs. Pharmacol. Ther. 2017. [Google Scholar] [CrossRef] [PubMed]
  89. Raina, K.; Lu, J.; Qian, Y.; Altieri, M.; Gordon, D.; Rossi, A.M.; Wang, J.; Chen, X.; Dong, H.; Siu, K.; et al. PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer. Proc. Natl. Acad. Sci. USA 2016, 113, 7124–7129. [Google Scholar] [CrossRef] [PubMed]
  90. Zou, J.X.; Guo, L.; Revenko, A.S.; Tepper, C.G.; Gemo, A.T.; Kung, H.J.; Chen, H.W. Androgen-induced coactivator ANCCA mediates specific androgen receptor signaling in prostate cancer. Cancer Res. 2009, 69, 3339–3346. [Google Scholar] [CrossRef] [PubMed]
  91. Theurillat, J.P.; Udeshi, N.D.; Errington, W.J.; Svinkina, T.; Baca, S.C.; Pop, M.; Wild, P.J.; Blattner, M.; Groner, A.C.; Rubin, M.A.; et al. Prostate cancer. Ubiquitylome analysis identifies dysregulation of effector substrates in SPOP-mutant prostate cancer. Science 2014, 346, 85–89. [Google Scholar] [CrossRef] [PubMed]
  92. Groner, A.C.; Cato, L.; de Tribolet-Hardy, J.; Bernasocchi, T.; Janouskova, H.; Melchers, D.; Houtman, R.; Cato, A.C.; Tschopp, P.; Gu, L.; et al. TRIM24 is an oncogenic transcriptional activator in prostate cancer. Cancer Cell 2016, 29, 846–858. [Google Scholar] [CrossRef] [PubMed]
  93. Tavassoli, P.; Wafa, L.A.; Cheng, H.; Zoubeidi, A.; Fazli, L.; Gleave, M.; Snoek, R.; Rennie, P.S. TAF1 differentially enhances androgen receptor transcriptional activity via its N-terminal kinase and ubiquitin-activating and -conjugating domains. Mol. Endocrinol. 2010, 24, 696–708. [Google Scholar] [CrossRef] [PubMed]
  94. Bouché, L.; Christ, C.D.; Siegel, S.; Fernández-Montalván, A.E.; Holton, S.J.; Fedorov, O.; Ter Laak, A.; Sugawara, T.; Stöckigt, D.; Tallant, C.; et al. Benzoisoquinolinediones as potent and selective inhibitors of BRPF2 and TAF1/TAF1L bromodomains. J. Med. Chem. 2017. [Google Scholar] [CrossRef] [PubMed]
  95. Bennett, J.; Fedorov, O.; Tallant, C.; Monteiro, O.; Meier, J.; Gamble, V.; Savitsky, P.; Nunez-Alonso, G.A.; Haendler, B.; Rogers, C.; et al. Discovery of a chemical tool inhibitor targeting the bromodomains of TRIM24 and BRPF. J. Med. Chem. 2016, 59, 1642–1647. [Google Scholar] [CrossRef] [PubMed]
  96. Palmer, W.S.; Poncet-Montange, G.; Liu, G.; Petrocchi, A.; Reyna, N.; Subramanian, G.; Theroff, J.; Yau, A.; Kost-Alimova, M.; Bardenhagen, J.P.; et al. Structure-guided design of IACS-9571, a selective high-affinity dual TRIM24-BRPF1 bromodomain inhibitor. J. Med. Chem. 2016, 59, 1440–1454. [Google Scholar] [CrossRef] [PubMed]
  97. Seligson, D.B.; Horvath, S.; Shi, T.; Yu, H.; Tze, S.; Grunstein, M.; Kurdistani, S.K. Global histone modification patterns predict risk of prostate cancer recurrence. Nature 2005, 435, 1262–1266. [Google Scholar] [CrossRef] [PubMed]
  98. Pang, J.; Yang, Y.W.; Huang, Y.; Yang, J.; Zhang, H.; Chen, R.; Dong, L.; Huang, Y.; Wang, D.; Liu, J.; et al. P110β inhibition reduces histone H3K4 di-methylation in prostate cancer. Prostate 2017, 77, 299–308. [Google Scholar] [CrossRef] [PubMed]
  99. Behbahani, T.E.; Kahl, P.; von der Gathen, J.; Heukamp, L.C.; Baumann, C.; Gutgemann, I.; Walter, B.; Hofstadter, F.; Bastian, P.J.; von Ruecker, A.; et al. Alterations of global histone H4K20 methylation during prostate carcinogenesis. BMC Urol. 2012, 12, 5. [Google Scholar] [CrossRef] [PubMed]
  100. Cai, C.; Yuan, X.; Balk, S.P. Androgen receptor epigenetics. Transl. Androl. Urol. 2013, 2, 148–157. [Google Scholar] [PubMed]
  101. Yang, Y.A.; Yu, J. EZH2, an epigenetic driver of prostate cancer. Protein Cell 2013, 4, 331–341. [Google Scholar] [CrossRef] [PubMed]
