Transcription factor B-MYB activates lncRNA CCAT1 and upregulates SOCS3 to promote chemoresistance in colorectal cancer. (1st April 2023)

• Record Type: Journal Article
• Authors: Liu, Feng; Wang, Yutingzi; Cao, Yang; Wu, Zhiwei; Ma, De; Cai, Jun; Sha, Jie; Chen, Qing
• Is Part Of: Chemico-biological interactions. Volume 374(2023)
• Publication Date: 2023-04-01
• Subjects: Colorectal cancer -- Methylation -- B-MYB -- LncRNA CCAT1 -- DNMT1 -- SOCS3 -- Chemoresistance; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2023.110412
• Languages: English
• ISSNs: 0009-2797

Abstract

Abstract: Currently, resistance to oxaliplatin (OXA) has become an important obstacle to improving the clinical outcome of patients with colorectal cancer (CRC). Moreover, long non-coding RNAs (lncRNAs) have been documented in cancer chemoresistance, and our bioinformatic analysis suggested an involvement of lncRNA CCAT1 in CRC development. In this context, this study aimed to clarify the upstream and downstream mechanisms underpinning the effect of CCAT1 in the resistance of CRC to OXA. The expression of CCAT1 and the upstream B-MYB in the CRC samples was predicted by bioinformatics analysis and then verified using RT-qPCR in CRC cell lines. Accordingly, overexpression of B-MYB and CCAT1 was observed in CRC cells. SW480 cell line was used for the construction of OXA-resistant cell line (SW480R). Ectopic expression and knockdown experiments of B-MYB and CCAT1 were conducted in SW480R cells to delineate their roles in the malignant phenotypes and half-maximal (50%) inhibitory concentration (IC50 ) of OXA. It was found that CCAT1 promoted the resistance of CRC cells to OXA. Mechanistically, B-MYB transcriptionally activated CCAT1, which recruited DNMT1 to inhibit SOCS3 expression through elevating the SOCS3 promoter methylation. By this mechanism, the resistance of CRC cells to OXA was enhanced. Meanwhile, these in vitro findings were reproduced in vivo on xenografts of SW480R cells in nude mice. To sum up, B-MYB might promote the chemoresistance of CRC cells to OXA via regulating the CCAT1/DNMT1/SOCS3 axis. Highlights: B-MYB and CCAT1 are up-regulated in CRC samples. B-MYB enhances transcription expression of CCAT1. CCAT1 recruits DNMT1 to increase SOCS3 promoter methylation. B-MYB boosts chemoresistance of CRC cells via the CCAT1/DNMT1/SOCS3 axis. This study provides a novel target for controlling chemoresistance of CRC cells.