BMAL1-HIF2α heterodimers contribute to ccRCC

BMAL1-HIF2α heterodimers contribute to ccRCC | 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 BMAL1-HIF2α heterodimers contribute to ccRCC Katja A Lamia, Rebecca Mello, Diego Gomez Ceballos, Colby Sandate, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4651047/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 Jul, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract Circadian disruption enhances cancer risk, and many tumors exhibit disordered circadian gene expression. We show rhythmic gene expression is unexpectedly robust in clear cell renal cell carcinoma (ccRCC). Furthermore, the clock gene BMAL1 is higher in ccRCC than in healthy kidneys, unlike in other tumor types. BMAL1 is closely related to ARNT, and we show that BMAL1-HIF2α regulates a subset of HIF2α target genes in ccRCC cells. Depletion of BMAL1 reprograms HIF2α chromatin association and target gene expression and reduces ccRCC growth in culture and in xenografts. Analysis of pre-existing data reveals higher BMAL1 in patient-derived xenografts that are sensitive to growth suppression by a HIF2α antagonist (PT2399). We show that BMAL1-HIF2α is more sensitive than ARNT-HIF2α to suppression by PT2399, and increasing BMAL1 sensitizes 786O cells to growth inhibition by PT2399. Together, these findings indicate that an alternate HIF2α heterodimer containing the circadian partner BMAL1 contributes to HIF2α activity, growth, and sensitivity to HIF2α antagonist drugs in ccRCC cells. Biological sciences/Cell biology/Circadian rhythms Biological sciences/Cancer/Urological cancer/Renal cancer Full Text Additional Declarations There is NO Competing Interest. Supplementary Files Mello062624Supplement.docx rs.pdf Reporting Summary Cite Share Download PDF Status: Published Journal Publication published 01 Jul, 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. 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-4651047","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":326231388,"identity":"31040ce6-68c5-4ca3-9da6-33b6ec2ba7d6","order_by":0,"name":"Katja A Lamia","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA00lEQVRIiWNgGAWjYBACCXYgkcBgAyQZGyBCBwhpYQZrSSNVCwPDYSQhQlokm5mfbnhQc96ef/bhtscFfxjk+G4k4NcizcxmdiPh2O3EGecS241ntjEYSxLSIsfMANTCdjvBgIexTZq3gSFxA2Et7N9uJPw7Zw/WwvOHoZ6gFmlmHrMbiW0HGDeAtbAxJBgQ0iLZzFN2I7EvOXHGGUaQXyQMZ555gF+LxPH2bTd/fLOz5+9hfwYMMRt5vuMEbEEGbMA4kiBeOUzLKBgFo2AUjAJMAAAjaEJp9tx1pwAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0001-9533-0499","institution":"Scripps Research","correspondingAuthor":true,"prefix":"","firstName":"Katja","middleName":"A","lastName":"Lamia","suffix":""},{"id":326231389,"identity":"a91f0d00-b95b-4c75-bcf7-b084ea562065","order_by":1,"name":"Rebecca Mello","email":"","orcid":"https://orcid.org/0000-0002-2397-6693","institution":"Scripps Research","correspondingAuthor":false,"prefix":"","firstName":"Rebecca","middleName":"","lastName":"Mello","suffix":""},{"id":326231390,"identity":"1367ddb1-54eb-4449-ae4a-c8b04ea0e784","order_by":2,"name":"Diego Gomez Ceballos","email":"","orcid":"https://orcid.org/0009-0001-6176-2573","institution":"Scripps Research","correspondingAuthor":false,"prefix":"","firstName":"Diego","middleName":"Gomez","lastName":"Ceballos","suffix":""},{"id":326231391,"identity":"2a863b94-9d70-48bd-8b39-f8d4fe9bcf8e","order_by":3,"name":"Colby Sandate","email":"","orcid":"","institution":"Friedrich Miescher Institute for Biomedical Research","correspondingAuthor":false,"prefix":"","firstName":"Colby","middleName":"","lastName":"Sandate","suffix":""},{"id":326231392,"identity":"d3c9e5ac-3010-4442-b36f-f6918f8e8aec","order_by":4,"name":"Daniel Agudelo","email":"","orcid":"","institution":"Institute for Diabetes and Endocrinology (IDE), Helmholtz Munich","correspondingAuthor":false,"prefix":"","firstName":"Daniel","middleName":"","lastName":"Agudelo","suffix":""},{"id":326231393,"identity":"8e8a8082-8c9e-450a-9a74-2e8b7c687bb3","order_by":5,"name":"Celine Jouffe","email":"","orcid":"https://orcid.org/0000-0002-7176-4724","institution":"Institute for Diabetes and Endocrinology (IDE), Helmholtz Munich","correspondingAuthor":false,"prefix":"","firstName":"Celine","middleName":"","lastName":"Jouffe","suffix":""},{"id":326231394,"identity":"50521f16-c209-4d2a-8d06-99bc1a6e2342","order_by":6,"name":"Nina Uhlenhaut","email":"","orcid":"","institution":"Institute for Diabetes and Endocrinology (IDE), Helmholtz Munich","correspondingAuthor":false,"prefix":"","firstName":"Nina","middleName":"","lastName":"Uhlenhaut","suffix":""},{"id":326231395,"identity":"2b40594d-6c32-4a60-b9d9-a4315d93ee27","order_by":7,"name":"Nicolas