  102. Melling, N.; Thomsen, E.; Tsourlakis, M.C.; Kluth, M.; Hube-Magg, C.; Minner, S.; Koop, C.; Graefen, M.; Heinzer, H.; Wittmer, C.; et al. Overexpression of enhancer of zeste homolog 2 (EZH2) characterizes an aggressive subset of prostate cancers and predicts patient prognosis independently from pre- and postoperatively assessed clinicopathological parameters. Carcinogenesis 2015, 36, 1333–1340. [Google Scholar] [CrossRef] [PubMed]
  103. Yu, J.; Yu, J.; Mani, R.S.; Cao, Q.; Brenner, C.J.; Cao, X.; Wang, X.; Wu, L.; Li, J.; Hu, M.; et al. An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression. Cancer Cell 2010, 17, 443–454. [Google Scholar] [CrossRef] [PubMed]
  104. Crea, F. EZH2 and cancer stem cells: Fact or fiction? Epigenomics 2011, 3, 127–128. [Google Scholar] [CrossRef] [PubMed]
  105. Volkel, P.; Dupret, B.; Le Bourhis, X.; Angrand, P.O. Diverse involvement of EZH2 in cancer epigenetics. Am. J. Transl. Res. 2015, 7, 175–193. [Google Scholar] [PubMed]
  106. Deb, G.; Thakur, V.S.; Gupta, S. Multifaceted role of EZH2 in breast and prostate tumorigenesis: Epigenetics and beyond. Epigenetics 2013, 8, 464–476. [Google Scholar] [CrossRef] [PubMed]
  107. Crea, F.; Hurt, E.M.; Mathews, L.A.; Cabarcas, S.M.; Sun, L.; Marquez, V.E.; Danesi, R.; Farrar, W.L. Pharmacologic disruption of Polycomb Repressive Complex 2 inhibits tumorigenicity and tumor progression in prostate cancer. Mol. Cancer 2011, 10, 40. [Google Scholar] [CrossRef] [PubMed]
  108. Wu, C.; Jin, X.; Yang, J.; Yang, Y.; He, Y.; Ding, L.; Pan, Y.; Chen, S.; Jiang, J.; Huang, H. Inhibition of EZH2 by chemo- and radiotherapy agents and small molecule inhibitors induces cell death in castration-resistant prostate cancer. Oncotarget 2016, 7, 3440–3452. [Google Scholar] [PubMed]
  109. He, Y.; Selvaraju, S.; Curtin, M.L.; Jakob, C.G.; Zhu, H.; Comess, K.M.; Shaw, B.; The, J.; Lima-Fernandes, E.; Szewczyk, M.M.; et al. The EED protein-protein interaction inhibitor A-395 inactivates the PRC2 complex. Nat. Chem. Biol 2017, 13, 389–395. [Google Scholar] [CrossRef] [PubMed]
  110. Qi, W.; Zhao, K.; Gu, J.; Huang, Y.; Wang, Y.; Zhang, H.; Zhang, M.; Zhang, J.; Yu, Z.; Li, L.; et al. An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED. Nat. Chem. Biol. 2017, 13, 381–388. [Google Scholar] [CrossRef] [PubMed]
  111. Huang, Y.; Zhang, J.; Yu, Z.; Zhang, H.; Wang, Y.; Lingel, A.; Qi, W.; Gu, J.; Zhao, K.; Shultz, M.D.; et al. Discovery of first-in-class, potent, and orally bioavailable Embryonic Ectoderm Development (EED) inhibitor with robust anticancer efficacy. J. Med. Chem. 2017, 60, 2215–2226. [Google Scholar] [CrossRef] [PubMed]
  112. Li, L.; Zhang, H.; Zhang, M.; Zhao, M.; Feng, L.; Luo, X.; Gao, Z.; Huang, Y.; Ardayfio, O.; Zhang, J.H.; Lin, Y.; et al. Discovery and molecular basis of a diverse set of Polycomb Repressive Complex 2 inhibitors recognition by EED. PLoS ONE 2017, 12, e0169855. [Google Scholar] [CrossRef] [PubMed]
  113. Huang, L.; Xu, A.M. SET and MYND domain containing protein 3 in cancer. Am. J. Transl. Res. 2017, 9, 1–14. [Google Scholar] [PubMed]
  114. Liu, C.; Wang, C.; Wang, K.; Liu, L.; Shen, Q.; Yan, K.; Sun, X.; Chen, J.; Liu, J.; Ren, H.; et al. SMYD3 as an oncogenic driver in prostate cancer by stimulation of androgen receptor transcription. J. Natl. Cancer Inst. 2013, 105, 1719–1728. [Google Scholar] [CrossRef] [PubMed]
  115. Vieira, F.Q.; Costa-Pinheiro, P.; Almeida-Rios, D.; Graca, I.; Monteiro-Reis, S.; Simoes-Sousa, S.; Carneiro, I.; Sousa, E.J.; Godinho, M.I.; Baltazar, F.; et al. SMYD3 contributes to a more aggressive phenotype of prostate cancer and targets Cyclin D2 through H4K20me3. Oncotarget 2015, 6, 13644–13657. [Google Scholar] [CrossRef] [PubMed]
