A Small-Molecule Probe of the Histone Methyltransferase G9a Induces Cellular Senescence in Pancreatic Adenocarcinoma
Kemp, Melissa M.
Adams, Drew J.
Wagner, Bridget K.
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CitationYuan, Yuan, Qiu Wang, Joshiawa Lanair James Paulk, Stefan Kubicek, Melissa M. Kemp, Drew J. Adams, Alykhan Farid Shamji, Bridget K. Wagner, and Stuart L. Schreiber. 2012. A small-molecule probe of the histone methyltransferase g9a induces cellular senescence in pancreatic adenocarcinoma. ACS Chemical Biology 7(7): 1152-1157.
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.
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