Genetic wiring of the m6A epitranscriptome drives prostate cancer progression

Genetic wiring of the m6A epitranscriptome drives prostate cancer progression | 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 Genetic wiring of the m 6 A epitranscriptome drives prostate cancer progression Gong-Hong Wei, Shengjie Zhai, Zixian Wang, Linxi Jiang, Qin Zhang, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8767361/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract N6-methyladenosine (m6A) is a pervasive RNA modification that modulates transcript stability and translation, yet how m6A deposition is coordinated with transcriptional programs and genetic context during cancer progression remains incompletely understood. Here, we integrate population-resolved m6A profiling with genomics, proteomics and functional modeling to delineate a conserved but selectively reprogrammed epitranscriptomic landscape associated with prostate cancer progression across ancestries. We identify recurrent alteration of ZC3H13, a core m6A regulator, as a central determinant of tumor-specific m6A attenuation and gene-level methylation reprogramming. An m6A regulator-derived risk score robustly stratifies clinical outcomes across multiple independent cohorts. Genetic and in vivo modeling establish ZC3H13 as a causal driver of tumor growth, invasion, and metastasis. Mechanistically, ZC3H13 physically associates with RNA polymerase II and functions as a transcription-coupling scaffold that directs site-specific, co-transcriptional m6A deposition on oncogenic transcripts. This program operates in a genetic context-dependent manner, reinforcing PI3K-AKT signaling in PTEN-intact tumors while sustaining TGF-β/SMAD-driven epithelial-mesenchymal transition following PTEN loss. Collectively, our findings define a transcription-coupled mechanism through which cancer genomes encode epitranscriptomic states and nominate ZC3H13-mediated m6A regulation as a potential genetically-informed therapeutic vulnerability. Biological sciences/Cancer/Urological cancer/Prostate cancer Biological sciences/Genetics/Gene regulation Prostate cancer m6A RNA modification ZC3H13-PMEPA1-PTEN axis co-transcriptional regulation epitranscriptomic vulnerability TGF-β/EMT Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryTables14.xlsx Dataset 1-4 ZhaietalFigS1S9.pdf Extended Data Figures 1-9 Cite Share Download PDF Status: Under Review Version 1 posted 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8767361","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":600872088,"identity":"b8319423-b18d-4308-ab5e-0240522470f7","order_by":0,"name":"Gong-Hong 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