  116. Peserico, A.; Germani, A.; Sanese, P.; Barbosa, A.J.; di Virgilio, V.; Fittipaldi, R.; Fabini, E.; Bertucci, C.; Varchi, G.; Moyer, M.P.; et al. A SMYD3 small-molecule inhibitor impairing cancer cell growth. J. Cell. Physiol. 2015, 230, 2447–2460. [Google Scholar] [CrossRef] [PubMed]
  117. Stopa, N.; Krebs, J.E.; Shechter, D. The PRMT5 arginine methyltransferase: Many roles in development, cancer and beyond. Cell. Mol. Life Sci. 2015, 72, 2041–2059. [Google Scholar] [CrossRef] [PubMed]
  118. Mounir, Z.; Korn, J.M.; Westerling, T.; Lin, F.; Kirby, C.A.; Schirle, M.; McAllister, G.; Hoffman, G.; Ramadan, N.; Hartung, A.; et al. ERG signaling in prostate cancer is driven through PRMT5-dependent methylation of the Androgen Receptor. eLife 2016, 5. [Google Scholar] [CrossRef] [PubMed]
  119. Deng, X.; Shao, G.; Zhang, H.T.; Li, C.; Zhang, D.; Cheng, L.; Elzey, B.D.; Pili, R.; Ratliff, T.L.; Huang, J.; et al. Protein arginine methyltransferase 5 functions as an epigenetic activator of the androgen receptor to promote prostate cancer cell growth. Oncogene 2017, 36, 1223–1231. [Google Scholar] [CrossRef] [PubMed]
  120. Kahl, P.; Gullotti, L.; Heukamp, L.C.; Wolf, S.; Friedrichs, N.; Vorreuther, R.; Solleder, G.; Bastian, P.J.; Ellinger, J.; Metzger, E.; et al. Androgen receptor coactivators lysine-specific histone demethylase 1 and four and a half LIM domain protein 2 predict risk of prostate cancer recurrence. Cancer Res. 2006, 66, 11341–11347. [Google Scholar] [CrossRef] [PubMed]
  121. Bjorkman, M.; Ostling, P.; Harma, V.; Virtanen, J.; Mpindi, J.P.; Rantala, J.; Mirtti, T.; Vesterinen, T.; Lundin, M.; Sankila, A.; et al. Systematic knockdown of epigenetic enzymes identifies a novel histone demethylase PHF8 overexpressed in prostate cancer with an impact on cell proliferation, migration and invasion. Oncogene 2012, 31, 3444–3456. [Google Scholar] [CrossRef] [PubMed]
  122. Coffey, K.; Rogerson, L.; Ryan-Munden, C.; Alkharaif, D.; Stockley, J.; Heer, R.; Sahadevan, K.; O'Neill, D.; Jones, D.; Darby, S.; et al. The lysine demethylase, KDM4B, is a key molecule in androgen receptor signalling and turnover. Nucleic Acids Res. 2013, 41, 4433–4446. [Google Scholar] [CrossRef] [PubMed]
  123. Kashyap, V.; Ahmad, S.; Nilsson, E.M.; Helczynski, L.; Kenna, S.; Persson, J.L.; Gudas, L.J.; Mongan, N.P. The lysine specific demethylase-1 (LSD1/KDM1A) regulates VEGF-A expression in prostate cancer. Mol. Oncol. 2013, 7, 555–566. [Google Scholar] [CrossRef] [PubMed]
  124. Han, M.; Xu, W.; Cheng, P.; Jin, H.; Wang, X. Histone demethylase lysine demethylase 5B in development and cancer. Oncotarget 2017, 8, 8980–8991. [Google Scholar] [CrossRef] [PubMed]
  125. Stratmann, A.; Haendler, B. Histone demethylation and steroid receptor function in cancer. Mol. Cell. Endocrinol. 2012, 348, 12–20. [Google Scholar] [CrossRef] [PubMed]
  126. Metzger, E.; Wissmann, M.; Yin, N.; Muller, J.M.; Schneider, R.; Peters, A.H.; Gunther, T.; Buettner, R.; Schule, R. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 2005, 437, 436–439. [Google Scholar] [CrossRef] [PubMed]
  127. Wissmann, M.; Yin, N.; Muller, J.M.; Greschik, H.; Fodor, B.D.; Jenuwein, T.; Vogler, C.; Schneider, R.; Gunther, T.; Buettner, R.; et al. Cooperative demethylation by JMJD2C and LSD1 promotes androgen receptor-dependent gene expression. Nat. Cell Biol. 2007, 9, 347–353. [Google Scholar] [CrossRef] [PubMed]
