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

NAT10 triggers colorectal cancer progression via promoting PPAN-regulated DNA damage repair | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article NAT10 triggers colorectal cancer progression via promoting PPAN-regulated DNA damage repair Hongsheng Wang, Haoran Wang, Jianing Li, Lichen Ge, Ke Zhong, and 17 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6627686/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 27 Dec, 2025 Read the published version in Oncogene → Version 1 posted 10 You are reading this latest preprint version Abstract 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. Biological sciences/Cancer/Cancer genetics Biological sciences/Molecular biology/Epigenetics ac4C NAT10 PPAN Colorectal cancer (CRC) DNA damage repair Full Text Additional Declarations There is NO conflict of interest to disclose. Supplementary Files SupplementaryMaterial.pdf Supplementary Material TableS.rar Table S Uneditedblotandgelimages.pdf Unedited blot and gel images Cite Share Download PDF Status: Published Journal Publication published 27 Dec, 2025 Read the published version in Oncogene → Version 1 posted Editorial decision: revise 19 Jun, 2025 Review # 1 received at journal 16 Jun, 2025 Review # 2 received at journal 06 Jun, 2025 Reviewer # 2 agreed at journal 23 May, 2025 Reviewer # 1 agreed at journal 18 May, 2025 Reviewers invited by journal 14 May, 2025 Submission checks completed at journal 13 May, 2025 First submitted to journal 12 May, 2025 Unknown event 12 May, 2025 Editor assigned by journal 09 May, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Colorectal cancer (CRC), DNA damage repair","lastPublishedDoi":"10.21203/rs.3.rs-6627686/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6627686/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"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. 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