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

Authors: Chen, L  Fu, L  Kong, X  Xu, J  Wang, Z  Ma, X  Akiyama, Y  Chen, Y  Fang, J 
Citation: Chen L, etal., Br J Cancer. 2014 Feb 18;110(4):1014-26. doi: 10.1038/bjc.2013.808. Epub 2014 Jan 28.
Pubmed: (View Article at PubMed) PMID:24473398
DOI: Full-text: DOI:10.1038/bjc.2013.808

BACKGROUND: Jumonji domain-containing protein 2B (JMJD2B), directly targeted by hypoxia-inducible factor 1alpha, 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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CRRD Object Information
CRRD ID: 9587755
Created: 2014-10-16
Species: All species
Last Modified: 2014-10-16
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.