piR-31470 epigenetically suppresses the expression of glutathione S-transferase pi 1 in prostate cancer via DNA methylation

Cell Signal. 2020 Mar:67:109501. doi: 10.1016/j.cellsig.2019.109501. Epub 2019 Dec 16.

Abstract

Inactivation of glutathione S-transferase pi 1 (GSTP1) via hypermethylation is an early and common event in prostate carcinogenesis. Functional inactivation of GSTP1 increases the susceptibility to oxidative stress and enhance progression risk of the prostatic carcinoma. In this study, we hypothesized that the Piwi-interacting RNA (piRNA) could be a sequence-recognition and guidance molecule for induction of promoter methylation of GSTP1 facilitating prostate carcinogenesis. We found that piR-31470 was highly expressed in prostate cancer cells, and piR-31470 could bind to piwi-like RNA-mediated gene silencing 4 (PIWIL4) to form the PIWIL4/piR-31470 complex. This complex could bind to the nascent RNA transcripts of GSTP1, and recruit DNA methyltransferase 1, DNA methyltransferase 3 alpha and methyl-CpG binding domain protein 2 to initiate and maintain the hypermethylation and inactivation of GSTP1. Our data demonstrated that the overexpression of piR-31470 inhibited the levels of GSTP1 and increased vulnerability to oxidative stress and DNA damage in human prostate epithelial RWPE1 cells. In conclusion, this study characterized the roles of the PIWIL4/piR-31470 complex in the regulation of the transcription of GSTP1 by methylating the CpG island of GSTP1. This discovery may provide a novel therapeutic strategy by targeting piRNAs for the epigenetic treatment of prostate cancer.

Keywords: DNA methylation; DNMTs; GSTP1; Prostate cancer; piR-31470; piwil4.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • DNA Methylation / drug effects
  • DNA Methylation / genetics*
  • Epigenesis, Genetic* / drug effects
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Gene Expression Regulation, Neoplastic* / drug effects
  • Glutathione S-Transferase pi / genetics*
  • Glutathione S-Transferase pi / metabolism
  • Humans
  • Hydrogen Peroxide / toxicity
  • Male
  • Neoplasm Proteins / metabolism
  • Oxidative Stress / drug effects
  • Prostatic Neoplasms / enzymology*
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / pathology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / metabolism*
  • RNA-Binding Proteins / metabolism

Substances

  • Neoplasm Proteins
  • PIWIL4 protein, human
  • RNA, Messenger
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • Hydrogen Peroxide
  • GSTP1 protein, human
  • Glutathione S-Transferase pi