  128. Cai, C.; He, H.H.; Chen, S.; Coleman, I.; Wang, H.; Fang, Z.; Chen, S.; Nelson, P.S.; Liu, X.S.; Brown, M.; et al. Androgen receptor gene expression in prostate cancer is directly suppressed by the androgen receptor through recruitment of lysine-specific demethylase 1. Cancer Cell 2011, 20, 457–471. [Google Scholar] [CrossRef] [PubMed]
  129. Etani, T.; Suzuki, T.; Naiki, T.; Naiki-Ito, A.; Ando, R.; Iida, K.; Kawai, N.; Tozawa, K.; Miyata, N.; Kohri, K.; et al. NCL1, a highly selective lysine-specific demethylase 1 inhibitor, suppresses prostate cancer without adverse effect. Oncotarget 2015, 6, 2865–2878. [Google Scholar] [CrossRef] [PubMed]
  130. Tong, D.; Liu, Q.; Liu, G.; Yuan, W.; Wang, L.; Guo, Y.; Lan, W.; Zhang, D.; Dong, S.; Wang, Y.; et al. The HIF/PHF8/AR axis promotes prostate cancer progression. Oncogenesis 2016, 5, e283. [Google Scholar] [CrossRef] [PubMed]
  131. Maina, P.K.; Shao, P.; Liu, Q.; Fazli, L.; Tyler, S.; Nasir, M.; Dong, X.; Qi, H.H. c-MYC drives histone demethylase PHF8 during neuroendocrine differentiation and in castration-resistant prostate cancer. Oncotarget 2016, 7, 75585–75602. [Google Scholar] [CrossRef] [PubMed]
  132. Ackloo, S.; Brown, P.J.; Muller, S. Chemical probes targeting epigenetic proteins: Applications beyond oncology. Epigenetics 2017, 1–23. [Google Scholar] [CrossRef] [PubMed]
  133. Grasso, C.S.; Wu, Y.M.; Robinson, D.R.; Cao, X.; Dhanasekaran, S.M.; Khan, A.P.; Quist, M.J.; Jing, X.; Lonigro, R.J.; Brenner, J.C.; et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature 2012, 487, 239–243. [Google Scholar] [CrossRef] [PubMed]
  134. Huang, S.; Gulzar, Z.G.; Salari, K.; Lapointe, J.; Brooks, J.D.; Pollack, J.R. Recurrent deletion of CHD1 in prostate cancer with relevance to cell invasiveness. Oncogene 2012, 31, 4164–4170. [Google Scholar] [CrossRef] [PubMed]
  135. Rodrigues, L.U.; Rider, L.; Nieto, C.; Romero, L.; Karimpour-Fard, A.; Loda, M.; Lucia, M.S.; Wu, M.; Shi, L.; Cimic, A.; et al. Coordinate loss of MAP3K7 and CHD1 promotes aggressive prostate cancer. Cancer Res. 2015, 75, 1021–1034. [Google Scholar] [CrossRef] [PubMed]
  136. Kari, V.; Mansour, W.Y.; Raul, S.K.; Baumgart, S.J.; Mund, A.; Grade, M.; Sirma, H.; Simon, R.; Will, H.; Dobbelstein, M.; et al. Loss of CHD1 causes DNA repair defects and enhances prostate cancer therapeutic responsiveness. EMBO Rep. 2016, 17, 1609–1623. [Google Scholar] [CrossRef] [PubMed]
  137. Zhao, D.; Lu, X.; Wang, G.; Lan, Z.; Liao, W.; Li, J.; Liang, X.; Chen, J.R.; Shah, S.; Shang, X.; et al. Synthetic essentiality of chromatin remodelling factor CHD1 in PTEN-deficient cancer. Nature 2017, 542, 484–488. [Google Scholar] [CrossRef] [PubMed]
  138. Du, H.N. Transcription, DNA damage and beyond: The roles of histone ubiquitination and deubiquitination. Current Prot. Pept. Sci. 2012, 13, 447–466. [Google Scholar] [CrossRef]
  139. Johnsen, S.A. The enigmatic role of H2Bub1 in cancer. FEBS Lett. 2012, 586, 1592–1601. [Google Scholar] [CrossRef] [PubMed]
  140. Cao, J.; Yan, Q. Histone ubiquitination and deubiquitination in transcription, DNA damage response, and cancer. Front. Oncol. 2012, 2, 26. [Google Scholar] [CrossRef] [PubMed]
  141. Jaaskelainen, T.; Makkonen, H.; Visakorpi, T.; Kim, J.; Roeder, R.G.; Palvimo, J.J. Histone H2B ubiquitin ligases RNF20 and RNF40 in androgen signaling and prostate cancer cell growth. Mol. Cell. Endocrinol. 2012, 350, 87–98. [Google Scholar] [CrossRef] [PubMed]
  142. Draker, R.; Sarcinella, E.; Cheung, P. USP10 deubiquitylates the histone variant H2A.Z and both are required for androgen receptor-mediated gene activation. Nucleic Acids Res. 2011, 39, 3529–3542. [Google Scholar] [CrossRef] [PubMed]
