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

Chemical Biology Program, Broad Institute, Cambridge, Massachusetts 02142, United States.
ACS Chemical Biology (Impact Factor: 5.33). 04/2012; 7(7):1152-7. DOI: 10.1021/cb300139y
Source: PubMed


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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    • "Knockdown of G9a by RNAi mediated gene silencing inhibits growth and further promotes apoptosis of breast cancer cells [8,12]. Pharmacological inhibition of G9a disturbs the cell cycle and induces senescent phenotypes, further inhibiting growth in prostate and pancreatic cancer [13,14]. Furthermore, inhibition of G9a may lead to autophagy in breast and colorectal cancers [15], suggesting that G9a may control cell growth in a variety of cancer types via multiple routes. "
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