title: A small-molecule probe of the histone methyltransferase G9a induces cellular senescence in pancreatic adenocarcinoma.
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.
authors.affiliation: Chemical Biology Program, Broad Institute, Cambridge, Massachusetts 02142, United States.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yuan
authors.forename: Qiu
authors.initials: Q
authors.lastname: Wang
authors.forename: Joshiawa
authors.initials: J
authors.lastname: Paulk
authors.forename: Stefan
authors.initials: S
authors.lastname: Kubicek
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Kemp
authors.forename: Drew J
authors.initials: DJ
authors.lastname: Adams
authors.forename: Alykhan F
authors.initials: AF
authors.lastname: Shamji
authors.forename: Bridget K
authors.initials: BK
authors.lastname: Wagner
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology* / Q000473:pathology; D001549:Benzamides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001562:Benzimidazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects* / Q000276:immunology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006367:HeLa Cells; D006649:Histocompatibility Antigens / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015335:Molecular Probes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000473:pathology
chemical_list: C586537:BRD4770; D001549:Benzamides; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D006649:Histocompatibility Antigens; D015335:Molecular Probes; C445405:EHMT2 protein, human; D011495:Histone-Lysine N-Methyltransferase