  143. Faus, H.; Meyer, H.A.; Huber, M.; Bahr, I.; Haendler, B. The ubiquitin-specific protease USP10 modulates androgen receptor function. Mol. Cell. Endocrinol. 2005, 245, 138–146. [Google Scholar] [CrossRef] [PubMed]
  144. Geng, C.; Rajapakshe, K.; Shah, S.S.; Shou, J.; Eedunuri, V.K.; Foley, C.; Fiskus, W.; Rajendran, M.; Chew, S.A.; Zimmermann, M.; et al. Androgen receptor is the key transcriptional mediator of the tumor suppressor SPOP in prostate cancer. Cancer Res. 2014, 74, 5631–5643. [Google Scholar] [CrossRef] [PubMed]
  145. Chen, S.T.; Okada, M.; Nakato, R.; Izumi, K.; Bando, M.; Shirahige, K. The deubiquitinating enzyme USP7 regulates androgen receptor activity by modulating its binding to chromatin. J. Biol. Chem. 2015, 290, 21713–21723. [Google Scholar] [CrossRef] [PubMed]
  146. Liao, Y.; Liu, N.; Hua, X.; Cai, J.; Xia, X.; Wang, X.; Huang, H.; Liu, J. Proteasome-associated deubiquitinase ubiquitin-specific protease 14 regulates prostate cancer proliferation by deubiquitinating and stabilizing androgen receptor. Cell Death Dis. 2017, 8, e2585. [Google Scholar] [CrossRef] [PubMed]
  147. Barbieri, C.E.; Baca, S.C.; Lawrence, M.S.; Demichelis, F.; Blattner, M.; Theurillat, J.P.; White, T.A.; Stojanov, P.; Van Allen, E.; Stransky, N.; et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat. Genet. 2012, 44, 685–689. [Google Scholar] [CrossRef] [PubMed]
  148. Blattner, M.; Liu, D.; Robinson, B.D.; Huang, D.; Poliakov, A.; Gao, D.; Nataraj, S.; Deonarine, L.D.; Augello, M.A.; Sailer, V.; et al. SPOP mutation drives prostate tumorigenesis in vivo through coordinate regulation of PI3K/mTOR and AR signaling. Cancer Cell 2017, 31, 436–451. [Google Scholar] [CrossRef] [PubMed]
  149. Qi, J.; Fan, L.; Hussain, A. Implications of ubiquitin ligases in castration-resistant prostate cancer. Curr. Opin. Oncol. 2015, 27, 172–176. [Google Scholar] [CrossRef] [PubMed]
  150. Faus, H.; Haendler, B. Post-translational modifications of steroid receptors. Biomed. Pharmacother. 2006, 60, 520–528. [Google Scholar] [CrossRef] [PubMed]
  151. Kim, J.Y.; Banerjee, T.; Vinckevicius, A.; Luo, Q.; Parker, J.B.; Baker, M.R.; Radhakrishnan, I.; Wei, J.J.; Barish, G.D.; Chakravarti, D. A role for WDR5 in integrating threonine 11 phosphorylation to lysine 4 methylation on histone H3 during androgen signaling and in prostate cancer. Mol. Cell 2014, 54, 613–625. [Google Scholar] [CrossRef] [PubMed]
  152. Kohler, J.; Erlenkamp, G.; Eberlin, A.; Rumpf, T.; Slynko, I.; Metzger, E.; Schule, R.; Sippl, W.; Jung, M. Lestaurtinib inhibits histone phosphorylation and androgen-dependent gene expression in prostate cancer cells. PLoS ONE 2012, 7, e34973. [Google Scholar] [CrossRef] [PubMed]
  153. Thibault, A.; Figg, W.D.; Bergan, R.C.; Lush, R.M.; Myers, C.E.; Tompkins, A.; Reed, E.; Samid, D. A phase II study of 5-aza-2′deoxycytidine (decitabine) in hormone independent metastatic (D2) prostate cancer. Tumori 1998, 84, 87–89. [Google Scholar] [PubMed]
  154. Singal, R.; Ramachandran, K.; Gordian, E.; Quintero, C.; Zhao, W.; Reis, I.M. Phase I/II study of azacitidine, docetaxel, and prednisone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel-based therapy. Clin. Genitourin. Cancer 2015, 13, 22–31. [Google Scholar] [CrossRef] [PubMed]
  155. Bradley, D.; Rathkopf, D.; Dunn, R.; Stadler, W.M.; Liu, G.; Smith, D.C.; Pili, R.; Zwiebel, J.; Scher, H.; Hussain, M. Vorinostat in advanced prostate cancer patients progressing on prior chemotherapy (National Cancer Institute Trial 6862): Trial results and interleukin-6 analysis: A study by the Department of Defense Prostate Cancer Clinical Trial Consortium and University of Chicago Phase 2 Consortium. Cancer 2009, 115, 5541–5549. [Google Scholar] [PubMed]
