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The role of epigenetic modifications in retinoic acid receptor beta2 gene expression in human prostate cancers

T Nakayama1, M Watanabe, M Yamanaka

  • 1Second Department of Pathology, Mie University School of Medicine, Mie, Japan.

Laboratory Investigation; a Journal of Technical Methods and Pathology
|July 17, 2001
PubMed

Insights

Epigenetic silencing of the retinoic acid receptor (RAR) beta2 gene, through aberrant methylation and histone hypoacetylation, is frequent in prostate cancer (PCa). This silencing can be reversed by demethylating and histone deacetylase inhibitor treatments, restoring RARbeta2 expression.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • The retinoic acid receptor (RAR) beta gene is a potential tumor suppressor located on chromosome 3p24.
  • RARbeta plays a crucial role in mediating anticancer effects by suppressing cancer cell growth.
  • Loss or down-regulation of RARbeta in prostate cancer (PCa) suggests a role in tumorigenesis, but the mechanisms are unclear.

Purpose of the Study:

  • To investigate the role of epigenetic modifications in the silencing of the RARbeta2 gene in prostate cancer.
  • To determine if aberrant methylation and histone modifications contribute to RARbeta2 gene silencing in PCa.

Main Methods:

  • Analysis of aberrant methylation in primary PCa, hormone-refractory PCa, and PCa cell lines using methylation detection.
  • Chromatin immunoprecipitation (ChIP) assay to assess histone acetylation (H3 and H4) in RARbeta2-negative cells.
  • Treatment of RARbeta2-negative cells with epigenetic modifiers (5-aza-2'-deoxycytidine, Trichostatin A, all-trans retinoic acid) to assess gene expression restoration.

Main Results:

  • Aberrant methylation of the RARbeta2 gene was detected in a high percentage of primary PCa (79%), hormone-refractory PCa (90%), and PCa cell lines (50%), but not in normal prostate samples.
  • RARbeta2-negative PCa cells exhibited hypoacetylation of histones H3 and H4.
  • Treatment with epigenetic modifiers partially reversed RARbeta2 gene silencing, inducing demethylation, increasing histone acetylation, and restoring RARbeta2 expression.

Conclusions:

  • Epigenetic modifications, specifically aberrant methylation and histone hypoacetylation, are implicated in the silencing of the RARbeta2 gene in prostate cancer.
  • The RARbeta2 gene is likely frequently silenced by epigenetic mechanisms in PCa.
  • Reversal of epigenetic silencing offers a potential therapeutic strategy for restoring RARbeta2 function in prostate cancer.

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