Epigenetic regulation of RGS2 (Regulator of G-protein signaling 2) in chemoresistant ovarian cancer cells

J Chemother. 2017 Jun;29(3):173-178. doi: 10.1080/1120009X.2016.1277007. Epub 2017 Jan 19.

Abstract

Regulator of G-protein signaling 2 (RGS2) is a GTPase-activating protein functioning as an inhibitor of G-protein coupled receptors (GPCRs). RGS2 dysregulation was implicated in solid tumour development and RGS2 downregulation has been reported in prostate and ovarian cancer progression. However, the molecular mechanism by which RGS2 expression is suppressed in ovarian cancer remains unknown. The expression and epigenetic regulation of RGS2 in chemosensitive and chemoresistant ovarian cancer cells were determined by qRT-PCR and chromatin immunoprecipitation assays, respectively. In the present study, the molecular mechanisms contributing to the loss of RGS2 expression were determined in ovarian cancer. The data indicated that suppression of RGS2 gene in chemoresistant ovarian cancer cells, in part, due to accumulation of histone deacetylases (HDACs) and DNA methyltransferase I (DNMT1) at the promoter region of RGS2. Inhibition of HDACs or DNMTs significantly increases RGS2 expression. These results suggest that epigenetic changes in histone modifications and DNA methylation may contribute to the loss of RGS2 expression in chemoresistant ovarian cancer cells. The results further suggest that class I HDACs and DNMT1 contribute to the suppression of RGS2 during acquired chemoresistance and support growing evidence that inhibition of HDACs/DNMTs represents novel therapeutic approaches to overcome ovarian cancer chemoresistance.

Keywords: DNA Methylation; RGS2; chemoresistance; histone acetylation; ovarian cancer.

MeSH terms

  • Acetylation / drug effects
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation
  • Cisplatin / pharmacology
  • DNA (Cytosine-5-)-Methyltransferases / antagonists & inhibitors
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA (Cytosine-5-)-Methyltransferases / metabolism*
  • DNA Methylation / drug effects
  • Drug Resistance, Neoplasm* / drug effects
  • Epigenetic Repression* / drug effects
  • Female
  • Gene Expression Regulation, Neoplastic* / drug effects
  • Histone Deacetylase 1 / chemistry
  • Histone Deacetylase 1 / genetics
  • Histone Deacetylase 1 / metabolism*
  • Humans
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / enzymology
  • Ovarian Neoplasms / metabolism*
  • Promoter Regions, Genetic / drug effects
  • Protein Processing, Post-Translational / drug effects
  • RGS Proteins / antagonists & inhibitors
  • RGS Proteins / genetics
  • RGS Proteins / metabolism*
  • RNA Interference
  • RNA, Small Interfering

Substances

  • Antineoplastic Agents
  • Neoplasm Proteins
  • RGS Proteins
  • RGS2 protein, human
  • RNA, Small Interfering
  • DNA (Cytosine-5-)-Methyltransferases
  • HDAC1 protein, human
  • Histone Deacetylase 1
  • Cisplatin