NAT10 triggers colorectal cancer progression via promoting PPAN-regulated DNA damage repair

RNA modification recognition proteins are crucial in cancer development and progression. Among all RNA modification-related proteins (RMRPs), Weighted Gene Co-expression Network Analysis (WGCNA), along with comprehensive and thorough analysis, suggests that NAT10, the sole known writer of N4-acetylcysteine (ac4C), as a critical regulatory protein associated with colorectal cancer (CRC) progression. NAT10 facilitates the malignancy and DNA damage repair of CRC cells via its ac4C transferase activity and regulation of Peter Pan (PPAN). Specifically, NAT10 enhanced the translation efficiency of PPAN via acetylation at the C744 and the C747 site. In addition, NAT10 can trigger the translation of ac4C-modified MYC mRNA and its expression, which can bind with the regulatory element in the PPAN promoter to increase PPAN transcription. The novel identified ac4C reader protein MYBBP1A mediates NAT10-induced translation of PPAN and MYC. We further found that VDR can bind with NAT10 promoter to activate its transcription, resulting in the high expression of NAT10 in CRC. Xenograft study and clinical data confirmed the role of the NAT10-PPAN axis in promoting CRC development and DNA damage repair. Collectively, this study reveals the role and mechanism of mRNA ac4C modification in CRC progression, providing critical potential targets for CRC drug development.