XRCC5 cooperates with p300 to promote cyclooxygenase-2 expression and tumor growth in colon cancers

• Published in: PloS one 2017-10, Vol.12 (10), p.e0186900
• Main Authors: Zhang, Zhifeng, Zheng, Fufu, Yu, Zhenlong, Hao, Jiajiao, Chen, Miao, Yu, Wendan, Guo, Wei, Chen, Yiming, Huang, Wenlin, Duan, Zhijun, Deng, Wuguo
• Format: Article
• Language: English
• Subjects: Acetylation; Angiogenesis; Animals; Apoptosis; Assaying; Biology and life sciences; Biosynthesis; Cancer; Cancer therapies; Carcinogenesis; Carcinogens; Cell growth; Cell Line, Tumor; Cell Proliferation; Chemokine receptors; Clonal deletion; Collaboration; Colon; Colon cancer; Colonic Neoplasms - enzymology; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Colorectal cancer; Confocal microscopy; Cyclooxygenase 2 - metabolism; Cyclooxygenase-2; Cytokines; Cytotoxicity; Deletion mutant; Development and progression; DNA binding proteins; Drug development; Event-related potentials; Gene expression; Genetic aspects; Heterografts; Histone acetyltransferase; Hospitals; Humans; Immunofluorescence; Immunoprecipitation; Isoforms; Kinases; Ku Autoantigen - metabolism; Laboratories; Mass spectrometry; Mass spectroscopy; Medicine and Health Sciences; Mice; Microscopy; Nuclei; Nuclei (cytology); Oncology; p300-CBP Transcription Factors - metabolism; Physiological aspects; Prostaglandins; Protein Binding; Proteins; Research and Analysis Methods; Rodents; Signal transduction; siRNA; Stem cells; Streptavidin; Transcription factors; Tumor necrosis factor-TNF; Tumors; Vascular endothelial growth factor; Xenografts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0186900

Cyclooxygenase (COX) is the rate-limiting enzyme in prostaglandins (PGs) biosynthesis. Previous studies indicate that COX-2, one of the isoforms of COX, is highly expressed in colon cancers and plays a key role in colon cancer carcinogenesis. Thus, searching for novel transcription factors regulating COX-2 expression will facilitate drug development for colon cancer. In this study, we identified XRCC5 as a binding protein of the COX-2 gene promoter in colon cancer cells with streptavidin-agarose pulldown assay and mass spectrometry analysis, and found that XRCC5 promoted colon cancer growth through modulation of COX-2 signaling. Knockdown of XRCC5 by siRNAs inhibited the growth of colon cancer cells in vitro and of tumor xenografts in a mouse model in vivo by suppressing COX-2 promoter activity and COX-2 protein expression. Conversely, overexpression of XRCC5 promoted the growth of colon cancer cells by activating COX-2 promoter and increasing COX-2 protein expression. Moreover, the role of p300 (a transcription co-activator) in acetylating XRCC5 to co-regulate COX-2 expression was also evaluated. Immunofluorescence assay and confocal microscopy showed that XRCC5 and p300 proteins were co-located in the nucleus of colon cancer cells. Co-immunoprecipitation assay also proved the interaction between XRCC5 and p300 in nuclear proteins of colon cancer cells. Cell viability assay indicated that the overexpression of wild-type p300, but not its histone acetyltransferase (HAT) domain deletion mutant, increased XRCC5 acetylation, thereby up-regulated COX-2 expression and promoted the growth of colon cancer cells. In contrast, suppression of p300 by a p300 HAT-specific inhibitor (C646) inhibited colon cancer cell growth by suppressing COX-2 expression. Taken together, our results demonstrated that XRCC5 promoted colon cancer growth by cooperating with p300 to regulate COX-2 expression, and suggested that the XRCC5/p300/COX-2 signaling pathway was a potential target in the treatment of colon cancers.