BAP1 modulates crucial cellular pathways that regulate genomic stability and cell death. BAP1 mutations on the one hand favor malignant transformation and mesothelioma development; on the other hand, they reduce mesothelioma aggressiveness. Investigating this apparent paradox, we discovered that BAP1 deubiquitylates and stabilizes HIF-1α in hypoxia; thus, BAP1 inactivating mutations significantly reduce HIF-1α. Given the critical role of HIF-1α in promoting tumor invasion, we propose that: 1) Reduced BAP1 in the tumor cells and tumor microenvironment of individuals carrying germline BAP1 mutations may contribute to the reduced invasion and the significantly improved prognosis of mesothelioma; 2) targeting wild-type BAP1 after tumor development could be a novel effective strategy to reduce HIF-1α protein levels in hypoxic tissues and impair tumor growth.
Angela Bononi, Qian Wang, Alicia A. Zolondick, Fang Bai, Mika Steele-Tanji, Joelle S. Suarez, Sandra Pastorino, Abigail Sipes, Valentina Signorato, Angelica Ferro, Flavia Novelli, Jin-Hee Kim, Michael Minaai, Yasutaka Takinishi, Laura Pellegrini, Andrea Napolitano, Ronghui Xu, Christine Farrar, Chandra Goparaju, Cristian Bassi, Massimo Negrini, Ian Pagano, Greg Sakamoto, Giovanni Gaudino, Harvey I. Pass, José N. Onuchic, Haining Yang, and Michele Carbone.