BAP1 is a novel regulator of HIF-1α

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dc.citation.articleNumbere2217840120en_US
dc.citation.issueNumber4en_US
dc.citation.journalTitleProceedings of the National Academy of Sciencesen_US
dc.citation.volumeNumber120en_US
dc.contributor.authorBononi, Angelaen_US
dc.contributor.authorWang, Qianen_US
dc.contributor.authorZolondick, Alicia A.en_US
dc.contributor.authorBai, Fangen_US
dc.contributor.authorSteele-Tanji, Mikaen_US
dc.contributor.authorSuarez, Joelle S.en_US
dc.contributor.authorPastorino, Sandraen_US
dc.contributor.authorSipes, Abigailen_US
dc.contributor.authorSignorato, Valentinaen_US
dc.contributor.authorFerro, Angelicaen_US
dc.contributor.authorNovelli, Flaviaen_US
dc.contributor.authorKim, Jin-Heeen_US
dc.contributor.authorMinaai, Michaelen_US
dc.contributor.authorTakinishi, Yasutakaen_US
dc.contributor.authorPellegrini, Lauraen_US
dc.contributor.authorNapolitano, Andreaen_US
dc.contributor.authorXu, Ronghuien_US
dc.contributor.authorFarrar, Christineen_US
dc.contributor.authorGoparaju, Chandraen_US
dc.contributor.authorBassi, Cristianen_US
dc.contributor.authorNegrini, Massimoen_US
dc.contributor.authorPagano, Ianen_US
dc.contributor.authorSakamoto, Gregen_US
dc.contributor.authorGaudino, Giovannien_US
dc.contributor.authorPass, Harvey I.en_US
dc.contributor.authorOnuchic, José N.en_US
dc.contributor.authorYang, Hainingen_US
dc.contributor.authorCarbone, Micheleen_US
dc.contributor.orgCenter for Theoretical Biological Physicsen_US
dc.date.accessioned2023-02-23T18:46:13Zen_US
dc.date.available2023-02-23T18:46:13Zen_US
dc.date.issued2023en_US
dc.description.abstractBAP1 is a powerful tumor suppressor gene characterized by haplo insufficiency. Individuals carrying germline BAP1 mutations often develop mesothelioma, an aggressive malignancy of the serosal layers covering the lungs, pericardium, and abdominal cavity. Intriguingly, mesotheliomas developing in carriers of germline BAP1 mutations are less aggressive, and these patients have significantly improved survival. We investigated the apparent paradox of a tumor suppressor gene that, when mutated, causes less aggressive mesotheliomas. We discovered that mesothelioma biopsies with biallelic BAP1 mutations showed loss of nuclear HIF-1α staining. We demonstrated that during hypoxia, BAP1 binds, deubiquitylates, and stabilizes HIF-1α, the master regulator of the hypoxia response and tumor cell invasion. Moreover, primary cells from individuals carrying germline BAP1 mutations and primary cells in which BAP1 was silenced using siRNA had reduced HIF-1α protein levels in hypoxia. Computational modeling and co-immunoprecipitation experiments revealed that mutations of BAP1 residues I675, F678, I679, and L691 -encompassing the C-terminal domain-nuclear localization signal- to A, abolished the interaction with HIF-1α. We found that BAP1 binds to the N-terminal region of HIF-1α, where HIF-1α binds DNA and dimerizes with HIF-1β forming the heterodimeric transactivating complex HIF. Our data identify BAP1 as a key positive regulator of HIF-1α in hypoxia. We propose that the significant reduction of HIF-1α activity in mesothelioma cells carrying biallelic BAP1 mutations, accompanied by the significant reduction of HIF-1α activity in hypoxic tissues containing germline BAP1 mutations, contributes to the reduced aggressiveness and improved survival of mesotheliomas developing in carriers of germline BAP1 mutations.en_US
dc.identifier.citationBononi, Angela, Wang, Qian, Zolondick, Alicia A., et al.. "BAP1 is a novel regulator of HIF-1α." <i>Proceedings of the National Academy of Sciences,</i> 120, no. 4 (2023) PNAS: https://doi.org/10.1073/pnas.2217840120.en_US
dc.identifier.digitalpnas-2217840120en_US
dc.identifier.doihttps://doi.org/10.1073/pnas.2217840120en_US
dc.identifier.urihttps://hdl.handle.net/1911/114478en_US
dc.language.isoengen_US
dc.publisherPNASen_US
dc.rightsThis article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).en_US
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/en_US
dc.titleBAP1 is a novel regulator of HIF-1αen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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