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Cells
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Regulation of Gene Expression in Cancer
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Regulation of Gene Expression in Cancer

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (31 May 2021) | Viewed by 34814

Special Issue Editor

Dr. Cédric Coulouarn

E-Mail Website
Guest Editor
Inserm, Univ Rennes 1, OSS (Oncogenesis, Stress, Signaling) Laboratory, UMR_S 1242, Centre de Lutte contre le Cancer Eugène Marquis, F-35042 Rennes, France
Interests: hepatocellular carcinoma; cholangiocarcinoma; cell plasticity; TGFβ signaling; circular RNA
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Regulation of gene expression is a fundamental process, not only in normal conditions, to maintain cellular and tissue homeostasis, but also in disease states, including carcinogenesis. Cancer cells are exposed to multiple intrinsic and extrinsic stimuli during tumor onset and progression, including crosstalk with the tumor microenvironment, leading to the activation of various signaling pathways. Cancer cells integrate these signals to adapt their response and to progress into malignancy. One of the key steps in this integrative response is the activation or the repression of a specific subset of genes. Thus, gene expression is tightly regulated in order to initiate a coordinated transcriptional program controlling all the basic cellular processes associated with the hallmarks of cancer cells (e.g., proliferation, apoptosis, differentiation, metabolism, migration, invasion).

This Special Issue aims at providing a review of the literature as well as emerging experimental evidence of the multifaceted regulation of gene expression in cancer, notably at epigenetic, transcriptional, and post-transcriptional level. The role of chemical modifications of histones, DNA and RNA (e.g., epitranscriptomics), transcription factors, and non-coding RNAs (e.g., lncRNA, miRNA, circRNA) will be taken into consideration. Specific topics in this Special Issue include the regulation of chromatin architecture, the role of chromatin remodeling complexes, the analysis of oncogene and tumor suppressor gene promoters, mutations of transcriptional regulators, post-transcriptional modifications leading to modified activity of transcriptional regulators, post-transcriptional RNA processing, regulation of RNA and protein abundance by non-coding RNAs, and RNA stability.

This Special Issue should serve as a forum for molecular and cell biologists to share their experimental data and theories that can help to better understand gene regulation in cancer and open new opportunities for innovative therapeutics.

We look forward to your contributions to this Special Issue.

Dr. Cédric Coulouarn
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cancer
  • gene expression
  • epigenetic
  • DNA methylation
  • chromatin remodeling
  • promoter
  • transcription
  • transcription factor
  • non-coding RNA
  • microRNA

Published Papers (11 papers)

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Editorial

Jump to: Research, Review

3 pages, 214 KiB  
Editorial
Regulation of Gene Expression in Cancer—An Overview
by Tanguy Ferlier and Cédric Coulouarn
Cells 2022, 11(24), 4058; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11244058 - 15 Dec 2022
Cited by 1 | Viewed by 1122
Abstract
Regulation of gene expression takes a central place in normal cells to maintain tissue homeostasis but also in cancer cells to respond to intra- and extra-cellular stimuli, such as therapeutic drugs [...] Full article
(This article belongs to the Special Issue Regulation of Gene Expression in Cancer)

