Down-regulation of G9a triggers DNA damage response and inhibits colorectal cancer cells proliferation
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Jie Zhang1, Pengxing He2, Yong Xi1, Meiyu Geng1, Yi Chen1, Jian Ding1
1Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
2School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
Jian Ding, e-mail: [email protected]
Yi Chen, e-mail: [email protected]
Keywords: colorectal cancer, G9a, epigenetics, DNA damage response (DDR), SN38/CPT, synergistic effect
Received: August 10, 2014 Accepted: November 19, 2014 Published: December 09, 2014
G9a, a histone methyltransferase, is aberrantly expressed in some human tumor types. By comparing 182 paired colorectal cancer and peritumoral tissues, we found that G9a was highly expressed in colorectal cancer (CRC). Overexpression of G9a promoted CRC cells proliferation and colony formation, whereas knockdown of G9a inhibited CRC cells proliferation. Depletion of G9a increased the rate of chromosome aberration, induced DNA double strand breaks and CRC cells senescence. G9a inhibition synergistically increased γH2AX expression induced by topoisomerase I inhibitors and ultimately led to CRC cell death. The findings that down-regulation of G9a triggers DNA damage response and inhibits colorectal cancer cells proliferation may define G9a as potential oncotarget in CRC.
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