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Epigenetic inactivation of the tumor suppressor gene RIZ1 in hepatocellular carcinoma involves both DNA methylation

Cuijuan Zhang1, Hiuming Li, Yan Wang

  • 1Institute of Pathology and Pathophysiology, Shandong University School of Medicine, Jinan 250012, China. zhangcuijuan@yahoo.com.cn

Journal of Hepatology
|August 3, 2010
PubMed
Abstract

Insights

Epigenetic silencing of the RIZ1 gene in hepatocellular carcinoma (HCC) involves DNA methylation and histone modifications. Combined drug treatment partially reversed methylation and synergistically restored RIZ1 expression.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Molecular Oncology

Background:

  • The retinoblastoma-interacting zinc finger gene RIZ1 is frequently inactivated in various cancers.
  • Mechanisms underlying RIZ1 inactivation, particularly in hepatocellular carcinoma (HCC), are not fully understood.

Purpose of the Study:

  • To investigate the epigenetic mechanisms of RIZ1 inactivation in HCC.
  • To analyze the interplay between DNA methylation and histone modifications in regulating RIZ1 expression.

Main Methods:

  • Methylation-specific PCR, RT-PCR, and immunohistochemistry were used to assess RIZ1 methylation and expression.
  • Chromatin immunoprecipitation (ChIP) analyzed histone H3 lysine 9 (H3K9) modifications and histone deacetylases (HDACs) at the RIZ1 promoter.

Main Results:

  • RIZ1 promoter methylation was prevalent in HCC tissues and cell lines, correlating with RIZ1 protein loss.
  • While 5-aza-2-deoxycitidine (5-Aza-dC) and Trichostatin A (TSA) individually restored RIZ1 mRNA, their combination synergistically reactivated RIZ1 expression.
  • Combined treatment led to partial promoter demethylation and dynamic H3K9 modifications, with decreased trimethylation preceding increased acetylation.

Conclusions:

  • RIZ1 gene silencing in HCC is mediated by cooperative epigenetic mechanisms involving promoter methylation and H3K9 modifications.
  • 5-Aza-dC treatment influences histone modification levels, contributing to RIZ1 expression restoration.
  • These findings highlight the cooperative roles of distinct epigenetic modifications in gene regulation.

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