Research

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17 pages, 3567 KiB  
Article
NAD Modulates DNA Methylation and Cell Differentiation
by Simone Ummarino, Clinton Hausman, Giulia Gaggi, Lucrezia Rinaldi, Mahmoud A. Bassal, Yanzhou Zhang, Andy Joe Seelam, Ikei S. Kobayashi, Marta Borchiellini, Alexander K. Ebralidze, Barbara Ghinassi, Bon Q. Trinh, Susumu S. Kobayashi and Annalisa Di Ruscio
Cells 2021, 10(11), 2986; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10112986 - 02 Nov 2021
Cited by 14 | Viewed by 3577
Abstract
Nutritional intake impacts the human epigenome by directing epigenetic pathways in normal cell development via as yet unknown molecular mechanisms. Consequently, imbalance in the nutritional intake is able to dysregulate the epigenetic profile and drive cells towards malignant transformation. Here we present a [...] Read more.
Nutritional intake impacts the human epigenome by directing epigenetic pathways in normal cell development via as yet unknown molecular mechanisms. Consequently, imbalance in the nutritional intake is able to dysregulate the epigenetic profile and drive cells towards malignant transformation. Here we present a novel epigenetic effect of the essential nutrient, NAD. We demonstrate that impairment of DNMT1 enzymatic activity by NAD-promoted ADP-ribosylation leads to demethylation and transcriptional activation of the CEBPA gene, suggesting the existence of an unknown NAD-controlled region within the locus. In addition to the molecular events, NAD- treated cells exhibit significant morphological and phenotypical changes that correspond to myeloid differentiation. Collectively, these results delineate a novel role for NAD in cell differentiation, and indicate novel nutri-epigenetic strategies to regulate and control gene expression in human cells. Full article
(This article belongs to the Special Issue Regulation of Gene Expression in Cancer)
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13 pages, 2330 KiB  
Article
DNA Methylation of TGFβ Target Genes: Epigenetic Control of TGFβ Functional Duality in Liver Cancer
by Kevin Bévant, Matthis Desoteux, Abdel Hady A. Abdel Wahab, Sabrin A. Abdel Wahab, Ayman Mohamed Metwally and Cédric Coulouarn
Cells 2021, 10(9), 2207; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10092207 - 26 Aug 2021
Cited by 9 | Viewed by 2473
Abstract
Transforming growth factor beta (TGFβ) plays a key role in liver carcinogenesis. However, its action is complex, since TGFβ exhibits tumor-suppressive or oncogenic properties, depending on the tumor stage. At an early stage TGFβ exhibits cytostatic features, but at a later stage it [...] Read more.
Transforming growth factor beta (TGFβ) plays a key role in liver carcinogenesis. However, its action is complex, since TGFβ exhibits tumor-suppressive or oncogenic properties, depending on the tumor stage. At an early stage TGFβ exhibits cytostatic features, but at a later stage it promotes cell growth and metastasis, as a potent inducer of epithelial to mesenchymal transition (EMT). Here, we evaluated DNA methylation as a possible molecular mechanism switching TGFβ activity toward tumor progression in hepatocellular carcinoma (HCC). We report that decitabine, a demethylating agent already used in the clinic for the treatment of several cancers, greatly impairs the transcriptional response of SNU449 HCC cells to TGFβ. Importantly, decitabine was shown to induce the expression of EMT-related transcription factors (e.g., SNAI1/2, ZEB1/2). We also report that the promoter of SNAI1 was hypomethylated in poor-prognosis human HCC, i.e., associated with high grade, high AFP level, metastasis and recurrence. Altogether, the data highlight an epigenetic control of several effectors of the TGFβ pathway in human HCC possibly involved in switching its action toward EMT and tumor progression. Thus, we conclude that epidrugs should be carefully evaluated for the treatment of HCC, as they may activate tumor promoting pathways. Full article
(This article belongs to the Special Issue Regulation of Gene Expression in Cancer)
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23 pages, 3408 KiB  
Article
Formation of an RNA Quadruplex-Duplex Hybrid in Living Cells between mRNA of the Epidermal Growth Factor Receptor (EGFR) and a G-Rich Antisense Oligoribonucleotide
by Dorota Gudanis, Damian Kaniowski, Katarzyna Kulik, Daniel Baranowski, Zofia Gdaniec and Barbara Nawrot
Cells 2020, 9(11), 2375; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9112375 - 29 Oct 2020
Cited by 6 | Viewed by 3080
Abstract
Antisense DNA oligonucleotides, short interfering RNAs (siRNAs), and CRISPR/Cas9 genetic tools are the most useful therapeutic nucleic acids regulating gene expression based on the antisense specificity towards messenger RNA. Here, we present an effective novel strategy for inhibiting translation based on the antisense-controlled [...] Read more.
