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ACS Chem Biol DOI:10.1021/cb300139y

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

Publication TypeJournal Article
Year of Publication2012
AuthorsYuan, Y, Wang, Q, Paulk, J, Kubicek, S, Kemp, MM, Adams, DJ, Shamji, AF, Wagner, BK, Schreiber, SL
JournalACS Chem Biol
Date Published2012 Jul 20
KeywordsAdenocarcinoma, Benzamides, Benzimidazoles, Cell Aging, Cell Line, Tumor, Enzyme Inhibitors, HeLa Cells, Histocompatibility Antigens, Histone-Lysine N-Methyltransferase, Humans, Molecular Probes, Pancreatic Neoplasms

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.


Alternate JournalACS Chem. Biol.
PubMed ID22536950
PubMed Central IDPMC3401036
Grant ListR01 GM038627 / GM / NIGMS NIH HHS / United States
R37 GM038627 / GM / NIGMS NIH HHS / United States
GM38627 / GM / NIGMS NIH HHS / United States