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 av...

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Bibliographic Details
Published in:ACS chemical biology 2012-07, Vol.7 (7), p.1152-1157
Main Authors: Yuan, Yuan, Wang, Qiu, Paulk, Joshiawa, Kubicek, Stefan, Kemp, Melissa M, Adams, Drew J, Shamji, Alykhan F, Wagner, Bridget K, Schreiber, Stuart L
Format: Article
Language:English
Subjects:
Adenocarcinoma - enzymology
Adenocarcinoma - pathology
Benzamides - chemistry
Benzamides - metabolism
Benzamides - pharmacology
Benzimidazoles - chemistry
Benzimidazoles - metabolism
Benzimidazoles - pharmacology
Cell Line, Tumor
Cellular Senescence - drug effects
Cellular Senescence - immunology
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - metabolism
Enzyme Inhibitors - pharmacology
HeLa Cells
Histocompatibility Antigens - metabolism
Histone-Lysine N-Methyltransferase - antagonists & inhibitors
Histone-Lysine N-Methyltransferase - metabolism
Humans
Letters
Molecular Probes - chemistry
Molecular Probes - metabolism
Molecular Probes - pharmacology
Pancreatic Neoplasms - enzymology
Pancreatic Neoplasms - pathology
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Summary: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.
ISSN:1554-8929
1554-8937
DOI:10.1021/cb300139y