Antisense DNA oligonucleotides, short interfering RNAs (siRNAs), and CRISPR/Cas9 genetic tools are the most useful therapeutic nucleic acids regulating gene expression based on the antisense specificity towards messenger RNA. Here, we present an effective novel strategy for inhibiting translation based on the antisense-controlled formation of an RNA quadruplex-duplex hybrid (QDH) between a G-rich RNA antisense oligoribonucleotide (Q-ASO) and specific mRNA, comprising two distant G-tracts. We selected epidermal growth factor receptor (EGFR) as a well-established target protein in anticancer therapy. The chemically modified, bi-functional anti-EGFR Q-ASO and a 56-nt long EGFR mRNA fragment, in the presence of potassium ions, were shown to form in vitro very stable parallel G-quadruplex containing a 28-nt long external loop folding to two duplex-stem structure. Besides, the Q-ASOs effectively reduced EGFR mRNA levels compared to the non-modified RNA and DNA antisense oligonucleotides (rASO, dASO). In addition, the hybridization specificity of Q-ASO comprising a covalently attached fluorescent tag was confirmed in living cells by visualization of the G4 green fluorescent species in the presence of other antisense inhibitors under competitive conditions. The results presented here offer novel insights into the potential application of Q-ASOs for the detection and/or alteration of (patho)biological processes through RNA:RNA quadruplex-duplex formation in cellular systems. Full article
(This article belongs to the Special Issue Regulation of Gene Expression in Cancer)
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14 pages, 2407 KiB  
Article
The Tumor Suppressive mir-148a Is Epigenetically Inactivated in Classical Hodgkin Lymphoma
by Julia Paczkowska, Joanna Janiszewska, Julia Bein, Markus Schneider, Kinga Bednarek, Adam Ustaszewski, Sylvia Hartmann, Martin-Leo Hansmann and Maciej Giefing
Cells 2020, 9(10), 2292; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9102292 - 14 Oct 2020
Cited by 11 | Viewed by 2629
Abstract
DNA methylation was shown previously to be a crucial mechanism responsible for transcriptional deregulation in the pathogenesis of classical Hodgkin lymphoma (cHL). To identify epigenetically inactivated miRNAs in cHL, we have analyzed the set of miRNAs downregulated in cHL cell lines using bisulfite [...] Read more.
DNA methylation was shown previously to be a crucial mechanism responsible for transcriptional deregulation in the pathogenesis of classical Hodgkin lymphoma (cHL). To identify epigenetically inactivated miRNAs in cHL, we have analyzed the set of miRNAs downregulated in cHL cell lines using bisulfite pyrosequencing. We focused on miRNAs with promoter regions located within or <1000 bp from a CpG island. Most promising candidate miRNAs were further studied in primary Hodgkin and Reed-Sternberg (HRS) cells obtained by laser capture microdissection. Last, to evaluate the function of identified miRNAs, we performed a luciferase reporter assay to confirm miRNA: mRNA interactions and therefore established cHL cell lines with stable overexpression of selected miRNAs for proliferation tests. We found a significant reverse correlation between DNA methylation and expression levels of mir-339-3p, mir-148a-3p, mir-148a-5p and mir-193a-5 demonstrating epigenetic regulation of these miRNAs in cHL cell lines. Moreover, we demonstrated direct interaction between miR-148a-3p and IL15 and HOMER1 transcripts as well as between mir-148a-5p and SUB1 and SERPINH1 transcripts. Furthermore, mir-148a overexpression resulted in reduced cell proliferation in the KM-H2 cell line. In summary, we report that mir-148a is a novel tumor suppressor inactivated in cHL and that epigenetic silencing of miRNAs is a common phenomenon in cHL. Full article
(This article belongs to the Special Issue Regulation of Gene Expression in Cancer)
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18 pages, 2406 KiB  
Article
Nuclear Heparanase Regulates Chromatin Remodeling, Gene Expression and PTEN Tumor Suppressor Function
by Rada Amin, Kaushlendra Tripathi and Ralph D. Sanderson
Cells 2020, 9(9), 2038; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9092038 - 06 Sep 2020
Cited by 12 | Viewed by 2916
Abstract
Heparanase (HPSE) is an endoglycosidase that cleaves heparan sulfate and has been shown in various cancers to promote metastasis, angiogenesis, osteolysis, and chemoresistance. Although heparanase is thought to act predominantly extracellularly or within the cytoplasm, it is also present in the nucleus, where [...] Read more.
Heparanase (HPSE) is an endoglycosidase that cleaves heparan sulfate and has been shown in various cancers to promote metastasis, angiogenesis, osteolysis, and chemoresistance. Although heparanase is thought to act predominantly extracellularly or within the cytoplasm, it is also present in the nucleus, where it may function in regulating gene transcription. Using myeloma cell lines, we report here that heparanase enhances chromatin accessibility and confirm a previous report that it also upregulates the acetylation of histones. Employing the Multiple Myeloma Research Foundation CoMMpass database, we demonstrate that patients expressing high levels of heparanase display elevated expression of proteins involved in chromatin remodeling and several oncogenic factors compared to patients expressing low levels of heparanase. These signatures were consistent with the known function of heparanase in driving tumor progression. Chromatin opening and downstream target genes were abrogated by inhibition of heparanase. Enhanced levels of heparanase in myeloma cells led to a dramatic increase in phosphorylation of PTEN, an event known to stabilize PTEN, leading to its inactivity and loss of tumor suppressor function. Collectively, this study demonstrates that heparanase promotes chromatin opening and transcriptional activity, some of which likely is through its impact on diminishing PTEN tumor suppressor activity. Full article
(This article belongs to the Special Issue Regulation of Gene Expression in Cancer)
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Graphical abstract

