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

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.