BAP1 is a novel regulator of HIF-1

BAP1 is a powerful tumor suppressor gene characterized by haplo insufficiency. Individuals carrying germline BAP1 mutations often develop mesothelioma, an aggres-sive 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 inves-tigated 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-1 alpha staining. We demonstrated that during hypoxia, BAP1 binds, deubiquitylates, and stabilizes HIF-1 alpha, the master regulator of the hypoxia response and tumor cell invasion. Moreover, primary cells from individu-als carrying germline BAP1 mutations and primary cells in which BAP1 was silenced using siRNA had reduced HIF-1 alpha 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-1 alpha. We found that BAP1 binds to the N-terminal region of HIF-1 alpha, where HIF-1 alpha binds DNA and dimerizes with HIF-1 alpha forming the heterodimeric transactivating complex HIF. Our data identify BAP1 as a key positive regulator of HIF-1 alpha in hypoxia. We propose that the significant reduction of HIF-1 alpha activity in mesothelioma cells carrying biallelic BAP1 mutations, accompanied by the significant reduction of HIF-1 alpha 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.