14 pages, 3814 KiB  
Article
Low ARID1A Expression is Associated with Poor Prognosis in Hepatocellular Carcinoma
by Sun Young Yim, Sang Hee Kang, Ji-Hyun Shin, Yun Seong Jeong, Bo Hwa Sohn, Soon Ho Um and Ju-Seog Lee
Cells 2020, 9(9), 2002; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9092002 - 01 Sep 2020
Cited by 25 | Viewed by 2686
Abstract
AT-rich interactive domain 1A (ARID1A) is one of the most frequently mutated genes in hepatocellular carcinoma (HCC), but its clinical significance is not clarified. We aimed to evaluate the clinical significance of low ARID1A expression in HCC. By analyzing the gene [...] Read more.
AT-rich interactive domain 1A (ARID1A) is one of the most frequently mutated genes in hepatocellular carcinoma (HCC), but its clinical significance is not clarified. We aimed to evaluate the clinical significance of low ARID1A expression in HCC. By analyzing the gene expression data of liver from Arid1a-knockout mice, hepatic Arid1a-specific gene expression signature was identified (p < 0.05 and 0.5-fold difference). From this signature, a prediction model was developed to identify tissues lacking Arid1a activity and was applied to gene expression data from three independent cohorts of HCC patients to stratify patients according to ARID1A activity. The molecular features associated with loss of ARID1A were analyzed using The Cancer Genome Atlas (TCGA) multi-platform data, and Ingenuity Pathway Analysis (IPA) was done to uncover potential signaling pathways associated with ARID1A loss. ARID1A inactivation was clinically associated with poor prognosis in all three independent cohorts and was consistently related to poor prognosis subtypes of previously reported gene signatures (highly proliferative, hepatic stem cell, silence of Hippo pathway, and high recurrence signatures). Immune activity, indicated by significantly lower IFNG6 and cytolytic activity scores and enrichment of regulatory T-cell composition, was lower in the ARID1A-low subtype than ARID1A-high subtype. Ingenuity pathway analysis revealed that direct upstream transcription regulators of the ARID1A signature were genes associated with cell cycle, including E2F group, CCND1, and MYC, while tumor suppressors such as TP53, SMAD3, and CTNNB1 were significantly inhibited. ARID1A plays an important role in immune activity and regulating multiple genes involved in HCC development. Low-ARID1A subtype was associated with poor clinical outcome and suggests the possibility of ARID1A as a prognostic biomarker in HCC patients. Full article
(This article belongs to the Special Issue Regulation of Gene Expression in Cancer)
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16 pages, 4038 KiB  
Article
Silence of Hippo Pathway Associates with Pro-Tumoral Immunosuppression: Potential Therapeutic Target of Glioblastomas
by Eui Hyun Kim, Bo Hwa Sohn, Young-Gyu Eun, Dong Jin Lee, Sun Young Yim, Seok-Gu Kang and Ju-Seog Lee
Cells 2020, 9(8), 1761; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9081761 - 23 Jul 2020
Cited by 7 | Viewed by 2429
Abstract
The critical role of the Hippo pathway has been recently investigated in various cancers, but little is known about its role in glioblastoma (GBM). In order to evaluate the clinical relevance of the Hippo pathway in GBM, we generated a core gene expression [...] Read more.
The critical role of the Hippo pathway has been recently investigated in various cancers, but little is known about its role in glioblastoma (GBM). In order to evaluate the clinical relevance of the Hippo pathway in GBM, we generated a core gene expression signature from four different previously-established silence of Hippo pathway (SOH) signatures. Based on a newly generated core SOH signature, a SOH and active Hippo pathway (AH) was predicted in GBM samples from The Cancer Genome Atlas (TCGA) and validated in a separate cohort. A comparative analysis was performed on multi-panel genomic datasets from TCGA and the possible association of SOH with immune activity and epithelial mesenchymal transition was also evaluated. The SOH signature was associated with poor prognosis in GBM in both cohorts. Expression levels of CTGF and CYR61, the most reliable and well-known downstream targets of YAP1, were markedly increased in the SOH subgroup of GBM patients. SOH signature was strongly associated with a high immune signature score and mesenchymal features. Genes differentially expressed between SOH and AH groups revealed many markers for inhibitory immune checkpoints and M2-polarized macrophages were upregulated in the SOH subgroup, suggesting that SOH may induce the resistance of cancer cells to host immune response in GBM. In summary, SOH is significantly associated with the poor prognosis of GBM patients and is possibly mediated by pro-tumoral immunosuppression. Full article
(This article belongs to the Special Issue Regulation of Gene Expression in Cancer)
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Review

