A Small-Molecule Probe of the Histone Methyltransferase G9a Induces Cellular Senescence in Pancreatic Adenocarcinoma
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- 作者：Yuan Yuan ; Qiu Wang ; Joshiawa Paulk ; Stefan Kubicek ; Melissa M. Kemp ; Drew J. Adams ; Alykhan F. Shamji ; Bridget K. Wagner ; Stuart L. Schreiber
- 刊名：ACS Chemical Biology
- 出版年：2012
- 出版时间：July 20, 2012
- 年：2012
- 卷：7
- 期：7
- 页码：1152-1157
- 全文大小：364K
- 年卷期：v.7,no.7(July 20, 2012)
- ISSN：1554-8937
文摘
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.