BAP1 is a novel regulator of HIF-1α
Abstract
BAP1 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 19, 2023
- Source ID
- 10.1073/pnas.2217840120
Entities
People
- Abigail Sipes
- Alicia A. Zolondick
- Andrea Napolitano
- Angela Bononi
- Angelica Ferro
- Chandra Goparaju
- Christine E Farrar
- Cristian Bassi
- Fang Bai
- Flavia Novelli
- Giovanni Gaudino
- Greg Sakamoto
- Haining Yang
- Harvey I Pass
- Ian Pagano
- Jin-hee Kim
- Joelle D Sacks
- José Onuchic
- Laura Pellegrini
- Massimo Negrini
- Michael Minaai
- Michele Carbone
- Mika Steele-tanji
- Qian Wang
- Ronghui Xu
- Sandra Pastorino
- Valentina Signorato
- Yasutaka Takinishi
Organizations
- National Cancer Institute
- National Institute of Environmental Health Sciences
- National Science Foundation
- New York University
- Rice University
- Robert A. Welch Foundation
- ShanghaiTech University
- United States Department of Defense
- University of Ferrara
- University of Hawaiʻi System
- University of Hawaiʻi at Mānoa
- University of Science and Technology of China