BAP1 is a novel regulator of HIF-1α.

Abstract

<i>BAP1</i> is a powerful tumor suppressor gene characterized by haplo insufficiency. Individuals carrying germline <i>BAP1</i> 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 <i>BAP1</i> 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 <i>BAP1</i> mutations showed loss of nuclear HIF-1α staining. We demonstrated that during hypoxia, <i>BAP1</i> binds, deubiquitylates, and stabilizes HIF-1α, the master regulator of the hypoxia response and tumor cell invasion. Moreover, primary cells from individuals carrying germline <i>BAP1</i> mutations and primary cells in which <i>BAP1</i> was silenced using siRNA had reduced HIF-1α protein levels in hypoxia. Computational modeling and co-immunoprecipitation experiments revealed that mutations of <i>BAP1</i> 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 <i>BAP1</i> 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 <i>BAP1</i> 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 <i>BAP1</i> mutations, accompanied by the significant reduction of HIF-1α activity in hypoxic tissues containing germline <i>BAP1</i> mutations, contributes to the reduced aggressiveness and improved survival of mesotheliomas developing in carriers of germline <i>BAP1</i> mutations.