Role of poly(ADP-ribose) glycohydrolase silencing in DNA hypomethylation induced by benzo(a)pyrene

Biochem Biophys Res Commun. 2014 Sep 26;452(3):708-14. doi: 10.1016/j.bbrc.2014.08.146. Epub 2014 Sep 6.

Abstract

Benzo(a)pyrene (BaP) is a known carcinogen cytotoxic which can trigger extensive cellular responses. Many evidences suggest that inhibitors of poly(ADP-ribose) glycohydrolase (PARG) are potent anticancer drug candidates. However, the role of PARG in BaP carcinogenesis is less understood. Here we used PARG-deficient human bronchial epithelial cell line (shPARG cell) as an in vitro model, and investigated the role of PARG silencing in DNA methylation pattern changed by BaP. Our study shows, BaP treatment decreased global DNA methylation levels in 16HBE cells in a dose-dependent manner, but no dramatic changes were observed in shPARG cells. Further investigation revealed PARG silencing protected DNA methyltransferases (DNMTs) activity from change by BaP exposure. Interestingly, Dnmt1 is PARylated in PARG-null cells after BaP exposure. The results show a role for PARG silencing in DNA hypomethylation induced by BaP that may provide new clue for cancer therapy.

Keywords: Benzo(a)pyrene; DNA methylation; Human bronchial epithelial (16HBE) cells; Poly(ADP-ribose) glycohydrolase; Poly(ADP-ribosyl)ation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzo(a)pyrene / toxicity*
  • Bronchi / drug effects
  • Bronchi / enzymology
  • Bronchi / pathology
  • Carcinogens / toxicity*
  • Cell Engineering
  • Cell Line
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA (Cytosine-5-)-Methyltransferases / metabolism*
  • DNA Methylation / drug effects
  • Dose-Response Relationship, Drug
  • Epithelial Cells / drug effects*
  • Epithelial Cells / enzymology
  • Epithelial Cells / pathology
  • Glycoside Hydrolases / antagonists & inhibitors
  • Glycoside Hydrolases / genetics
  • Glycoside Hydrolases / metabolism*
  • Humans
  • Poly Adenosine Diphosphate Ribose / metabolism
  • Protein Processing, Post-Translational*
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism

Substances

  • Carcinogens
  • RNA, Small Interfering
  • Poly Adenosine Diphosphate Ribose
  • Benzo(a)pyrene
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases
  • DNMT1 protein, human
  • Glycoside Hydrolases
  • poly ADP-ribose glycohydrolase