BAP1 is a novel regulator of HIF-1α

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dc.citation.articleNumbere2217840120
dc.citation.issueNumber4
dc.citation.journalTitleProceedings of the National Academy of Sciences
dc.citation.volumeNumber120
dc.contributor.authorBononi, Angela
dc.contributor.authorWang, Qian
dc.contributor.authorZolondick, Alicia A.
dc.contributor.authorBai, Fang
dc.contributor.authorSteele-Tanji, Mika
dc.contributor.authorSuarez, Joelle S.
dc.contributor.authorPastorino, Sandra
dc.contributor.authorSipes, Abigail
dc.contributor.authorSignorato, Valentina
dc.contributor.authorFerro, Angelica
dc.contributor.authorNovelli, Flavia
dc.contributor.authorKim, Jin-Hee
dc.contributor.authorMinaai, Michael
dc.contributor.authorTakinishi, Yasutaka
dc.contributor.authorPellegrini, Laura
dc.contributor.authorNapolitano, Andrea
dc.contributor.authorXu, Ronghui
dc.contributor.authorFarrar, Christine
dc.contributor.authorGoparaju, Chandra
dc.contributor.authorBassi, Cristian
dc.contributor.authorNegrini, Massimo
dc.contributor.authorPagano, Ian
dc.contributor.authorSakamoto, Greg
dc.contributor.authorGaudino, Giovanni
dc.contributor.authorPass, Harvey I.
dc.contributor.authorOnuchic, José N.
dc.contributor.authorYang, Haining
dc.contributor.authorCarbone, Michele
dc.contributor.orgCenter for Theoretical Biological Physics
dc.date.accessioned2023-02-23T18:46:13Z
dc.date.available2023-02-23T18:46:13Z
dc.date.issued2023
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.
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.
dc.identifier.digitalpnas-2217840120
dc.identifier.doihttps://doi.org/10.1073/pnas.2217840120
dc.identifier.urihttps://hdl.handle.net/1911/114478
dc.language.isoeng
dc.publisherPNAS
dc.rightsThis article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.titleBAP1 is a novel regulator of HIF-1α
dc.typeJournal article
dc.type.dcmiText
dc.type.publicationpublisher version
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