Thoma","email":"","orcid":"","institution":"Friedrich Miescher Institute for Biomedical Research","correspondingAuthor":false,"prefix":"","firstName":"Nicolas","middleName":"","lastName":"Thoma","suffix":""},{"id":326231396,"identity":"f5588b5a-4932-4001-8fe1-c9c5172430a1","order_by":8,"name":"M.Celeste Simon","email":"","orcid":"https://orcid.org/0000-0001-9106-447X","institution":"UPenn","correspondingAuthor":false,"prefix":"","firstName":"M.Celeste","middleName":"","lastName":"Simon","suffix":""}],"badges":[],"createdAt":"2024-06-27 22:20:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4651047/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4651047/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41467-025-60904-0","type":"published","date":"2025-07-01T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":85827249,"identity":"09a9d12d-4c81-4a44-a1e8-3c8eae2fbe27","added_by":"auto","created_at":"2025-07-02 07:23:01","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1539039,"visible":true,"origin":"","legend":"","description":"","filename":"Mello062624Main.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4651047/v1_covered_bbc9e8b1-99fd-4639-a69d-57b81f2a2e04.pdf"},{"id":60360213,"identity":"051ac208-6834-4346-be1c-b69092ff0b1b","added_by":"auto","created_at":"2024-07-16 02:07:24","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":1405134,"visible":true,"origin":"","legend":"","description":"","filename":"Mello062624Supplement.docx","url":"https://assets-eu.researchsquare.com/files/rs-4651047/v1/b8e78c299e65dce9d3b0d92a.docx"},{"id":60360212,"identity":"9775588e-67d2-4793-a342-fe6b0808484b","added_by":"auto","created_at":"2024-07-16 02:07:24","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":105035,"visible":true,"origin":"","legend":"Reporting Summary","description":"","filename":"rs.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4651047/v1/dda8c16cd001a2bfa68150ed.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"BMAL1-HIF2α heterodimers contribute to ccRCC","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4651047/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4651047/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Circadian disruption enhances cancer risk, and many tumors exhibit disordered circadian gene expression. We show rhythmic gene expression is unexpectedly robust in clear cell renal cell carcinoma (ccRCC). Furthermore, the clock gene BMAL1 is higher in ccRCC than in healthy kidneys, unlike in other tumor types. BMAL1 is closely related to ARNT, and we show that BMAL1-HIF2α regulates a subset of HIF2α target genes in ccRCC cells. Depletion of BMAL1 reprograms HIF2α chromatin association and target gene expression and reduces ccRCC growth in culture and in xenografts. Analysis of pre-existing data reveals higher BMAL1 in patient-derived xenografts that are sensitive to growth suppression by a HIF2α antagonist (PT2399). We show that BMAL1-HIF2α is more sensitive than ARNT-HIF2α to suppression by PT2399, and increasing BMAL1 sensitizes 786O cells to growth inhibition by PT2399. Together, these findings indicate that an alternate HIF2α heterodimer containing the circadian partner BMAL1 contributes to HIF2α activity, growth, and sensitivity to HIF2α antagonist drugs in ccRCC cells.","manuscriptTitle":"BMAL1-HIF2α heterodimers contribute to ccRCC","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-16 02:07:19","doi":"10.21203/rs.3.rs-4651047/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":"79741107-2345-4a39-9c8f-871cea511224","owner":[],"postedDate":"July 16th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":34524389,"name":"Biological sciences/Cell biology/Circadian rhythms"},{"id":34524390,"name":"Biological sciences/Cancer/Urological cancer/Renal cancer"}],"tags":[],"updatedAt":"2025-07-02T07:22:54+00:00","versionOfRecord":{"articleIdentity":"rs-4651047","link":"https://doi.org/10.1038/s41467-025-60904-0","journal":{"identity":"nature-communications","isVorOnly":false,"title":"Nature Communications"},"publishedOn":"2025-07-01 04:00:00","publishedOnDateReadable":"July 1st, 2025"},"versionCreatedAt":"2024-07-16 02:07:19","video":"","vorDoi":"10.1038/s41467-025-60904-0","vorDoiUrl":"https://doi.org/10.1038/s41467-025-60904-0","workflowStages":[]},"version":"v1","identity":"rs-4651047","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4651047","identity":"rs-4651047","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}