Year-end Sale % OFF 
Abstract
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.
Highlights
Colon and rectal cancer is the third most common carcinoma, and has become one of the leading causes of death from cancers worldwide [1]
Our study suggests that the X-ray repair cross-complementing protein 5 (XRCC5)/p300/COX-2 signaling pathway is a potential target in the treatment of colon cancers
XRCC5 was identified as a COX-2 promoter-binding protein in colon cancer cells
Summary
Colon and rectal cancer (colorectal cancer, CRC) is the third most common carcinoma, and has become one of the leading causes of death from cancers worldwide [1]. 9% of all cancer related death in males and 8% of all cancer related death in females can be attributed to CRC [2].Major advances in the understanding of CRC biology have led to the development of new diagnostic and prognostic biomarkers, and the development of novel molecular targeted therapies for CRC. When CRC develops into advanced stages, curative surgical resection is nearly impossible. The efficacy of the combination therapy with cytotoxic drugs for advanced staged CRC remains limited due to a combination of drug toxicity and resistance. It is not uncommon that CRC patients can develop drug resistance to bevacizumab and cetuximab. Searching for novel therapeutic targets for advanced CRC to maximize survival time is of great significance to both patients and clinicians
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
