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A Small-Molecule Probe of the Histone Methyltransferase G9a Induces Cellular Senescence in Pancreatic Adenocarcinoma.

Publication TypeJournal Article
AuthorsYuan, Y., Wang Q., Paulk J., Kubicek S., Kemp MM, Adams DJ, Shamji AF, Wagner BK, and Schreiber SL
AbstractPost-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.
Year of Publication2012
JournalACS chemical biology
Date Published (YYYY/MM/DD)2012/04/30
ISSN Number1554-8929
DOI10.1021/cb300139y
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/22536950?dopt=Abstract