  156. Molife, L.R.; Attard, G.; Fong, P.C.; Karavasilis, V.; Reid, A.H.; Patterson, S.; Riggs, C.E., Jr.; Higano, C.; Stadler, W.M.; McCulloch, W.; et al. Phase II, two-stage, single-arm trial of the histone deacetylase inhibitor (HDACi) romidepsin in metastatic castration-resistant prostate cancer (CRPC). Ann. Oncol. 2010, 21, 109–113. [Google Scholar] [CrossRef] [PubMed]
  157. Eigl, B.J.; North, S.; Winquist, E.; Finch, D.; Wood, L.; Sridhar, S.S.; Powers, J.; Good, J.; Sharma, M.; Squire, J.A.; et al. A phase II study of the HDAC inhibitor SB939 in patients with castration resistant prostate cancer: NCIC clinical trials group study IND195. Investig. New Drugs 2015, 33, 969–976. [Google Scholar] [CrossRef] [PubMed]
  158. Rathkopf, D.E.; Picus, J.; Hussain, A.; Ellard, S.; Chi, K.N.; Nydam, T.; Allen-Freda, E.; Mishra, K.K.; Porro, M.G.; Scher, H.I.; et al. A phase 2 study of intravenous panobinostat in patients with castration-resistant prostate cancer. Cancer Chemother. Pharmacol. 2013, 72, 537–544. [Google Scholar] [CrossRef] [PubMed]
  159. Rathkopf, D.; Carducci, M.A.; Morris, M.J.; Slovin, S.F.; Eisenberger, M.A.; Pili, R.; Denmeade, S.R.; Kelsen, M.; Curley, T.; Halter, M.; et al. Phase II trial of docetaxel with rapid androgen cycling for progressive noncastrate prostate cancer. J. Clin. Oncol. 2008, 26, 2959–2965. [Google Scholar] [CrossRef] [PubMed]
  160. Munster, P.N.; Marchion, D.; Thomas, S.; Egorin, M.; Minton, S.; Springett, G.; Lee, J.H.; Simon, G.; Chiappori, A.; Sullivan, D.; et al. Phase I trial of vorinostat and doxorubicin in solid tumours: Histone deacetylase 2 expression as a predictive marker. Br. J. Cancer 2009, 101, 1044–1050. [Google Scholar] [CrossRef] [PubMed]
  161. Kaushik, D.; Vashistha, V.; Isharwal, S.; Sediqe, S.A.; Lin, M.F. Histone deacetylase inhibitors in castration-resistant prostate cancer: Molecular mechanism of action and recent clinical trials. Ther. Adv. Urol. 2015, 7, 388–395. [Google Scholar] [CrossRef] [PubMed]
  162. Tsujikawa, L.; Norek, K.; Calosing, C.; Attwell, S.; Gilham, D.; Sharma, N.; Tobin, J.; Haager, M.; Jahagirdar, R.; Lakhotia, S.; et al. Preclinical development and clinical validation of a whole blood pharmacodynamic marker assay for the BET bromodomain inhibitor ZEN-3694 in metastatic castration-resistant prostate cancer (mCRPC) patients. In Proceedings of the AACR Annual Meeting 2017, Washington, DC, USA, 1–5 April 2017. [Google Scholar]
  163. Bertoli, G.; Cava, C.; Castiglioni, I. MicroRNAs as niomarkers for diagnosis, prognosis and theranostics in prostate cancer. Int. J. Mol. Sci. 2016, 17, 421. [Google Scholar] [CrossRef] [PubMed]
  164. Mitchell, P.S.; Parkin, R.K.; Kroh, E.M.; Fritz, B.R.; Wyman, S.K.; Pogosova-Agadjanyan, E.L.; Peterson, A.; Noteboom, J.; O’Briant, K.C.; Allen, A.; et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc. Natl. Acad. Sci. USA 2008, 105, 10513–10518. [Google Scholar] [CrossRef] [PubMed]
  165. Kojima, S.; Goto, Y.; Naya, Y. The roles of microRNAs in the progression of castration-resistant prostate cancer. J. Hum. Genet. 2017, 62, 25–31. [Google Scholar] [CrossRef] [PubMed]
  166. Ostling, P.; Leivonen, S.K.; Aakula, A.; Kohonen, P.; Makela, R.; Hagman, Z.; Edsjo, A.; Kangaspeska, S.; Edgren, H.; Nicorici, D.; et al. Systematic analysis of microRNAs targeting the androgen receptor in prostate cancer cells. Cancer Res. 2011, 71, 1956–1967. [Google Scholar] [CrossRef] [PubMed]
