Proceedings of the National Academy of Sciences of the United States of America · 2021
BAP1 forms a trimer with HMGB1 and HDAC1 that modulates gene × environment interaction with asbestos.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАПоддержка правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Novelli Flavia, Bononi Angela, Wang Qian, Bai Fang, Patergnani Simone, Kricek Franz, Haglund Ellinor, Suarez Joelle S, Tanji Mika, Xu Ronghui, Takanishi Yasutaka, Minaai Michael, Pastorino Sandra, Morris Paul, Sakamoto Greg, Pass Harvey I, Barbour Haithem, Gaudino Giovanni, Giorgi Carlotta, Pinton Paolo, Onuchic Jose N, Yang Haining, Carbone Michele
Аннотация
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.