BAP1 forms a trimer with HMGB1 and HDAC1 that modulates gene × environment interaction with asbestos

Proceeding of the National Academy of Sciences of the United States of America 2021 November 30 [Link]

Flavia Novelli, Angela Bononi, Qian Wang, Fang Bai, Simone Patergnani, Franz Kricek, Ellinor Haglund, Joelle S Suarez, Mika Tanji, Ronghui Xu, Yasutaka Takanishi, Michael Minaai, Sandra Pastorino, Paul Morris, Greg Sakamoto, Harvey I Pass, Haithem Barbour, Giovanni Gaudino, Carlotta Giorgi, Paolo Pinton, Jose N Onuchic, Haining Yang, Michele Carbone


Carriers of heterozygous germline BAP1 mutations (BAP1 +/-) are affected by the “BAP1 cancer syndrome.” Although they can develop almost any cancer type, they are unusually susceptible to asbestos carcinogenesis and mesothelioma. Here we investigate why among all carcinogens, BAP1 mutations cooperate with asbestos. Asbestos carcinogenesis and mesothelioma have been linked to a chronic inflammatory process promoted by the extracellular release of the high-mobility group box 1 protein (HMGB1). We report that BAP1 +/- cells secrete increased amounts of HMGB1, and that BAP1 +/- carriers have detectable serum levels of acetylated HMGB1 that further increase when they develop mesothelioma. We linked these findings to our discovery that BAP1 forms a trimeric protein complex with HMGB1 and with histone deacetylase 1 (HDAC1) that modulates HMGB1 acetylation and its release. Reduced BAP1 levels caused increased ubiquitylation and degradation of HDAC1, leading to increased acetylation of HMGB1 and its active secretion that in turn promoted mesothelial cell transformation.