  167. Cannistraci, A.; Federici, G.; Addario, A.; Di Pace, A.L.; Grassi, L.; Muto, G.; Collura, D.; Signore, M.; De Salvo, L.; Sentinelli, S.; et al. C-Met/miR-130b axis as novel mechanism and biomarker for castration resistance state acquisition. Oncogene 2017. [Google Scholar] [CrossRef] [PubMed]
  168. Hao, Z.; Fan, W.; Hao, J.; Wu, X.; Zeng, G.Q.; Zhang, L.J.; Nie, S.F.; Wang, X.D. Efficient delivery of micro RNA to bone-metastatic prostate tumors by using aptamer-conjugated atelocollagen in vitro and in vivo. Drug Deliv. 2016, 23, 874–881. [Google Scholar] [PubMed]
  169. Yao, C.; Liu, J.; Wu, X.; Tai, Z.; Gao, Y.; Zhu, Q.; Li, J.; Zhang, L.; Hu, C.; Gu, F.; Gao, J.; Gao, S. Reducible self-assembling cationic polypeptide-based micelles mediate co-delivery of doxorubicin and microRNA-34a for androgen-independent prostate cancer therapy. J. Control. Release 2016, 232, 203–214. [Google Scholar] [CrossRef] [PubMed]
  170. Shi, X.B.; Ma, A.H.; Xue, L.; Li, M.; Nguyen, H.G.; Yang, J.C.; Tepper, C.G.; Gandour-Edwards, R.; Evans, C.P.; Kung, H.J.; et al. miR-124 and androgen receptor signaling inhibitors repress prostate cancer growth by downregulating androgen receptor splice variants, EZH2, and Src. Cancer Res. 2015, 75, 5309–5317. [Google Scholar] [CrossRef] [PubMed]
  171. Larne, O.; Hagman, Z.; Lilja, H.; Bjartell, A.; Edsjo, A.; Ceder, Y. miR-145 suppress the androgen receptor in prostate cancer cells and correlates to prostate cancer prognosis. Carcinogenesis 2015, 36, 858–866. [Google Scholar] [CrossRef] [PubMed]
  172. Zhao, Y.; Yan, M.; Yun, Y.; Zhang, J.; Zhang, R.; Li, Y.; Wu, X.; Liu, Q.; Miao, W.; Jiang, H. MicroRNA-455–3p functions as a tumor suppressor by targeting eIF4E in prostate cancer. Oncol. Rep. 2017. [Google Scholar] [CrossRef] [PubMed]
  173. Nip, H.; Dar, A.A.; Saini, S.; Colden, M.; Varahram, S.; Chowdhary, H.; Yamamura, S.; Mitsui, Y.; Tanaka, Y.; Kato, T.; et al. Oncogenic microRNA-4534 regulates PTEN pathway in prostate cancer. Oncotarget 2016, 7, 68371–68384. [Google Scholar] [CrossRef] [PubMed]
  174. Rupaimoole, R.; Slack, F.J. MicroRNA therapeutics: Towards a new era for the management of cancer and other diseases. Nat. Rev. Drug Discov. 2017, 16, 203–222. [Google Scholar] [CrossRef] [PubMed]
  175. Rekoske, B.T.; McNeel, D.G. Immunotherapy for prostate cancer: False promises or true hope? Cancer 2016, 122, 3598–3607. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Overview of potential epigenetic targets and selected inhibitors. Straight arrows indicate the addition of acetyl (yellow), methyl (dark green) or phosphoryl (brown) groups to histones, or of a methyl group (purple) to DNA. Removal of these groups is indicated by half-circular black arrows.
Figure 1. Overview of potential epigenetic targets and selected inhibitors. Straight arrows indicate the addition of acetyl (yellow), methyl (dark green) or phosphoryl (brown) groups to histones, or of a methyl group (purple) to DNA. Removal of these groups is indicated by half-circular black arrows.
Ijms 18 01017 g001
Table 1. Clinical studies in prostate cancer, including castration-resistant prostate cancer (CRPC) and metastatic CRPC (mCRPC), with drugs addressing DNA methyltransferases (DNMTs) or histone deacetylases (HDACs). Source: https://clinicaltrials.gov/.
Table 1. Clinical studies in prostate cancer, including castration-resistant prostate cancer (CRPC) and metastatic CRPC (mCRPC), with drugs addressing DNA methyltransferases (DNMTs) or histone deacetylases (HDACs). Source: https://clinicaltrials.gov/.
