Jumonji domain-containing protein 2B silencing induces DNA damage response via STAT3 pathway in colorectal cancer

被引:35
作者
Chen, L. [1 ,2 ,3 ]
Fu, L. [1 ,2 ,3 ]
Kong, X. [1 ,2 ,3 ]
Xu, J. [1 ,2 ,3 ]
Wang, Z. [1 ,2 ,3 ]
Ma, X. [1 ,2 ,3 ]
Akiyama, Y. [4 ]
Chen, Y. [1 ,2 ,3 ]
Fang, J. [1 ,2 ,3 ]
机构
[1] Shanghai Jiao Tong Univ, Sch Med, Ren Ji Hosp, Dept Gastroenterol & Hepatol, Shanghai 200001, Peoples R China
[2] Shanghai Inst Digest Dis, Shanghai 200001, Peoples R China
[3] Shanghai Jiao Tong Univ, Minist Hlth, Key Lab Gastroenterol & Hepatol, Shanghai 200001, Peoples R China
[4] Tokyo Med & Dent Univ, Grad Sch Med & Dent Sci, Dept Mol Oncol, Tokyo 1130034, Japan
基金
中国国家自然科学基金;
关键词
JMJD2B; DNA damage response; hypoxia; STAT3; colorectal cancer; HISTONE DEMETHYLASE JMJD2B; CELL-CYCLE ARREST; GENE-EXPRESSION; DOWN-REGULATION; SIGNAL TRANSDUCER; MULTIPLE-MYELOMA; CHRONIC HYPOXIA; GASTRIC-CANCER; SENESCENCE; ACTIVATION;
D O I
10.1038/bjc.2013.808
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background: Jumonji domain-containing protein 2B (JMJD2B), directly targeted by hypoxia-inducible factor 1 alpha, maintains the histone methylation balance important for the transcriptional activation of many oncogenes. Jumonji domain-containing protein 2B has been implicated in colorectal cancer (CRC) progression; however, the mechanism remains unclear. Methods: Immunofluorescence and western blotting detected phosphorylated histone H2AX, characteristic of double-strand breaks, and comet assay was used to investigate DNA damage, in CRC cells after JMJD2B small interfering RNA (siRNA) transfection. We assessed the resulting in vitro responses, that is, cell cycle progression, apoptosis, and senescence coupled with JMJD2B silencing-induced DNA damage, studying the regulatory role of signal transducers and activators of transcription 3 (STAT3). The JMJD2B silencing anti-cancer effect was determined using an in vivo CRC xenograft model. Results: Jumonji domain-containing protein 2B knockdown induced DNA damage via ataxia telangiectasia-mutated (ATM) and ATM and Rad3-related pathway activation, resulting in cell cycle arrest, apoptosis, and senescence in both normoxia and hypoxia. Signal transducers and activators of transcription 3 suppression by JMJD2B silencing enhanced DNA damage. Intratumoural injection of JMJD2B siRNA suppressed tumour growth in vivo and activated the DNA damage response (DDR). Conclusions: Jumonji domain-containing protein 2B has an essential role in cancer cell survival and tumour growth via DDR mediation, which STAT3 partially regulates, suggesting that JMJD2B is a potential anti-cancer target.
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收藏
页码:1014 / 1026
页数:13
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