A New Molecular Mechanism Underlying the Antitumor Effect of DNA Methylation Inhibitors via an Antiviral Immune Response

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Chromatin remodeling mediated by DNA methylation and histone modifications play critical roles in the transcriptional regulation of protein-coding genes, noncoding RNAs such as microRNAs, and endogenous retroviruses (ERVs). Many studies have shown that aberrant DNA methylation and histone modifications are associated with the initiation and progression of various malignancies. Epigenetic silencing of tumor suppressor genes in cancer is generally mediated by DNA hypermethylation of CpG island promoters and histone modifications such as histone deacetylation, methylation of histone H3 lysine 9 (H3K9), and trimethylation of H3K27. Chromatin-modifying drugs such as DNA methylation inhibitors and histone deacetylase inhibitors have clinical promise for cancer therapy. However, details of the mechanisms responsible for the antitumor effects of these drugs have been unclear.Recently, a new molecular mechanism for the antitumor effect of DNA methylation inhibitors has been proposed: induction of interferon-responsive genes via double-stranded RNAs derived from ERVs. We have also confirmed the same effect of DNA demethylation using a 3D culture system for stem cells known as organoid culture. Our findings indicated that DNA demethylation suppresses the proliferation of cancer-initiating cells by inducing an antiviral response, including activation of interferon-responsive genes. Treatment with DNA methylation inhibitors to activate a growth-inhibiting immune response may be an effective therapeutic approach for malignant disorders.

Original languageEnglish
JournalAdvances in Protein Chemistry and Structural Biology
DOIs
Publication statusAccepted/In press - 2016

Fingerprint

DNA Methylation
Histone Code
Histones
Antiviral Agents
Genes
Endogenous Retroviruses
Cell culture
Interferons
Chromatin
DNA
Neoplasms
Organoids
Untranslated RNA
CpG Islands
Histone Deacetylase Inhibitors
Methylation
Chromatin Assembly and Disassembly
Double-Stranded RNA
Stem cells
Tumor Suppressor Genes

Keywords

  • Antiviral immune response
  • DNA methylation
  • Endogenous retrovirus
  • Histone modification
  • Interferon-responsive gene

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry

Cite this

@article{2362e035d7b044dfa36a89a9fc532ed5,
title = "A New Molecular Mechanism Underlying the Antitumor Effect of DNA Methylation Inhibitors via an Antiviral Immune Response",
abstract = "Chromatin remodeling mediated by DNA methylation and histone modifications play critical roles in the transcriptional regulation of protein-coding genes, noncoding RNAs such as microRNAs, and endogenous retroviruses (ERVs). Many studies have shown that aberrant DNA methylation and histone modifications are associated with the initiation and progression of various malignancies. Epigenetic silencing of tumor suppressor genes in cancer is generally mediated by DNA hypermethylation of CpG island promoters and histone modifications such as histone deacetylation, methylation of histone H3 lysine 9 (H3K9), and trimethylation of H3K27. Chromatin-modifying drugs such as DNA methylation inhibitors and histone deacetylase inhibitors have clinical promise for cancer therapy. However, details of the mechanisms responsible for the antitumor effects of these drugs have been unclear.Recently, a new molecular mechanism for the antitumor effect of DNA methylation inhibitors has been proposed: induction of interferon-responsive genes via double-stranded RNAs derived from ERVs. We have also confirmed the same effect of DNA demethylation using a 3D culture system for stem cells known as organoid culture. Our findings indicated that DNA demethylation suppresses the proliferation of cancer-initiating cells by inducing an antiviral response, including activation of interferon-responsive genes. Treatment with DNA methylation inhibitors to activate a growth-inhibiting immune response may be an effective therapeutic approach for malignant disorders.",
keywords = "Antiviral immune response, DNA methylation, Endogenous retrovirus, Histone modification, Interferon-responsive gene",
author = "Yoshimasa Saito and T. Nakaoka and Hidetsugu Saito",
year = "2016",
doi = "10.1016/bs.apcsb.2016.08.005",
language = "English",
journal = "Advances in Protein Chemistry and Structural Biology",
issn = "1876-1623",
publisher = "Academic Press Inc.",

}

TY - JOUR

T1 - A New Molecular Mechanism Underlying the Antitumor Effect of DNA Methylation Inhibitors via an Antiviral Immune Response

AU - Saito, Yoshimasa

AU - Nakaoka, T.

AU - Saito, Hidetsugu

PY - 2016

Y1 - 2016

N2 - Chromatin remodeling mediated by DNA methylation and histone modifications play critical roles in the transcriptional regulation of protein-coding genes, noncoding RNAs such as microRNAs, and endogenous retroviruses (ERVs). Many studies have shown that aberrant DNA methylation and histone modifications are associated with the initiation and progression of various malignancies. Epigenetic silencing of tumor suppressor genes in cancer is generally mediated by DNA hypermethylation of CpG island promoters and histone modifications such as histone deacetylation, methylation of histone H3 lysine 9 (H3K9), and trimethylation of H3K27. Chromatin-modifying drugs such as DNA methylation inhibitors and histone deacetylase inhibitors have clinical promise for cancer therapy. However, details of the mechanisms responsible for the antitumor effects of these drugs have been unclear.Recently, a new molecular mechanism for the antitumor effect of DNA methylation inhibitors has been proposed: induction of interferon-responsive genes via double-stranded RNAs derived from ERVs. We have also confirmed the same effect of DNA demethylation using a 3D culture system for stem cells known as organoid culture. Our findings indicated that DNA demethylation suppresses the proliferation of cancer-initiating cells by inducing an antiviral response, including activation of interferon-responsive genes. Treatment with DNA methylation inhibitors to activate a growth-inhibiting immune response may be an effective therapeutic approach for malignant disorders.

AB - Chromatin remodeling mediated by DNA methylation and histone modifications play critical roles in the transcriptional regulation of protein-coding genes, noncoding RNAs such as microRNAs, and endogenous retroviruses (ERVs). Many studies have shown that aberrant DNA methylation and histone modifications are associated with the initiation and progression of various malignancies. Epigenetic silencing of tumor suppressor genes in cancer is generally mediated by DNA hypermethylation of CpG island promoters and histone modifications such as histone deacetylation, methylation of histone H3 lysine 9 (H3K9), and trimethylation of H3K27. Chromatin-modifying drugs such as DNA methylation inhibitors and histone deacetylase inhibitors have clinical promise for cancer therapy. However, details of the mechanisms responsible for the antitumor effects of these drugs have been unclear.Recently, a new molecular mechanism for the antitumor effect of DNA methylation inhibitors has been proposed: induction of interferon-responsive genes via double-stranded RNAs derived from ERVs. We have also confirmed the same effect of DNA demethylation using a 3D culture system for stem cells known as organoid culture. Our findings indicated that DNA demethylation suppresses the proliferation of cancer-initiating cells by inducing an antiviral response, including activation of interferon-responsive genes. Treatment with DNA methylation inhibitors to activate a growth-inhibiting immune response may be an effective therapeutic approach for malignant disorders.

KW - Antiviral immune response

KW - DNA methylation

KW - Endogenous retrovirus

KW - Histone modification

KW - Interferon-responsive gene

UR - http://www.scopus.com/inward/record.url?scp=84995757498&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84995757498&partnerID=8YFLogxK

U2 - 10.1016/bs.apcsb.2016.08.005

DO - 10.1016/bs.apcsb.2016.08.005

M3 - Article

JO - Advances in Protein Chemistry and Structural Biology

JF - Advances in Protein Chemistry and Structural Biology

SN - 1876-1623

ER -