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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Yuan, Y; Wang, Q; Paulk, J; Kubicek, S; Kemp, MM; Adams, DJ; Shamji, AF; Wagner, BK; Schreiber, SL

Published Date

  • July 2012

Published In

Volume / Issue

  • 7 / 7

Start / End Page

  • 1152 - 1157

PubMed ID

  • 22536950

Pubmed Central ID

  • 22536950

Electronic International Standard Serial Number (EISSN)

  • 1554-8937

International Standard Serial Number (ISSN)

  • 1554-8929

Digital Object Identifier (DOI)

  • 10.1021/cb300139y

Language

  • eng