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