Special Issue "Epigenetic Cancer Therapy: Targeting DNA and Histone Methylation"

A special issue of Epigenomes (ISSN 2075-4655).

Deadline for manuscript submissions: closed (1 May 2021).

Special Issue Editor

Prof. Dr. Richard L. Momparler
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Guest Editor
Département de Pharmacologie, Université de Montréal, Montreal, QC, Canada
Interests: epigenetic therapy cancer; inhibitors DNA methylation; inhibitors of EZH2

Special Issue Information

Dear Colleagues,

Epigenetic silencing of genes that suppress malignancy by DNA and histone methylation plays an important role in the development of cancer. Several observations suggest that these epigenetic alterations are promising targets for chemotherapeutic intervention. The potent inhibitor of DNA methylation, 5-Aza-2’-deoxycytidine (5AZA-CdR, decitabine), was shown to induce remissions in patients with acute myeloid leukemia (AML). However, these remissions were of limited duration, possibly due to suboptimal activation of tumor suppressor genes (TSGs) by 5AZA-CdR due to the presence of a second gene-silencing marker, such as histone H3-trimethylated lysine 27 (H3K27me3). EZH2 catalyzes the methylation of H3K27, and 3-deazaneplanocin-A (DZNep), a potent inhibitor of EZH2, displays potent antineoplastic action against AML cells. The combination of DZNep and 5AZA-CdR exhibits a remarkable antileukemic synergy. Investigations on isocitrate dehydrogenase mutations (mut-IDH) provide additional support that these epigenetic alterations are interesting targets for chemotherapy. AML cells with mut-IDH produce 2-hydroxy-glutarate (2HG), an oncometabolite that inhibits the catalytic activity of the TET family and Jumonji-C histone demethylases (JHDMs). This action blocks the demethylation of DNA and H3K27me3, which prevents TSG reactivation. An intriguing hypothesis to explain these interactions is that cells possess enzymatic mechanisms that attenuate their capacity for excessive proliferation, decreasing the probability of progression to malignancy. This natural enzymatic mechanism has the potential to enhance the effectiveness of 5AZA-CdR and DZNep. This novel epigenetic therapy merits clinical investigation in cancer patients with high priority.

Prof. Richard L. Momparler
Guest Editor

Manuscript Submission Information

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Keywords

  • cancer stem cells
  • self-renewal
  • 5-aza-2’-deoxycytidine
  • 3-deazaneplanocin-A
  • combination chemotherapy
  • EZH2
  • TET
  • histone demethylases
  • natural anticancer mechanism

Published Papers (2 papers)

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Research

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Open AccessCommunication
Enhancement of the Antileukemic Action of the Inhibitors of DNA and Histone Methylation: 5-Aza-2′-Deoxycytidine and 3-Deazaneplanocin-A by Vitamin C
Epigenomes 2021, 5(2), 7; https://0-doi-org.brum.beds.ac.uk/10.3390/epigenomes5020007 - 24 Mar 2021
Viewed by 430
Abstract
Epigenetic gene silencing by DNA methylation and histone methylation by EZH2 play an important role in the development of acute myeloid leukemia (AML). EZH2 catalyzes the trimethylation of histone H3-lysine 27-trimethylated (H3K27me3). These epigenetic alterations silence the expression of the genes that suppress [...] Read more.
Epigenetic gene silencing by DNA methylation and histone methylation by EZH2 play an important role in the development of acute myeloid leukemia (AML). EZH2 catalyzes the trimethylation of histone H3-lysine 27-trimethylated (H3K27me3). These epigenetic alterations silence the expression of the genes that suppress leukemogenesis. Reversal of this gene silencing by 5-aza-2′-deoxycytidine (5-Aza-CdR), an inhibitor of DNA methylation, and by 3-deazaneplanocin-A (DZNep), an inhibitor of EZH2, results in synergistic gene reactivation and antileukemic interaction. The objective of this study is to determine if the addition of another epigenetic agent could further enhance the antileukemic action of these inhibitors of DNA and histone methylation. Vitamin C (Vit C) is reported to enhance the antineoplastic action of 5-Aza-CdR on AML cells. The mechanism responsible for this action of Vit C is due to its function as a cofactor of alpha-ketoglutarate-dependent dioxygenases (α-KGDD). The enhancement by Vit C of the catalytic activity of α-KGDD of the ten eleven translocation (TET) pathway, as well as of the Jumonji C histone demethylases (JHDMs), is shown to result in demethylation of DNA and histones, leading to reactivation of tumor suppressor genes and an antineoplastic effect. This action of Vit C has the potential to complement the antileukemic action of 5-Aza-CdR and DZNep. We observe that Vit C remarkably increases the antineoplastic activity of 5-Aza-CdR and DZNep against myeloid leukemic cells. An important step to bring this novel epigenetic therapy to clinical trial in patients with AML is the determination of its optimal dose schedule. Full article
(This article belongs to the Special Issue Epigenetic Cancer Therapy: Targeting DNA and Histone Methylation)
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Open AccessFeature PaperReview
Epigenetic Modulation of Self-Renewal Capacity of Leukemic Stem Cells and Implications for Chemotherapy
Epigenomes 2020, 4(1), 3; https://0-doi-org.brum.beds.ac.uk/10.3390/epigenomes4010003 - 01 Mar 2020
Cited by 2 | Viewed by 875
Abstract
Most patients with acute myeloid leukemia (AML) have a poor prognosis. Curative therapy of AML requires the complete eradication of the leukemic stem cells (LSCs). One aspect of LSCs that is poorly understood is their low frequency in the total population of leukemic [...] Read more.
Most patients with acute myeloid leukemia (AML) have a poor prognosis. Curative therapy of AML requires the complete eradication of the leukemic stem cells (LSCs). One aspect of LSCs that is poorly understood is their low frequency in the total population of leukemic cells in AML patients. After each cell division of LSCs, most of the daughter cells lose their capacity for self-renewal. Investigations into the role of Isocitrate dehydrogenase (IDH) mutations in AML provide some insight on the regulation of the proliferation of LSCs. The primary role of IDH is to convert isocitrate to alpha-keto-glutarate (α-KG). When IDH is mutated, it converts α-KG to 2-hydroxyglutarate (2-HG), an inhibitor of the TET pathway and Jumonji-C histone demethylases (JHDMs). The demethylating action of these enzymes removes the epigenetic gene-silencing markers, DNA methylation, H3K27me3 and H3K9me2 and can lead to the differentiation of LSCs. This enzymatic action is blocked by 2-HG in mutated IDH (mut-IDH) AML patients, who can be induced into remission with antagonists of 2-HG. These observations suggest that there exists in cells a natural enzymatic mechanism that uses demethylation to reverse epigenetic gene-silencing, leading to a loss of the self-renewal capacity of LSCs. This mechanism limits the proliferative potential of LSCs. Epigenetic agents that inhibit DNA and histone methylation exhibit a synergistic antineoplastic action on AML cells. It is possible that the therapeutic potential of this epigenetic therapy may be enhanced by demethylation enzymes, resulting in a very effective treatment for AML. Full article
(This article belongs to the Special Issue Epigenetic Cancer Therapy: Targeting DNA and Histone Methylation)
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