Impairment of FBXO31-mediated Ubiquitination of OGT Upregulates O-GlcNAcylation to Advance Endometrial Malignancy

Impairment of FBXO31-mediated Ubiquitination of OGT Upregulates O-GlcNAcylation to Advance Endometrial Malignancy | 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 Impairment of FBXO31-mediated Ubiquitination of OGT Upregulates O-GlcNAcylation to Advance Endometrial Malignancy Kai Yuan, Na Zhang, Yang Meng, Song Mao, Huiling Ni, Canhua Huang, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4019799/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Feb, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract Aberrant O-GlcNAc cycling of the cancer proteome is a manifestation of its metabolic plasticity. As one of the most common cancer of the female genital tract associated with metabolic syndrome, endometrial cancer (EC) tissues often bear altered O-GlcNAcylation patterns. However, integration of O-GlcNAc status with existing histomorphologic and molecular subtypes of EC in large cohorts and identification of molecular modules controlling the O-GlcNAc homeostasis remain to be accomplished. Here we establish a positive correlation of O-GlcNAcylation with histologic grade of EC in a Chinese cohort containing 219 tumors and consolidate it in The Cancer Genome Atlas (TCGA) EC dataset. Higher O-GlcNAc level is associated with less pathological differentiation and poorer prognosis. Functionally, increasing O-GlcNAcylation promotes proliferation and stem-like cell properties in normal endometrial epithelial organoids (EE-Os), whereas decreasing O-GlcNAcylation limits the growth of endometrial cancer organoids (EC-Os). Using genome-wide CRISPR screen, we further identify that the F-box only protein 31 ( FBXO31 ), whose loss of heterozygosity is frequently observed in cancer, regulates O-GlcNAc homeostasis. FBXO31 acts as a substrate receptor of the SCF ubiquitin ligase complex to ubiquitinate the O-GlcNAc transferase OGT. Loss of FBXO31 results in accumulation of OGT and upregulation of O-GlcNAcylation in EC. Our study highlights the O-GlcNAcylation as a useful stratification marker and potential therapeutic target for the advanced, poorly differentiated EC cases. Biological sciences/Cancer/Gynaecological cancer/Endometrial cancer Biological sciences/Cell biology/Post-translational modifications/Glycosylation Full Text Additional Declarations There is NO Competing Interest. Supplementary Files Supplementarytable1.xlsx Supplementary Table 1 Supplementarytable2.xlsx Supplementary Table 2 Supplementarytable3.xlsx Supplementary Table 3 Supplementarytable4.xlsx Supplementary Table 4 Supplementarytable5.xlsx Supplementary Table 5 Supplementarytable6.xlsx Supplementary Table 6 Supplementarytable7.xlsx Supplementary Table 7 Supplementarytable8.xlsx Supplementary Table 8 Supplementarytable9.xlsx Supplementary Table 9 Cite Share Download PDF Status: Published Journal Publication published 02 Feb, 2025 Read the published version in Nature Communications → 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. 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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-4019799","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":280780252,"identity":"0fb3a3af-a953-496c-af16-5c7a769cbaec","order_by":0,"name":"Kai 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Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4019799/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4019799/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAberrant O-GlcNAc cycling of the cancer proteome is a manifestation of its metabolic plasticity. As one of the most common cancer of the female genital tract associated with metabolic syndrome, endometrial cancer (EC) tissues often bear altered O-GlcNAcylation patterns. However, integration of O-GlcNAc status with existing histomorphologic and molecular subtypes of EC in large cohorts and identification of molecular modules controlling the O-GlcNAc homeostasis remain to be accomplished. Here we establish a positive correlation of O-GlcNAcylation with histologic grade of EC in a Chinese cohort containing 219 tumors and consolidate it in The Cancer Genome Atlas (TCGA) EC dataset. Higher O-GlcNAc level is associated with less pathological differentiation and poorer prognosis. Functionally, increasing O-GlcNAcylation promotes proliferation and stem-like cell properties in normal endometrial epithelial organoids (EE-Os), whereas decreasing O-GlcNAcylation limits the growth of endometrial cancer organoids (EC-Os). Using genome-wide CRISPR screen, we further identify that the \u003cem\u003eF-box only protein 31\u003c/em\u003e (\u003cem\u003eFBXO31\u003c/em\u003e), whose loss of heterozygosity is frequently observed in cancer, regulates O-GlcNAc homeostasis. FBXO31 acts as a substrate receptor of the SCF ubiquitin ligase complex to ubiquitinate the O-GlcNAc transferase OGT. Loss of FBXO31 results in accumulation of OGT and upregulation of O-GlcNAcylation in EC. Our study highlights the O-GlcNAcylation as a useful stratification marker and potential therapeutic target for the advanced, poorly differentiated EC cases.\u003c/p\u003e","manuscriptTitle":"Impairment of FBXO31-mediated Ubiquitination of OGT Upregulates O-GlcNAcylation to Advance Endometrial Malignancy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-12 04:21:07","doi":"10.21203/rs.3.rs-4019799/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"e1a90f12-71ed-4a62-87b7-96e93d3581aa","owner":[],"postedDate":"April 12th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":29562713,"name":"Biological sciences/Cancer/Gynaecological cancer/Endometrial cancer"},{"id":29562714,"name":"Biological sciences/Cell biology/Post-translational modifications/Glycosylation"}],"tags":[],"updatedAt":"2025-02-03T08:05:39+00:00","versionOfRecord":{"articleIdentity":"rs-4019799","link":"https://doi.org/10.1038/s41467-025-56633-z","journal":{"identity":"nature-communications","isVorOnly":false,"title":"Nature Communications"},"publishedOn":"2025-02-02 05:00:00","publishedOnDateReadable":"February 2nd, 2025"},"versionCreatedAt":"2024-04-12 04:21:07","video":"","vorDoi":"10.1038/s41467-025-56633-z","vorDoiUrl":"https://doi.org/10.1038/s41467-025-56633-z","workflowStages":[]},"version":"v1","identity":"rs-4019799","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4019799","identity":"rs-4019799","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}