TargetCompoundCombinationIndicationPhaseIdentifierStatus
DNMTAzacitidinePhenylbutirateProstate cancer2NCT00006019Completed
DNMTAzacitidine Prostate cancer2NCT00384839Completed
DNMTAzacitidineDocetaxel, prednisonemCRPC
Post-chemotherapy
1/2NCT00503984Terminated
HDACVorinostat Includes prostate cancer1NCT00005634Completed
HDACVorinostat Includes prostate cancer1NCT00045006Completed
HDACVorinostat Advanced CRPC
Post-chemotherapy
2NCT00330161Completed
HDACVorinostatDocetaxelIncludes prostate cancer1NCT00565227Terminated
HDACVorinostatAndrogen deprivationLocalized prostate cancer2NCT00589472Completed
HDACVorinostatTemsirolimusmCRPC1NCT01174199Terminated
HDACEntinostat Includes prostate cancer1NCT00020579Completed
HDACRomidpesin Prostatic neoplasms2NCT00106301Completed
HDACRomidepsin mCRPC2NCT00106418Completed
HDACRomidepsin CRPC1NCT01638533Recruiting
HDACBelinostat Includes prostate cancer1NCT00413075Completed
HDACBelinostat5-fluorouracilIncludes prostate cancer1NCT00413322Completed
HDACPanobinostatDocetaxel, prednisoneCRPC1NCT00419536Terminated
HDACPanobinostatDocetaxel, prednisoneCRPC1NCT00493766Terminated
HDACPanobinostatDocetaxel, prednisoneCRPC1NCT00663832Completed
HDACPanobinostat mCRPC2NCT00667862Completed
HDACPanobinostatExternal beam radiotherapyIncludes prostate cancer1NCT00670553Completed
HDACPanobinostatBicalutamideRecurrent CRPC1/2NCT00878436Completed
HDACMocetinostatDocetaxelIncludes prostate cancer1NCT00511576Terminated
HDACValproic acid CRPC2NCT00670046Unknown
HDACPracinostat mCRPC2NCT01075308Completed
Table 2. Clinical studies in prostate cancer with drugs addressing the novel epigenetic targets bromodomain and extra-terminal protein (BET), embryonic ectoderm development protein (EED) and protein arginine methyltransferase 5 (PRMT5). Source: https://clinicaltrials.gov/.
Table 2. Clinical studies in prostate cancer with drugs addressing the novel epigenetic targets bromodomain and extra-terminal protein (BET), embryonic ectoderm development protein (EED) and protein arginine methyltransferase 5 (PRMT5). Source: https://clinicaltrials.gov/.
TargetCompoundCombinationIndicationPhaseIdentifierStatus
BETGSK525762 CRPC1NCT01587703Recruiting
BETOTX105
MK-8628
CRPC1NCT02259114Active, not recruting
BETOTX105
MK-8628
CRPC1NCT02698176Active, not recruting
BETINCB054329 CRPC1/2NCT02431260Recruiting
BETINCB057643 CRPC1/2NCT02711137Recruitng
BETZEN003694 mCRPC1NCT02705469Recuiting
BETZEN003694EnzalutamidemCRPC1bNCT02711956Recruiting
EEDMAK683 Includes prostate cancer1NCT02900651Recruiting
PRMT5GSK3326595 Includes prostate cancer1NCT02783300Recruiting
Table 3. Clinical studies in prostate cancer, including metastatic castration-resistant prostate cancer (mCRPC), evaluating microRNAs (miRNA) as potential biomarkers. Source: https://clinicaltrials.gov/.
Table 3. Clinical studies in prostate cancer, including metastatic castration-resistant prostate cancer (mCRPC), evaluating microRNAs (miRNA) as potential biomarkers. Source: https://clinicaltrials.gov/.
Outcome MeasureTreatmentIndicationIdentifierStatus
miRNA profiling Prostate cancerNCT01220427Terminated
miRNA profiling using Nano-string technology Prostate cancerNCT02964351Not yet recruiting
Serum exosomal miRNA profiling using next-generation sequencingAndrogen deprivationProstate cancerNCT02366494Recruiting
Preselected miRNA profilingEnzalutamidemCRPCNCT02471469Recruiting
miRNA profilingRadiotherapyProstate cancerNCT02745587Recruiting
Preselected miRNA profilingAbiraterone acetatemCRPCNCT01503229Ongoing, not recruiting
miRNA-141, -375 levelsFocal brachytherapyLow-risk prostate cancerNCT02391051Recruiting
miRNA profilingAndrogen deprivation + cixutumumabMetastatic prostate cancerNCT01120236Ongoing, not recruiting

Share and Cite

MDPI and ACS Style

Baumgart, S.J.; Haendler, B. Exploiting Epigenetic Alterations in Prostate Cancer. Int. J. Mol. Sci. 2017, 18, 1017. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18051017

AMA Style

Baumgart SJ, Haendler B. Exploiting Epigenetic Alterations in Prostate Cancer. International Journal of Molecular Sciences. 2017; 18(5):1017. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18051017

Chicago/Turabian Style

Baumgart, Simon J., and Bernard Haendler. 2017. "Exploiting Epigenetic Alterations in Prostate Cancer" International Journal of Molecular Sciences 18, no. 5: 1017. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18051017

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop