A small-molecule probe of the histone methyltransferase G9a induces cellular senescence in pancreatic adenocarcinoma

ACS Chem Biol. 2012 Jul 20;7(7):1152-7. doi: 10.1021/cb300139y. Epub 2012 Apr 30.

Abstract

Post-translational modifications of histones alter chromatin structure and play key roles in gene expression and specification of cell states. Small molecules that target chromatin-modifying enzymes selectively are useful as probes and have promise as therapeutics, although very few are currently available. G9a (also named euchromatin histone methyltransferase 2 (EHMT2)) catalyzes methylation of lysine 9 on histone H3 (H3K9), a modification linked to aberrant silencing of tumor-suppressor genes, among others. Here, we report the discovery of a novel histone methyltransferase inhibitor, BRD4770. This compound reduced cellular levels of di- and trimethylated H3K9 without inducing apoptosis, induced senescence, and inhibited both anchorage-dependent and -independent proliferation in the pancreatic cancer cell line PANC-1. ATM-pathway activation, caused by either genetic or small-molecule inhibition of G9a, may mediate BRD4770-induced cell senescence. BRD4770 may be a useful tool to study G9a and its role in senescence and cancer cell biology.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenocarcinoma / enzymology*
  • Adenocarcinoma / pathology
  • Benzamides / chemistry
  • Benzamides / metabolism
  • Benzamides / pharmacology
  • Benzimidazoles / chemistry
  • Benzimidazoles / metabolism
  • Benzimidazoles / pharmacology
  • Cell Line, Tumor
  • Cellular Senescence / drug effects*
  • Cellular Senescence / immunology
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology
  • HeLa Cells
  • Histocompatibility Antigens / metabolism
  • Histone-Lysine N-Methyltransferase / antagonists & inhibitors*
  • Histone-Lysine N-Methyltransferase / metabolism
  • Humans
  • Molecular Probes / chemistry
  • Molecular Probes / metabolism
  • Molecular Probes / pharmacology*
  • Pancreatic Neoplasms / enzymology*
  • Pancreatic Neoplasms / pathology

Substances

  • BRD4770
  • Benzamides
  • Benzimidazoles
  • Enzyme Inhibitors
  • Histocompatibility Antigens
  • Molecular Probes
  • EHMT2 protein, human
  • Histone-Lysine N-Methyltransferase