A small-molecule probe of the histone methyltransferase G9a induces cellular senescence in pancreatic adenocarcinoma |
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Authors: | Yuan Yuan Wang Qiu Paulk Joshiawa Kubicek Stefan Kemp Melissa M Adams Drew J Shamji Alykhan F Wagner Bridget K Schreiber Stuart L |
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Affiliation: | Chemical Biology Program, Broad Institute, Cambridge, Massachusetts 02142, United States. |
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Abstract: | 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. |
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