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17 pages, 357 KiB  
Review
Prognostic Cancer Gene Expression Signatures: Current Status and Challenges
by Yuquan Qian, Jimmy Daza, Timo Itzel, Johannes Betge, Tianzuo Zhan, Frederik Marmé and Andreas Teufel
Cells 2021, 10(3), 648; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10030648 - 15 Mar 2021
Cited by 45 | Viewed by 3549
Abstract
Current staging systems of cancer are mainly based on the anatomical extent of disease. They need refinement by biological parameters to improve stratification of patients for tumor therapy or surveillance strategies. Thanks to developments in genomic, transcriptomic, and big-data technologies, we are now [...] Read more.
Current staging systems of cancer are mainly based on the anatomical extent of disease. They need refinement by biological parameters to improve stratification of patients for tumor therapy or surveillance strategies. Thanks to developments in genomic, transcriptomic, and big-data technologies, we are now able to explore molecular characteristics of tumors in detail and determine their clinical relevance. This has led to numerous prognostic and predictive gene expression signatures that have the potential to establish a classification of tumor subgroups by biological determinants. However, only a few gene signatures have reached the stage of clinical implementation so far. In this review article, we summarize the current status, and present and future challenges of prognostic gene signatures in three relevant cancer entities: breast cancer, colorectal cancer, and hepatocellular carcinoma. Full article
(This article belongs to the Special Issue Regulation of Gene Expression in Cancer)
13 pages, 1110 KiB  
Review
Tolerant/Persister Cancer Cells and the Path to Resistance to Targeted Therapy
by Mirna Swayden, Houssein Chhouri, Youssef Anouar and Luca Grumolato
Cells 2020, 9(12), 2601; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9122601 - 04 Dec 2020
Cited by 26 | Viewed by 4555
Abstract
The capacity of cancer to adapt to treatment and evolve is a major limitation for targeted therapies. While the role of new acquired mutations is well-established, recent findings indicate that resistance can also arise from subpopulations of tolerant/persister cells that survive in the [...] Read more.
The capacity of cancer to adapt to treatment and evolve is a major limitation for targeted therapies. While the role of new acquired mutations is well-established, recent findings indicate that resistance can also arise from subpopulations of tolerant/persister cells that survive in the presence of the treatment. Different processes contribute to the emergence of these cells, including pathway rebound through the release of negative feedback loops, transcriptional rewiring mediated by chromatin remodeling and autocrine/paracrine communication among tumor cells and within the tumor microenvironment. In this review, we discuss the non-genetic mechanisms that eventually result in cancer resistance to targeted therapies, with a special focus on those involving changes in gene expression. Full article
(This article belongs to the Special Issue Regulation of Gene Expression in Cancer)
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13 pages, 1974 KiB  
Review
ARID2 Chromatin Remodeler in Hepatocellular Carcinoma
by Robin Loesch, Linda Chenane and Sabine Colnot
Cells 2020, 9(10), 2152; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9102152 - 23 Sep 2020
Cited by 15 | Viewed by 4591
Abstract
Chromatin remodelers are found highly mutated in cancer including hepatocellular carcinoma. These mutations frequently occur in ARID (AT-rich Interactive Domain) genes, encoding subunits of the ATP-dependent SWI/SNF remodelers. The increasingly prevalent complexity that surrounds the functions and specificities of the highly [...] Read more.
Chromatin remodelers are found highly mutated in cancer including hepatocellular carcinoma. These mutations frequently occur in ARID (AT-rich Interactive Domain) genes, encoding subunits of the ATP-dependent SWI/SNF remodelers. The increasingly prevalent complexity that surrounds the functions and specificities of the highly modular BAF (BG1/BRM-associated factors) and PBAF (polybromo-associated BAF) complexes, including ARID1A/B or ARID2, is baffling. The involvement of the SWI/SNF complexes in diverse tissues and processes, and especially in the regulation of gene expression, multiplies the specific outcomes of specific gene alterations. A better understanding of the molecular consequences of specific mutations impairing chromatin remodelers is needed. In this review, we summarize what we know about the tumor-modulating properties of ARID2 in hepatocellular carcinoma. Full article
(This article belongs to the Special Issue Regulation of Gene Expression in Cancer)
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