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

被引：25

作者：

Novelli, Flavia ^{[1
]}

Bononi, Angela ^{[1
]}

Wang, Qian ^{[2
,3
]}

Bai, Fang ^{[2
]}

Patergnani, Simone ^{[4
]}

Kricek, Franz ^{[5
]}

Haglund, Ellinor ^{[6
]}

Suarez, Joelle S. ^{[1
]}

Tanji, Mika ^{[1
]}

Xu, Ronghui ^{[1
]}

Takanishi, Yasutaka ^{[1
]}

Minaai, Michael ^{[1
]}

Pastorino, Sandra ^{[1
]}

Morris, Paul ^{[1
]}

Sakamoto, Greg ^{[1
]}

Pass, Harvey, I ^{[7
]}

Barbour, Haithem ^{[8
]}

Gaudino, Giovanni ^{[1
]}

Giorgi, Carlotta ^{[4
]}

Pinton, Paolo ^{[4
]}

Onuchic, Jose N. ^{[2
]}

Yang, Haining ^{[1
]}

Carbone, Michele ^{[1
]}

机构：

[1] Univ Hawaii, Thorac Oncol, Canc Ctr, Honolulu, HI 96816 USA

[2] Rice Univ, Ctr Theoret Biol Phys, Houston, TX 77005 USA

[3] Univ Sci & Technol China, Dept Phys, Hefei Natl Lab Phys Sci Microscale, Hefei 230026, Anhui, Peoples R China

[4] Univ Ferrara, Dept Med Sci, Lab Technol Adv Therapies, I-44121 Ferrara, Italy

[5] NBS C BioSci & Consulting GmbH, A-1230 Vienna, Austria

[6] Univ Hawaii, Dept Chem, Honolulu, HI 96822 USA

[7] NYU, Dept Cardiothorac Surg, New York, NY 10016 USA

[8] Univ Montreal, Dept Med, Montreal, PQ H1T 2M4, Canada

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2021年 / 118卷 / 48期

基金：

欧洲研究理事会;

关键词：

mesothelioma; gene x environment; germline BAP1 mutations; asbestos; HMGB1; GROUP BOX 1; HUMAN MESOTHELIAL CELLS; MOBILITY GROUP BOX-1; CHROMATIN PROTEIN HMGB1; STRUCTURE PREDICTION; TRANSFORMATION; INFLAMMATION; EXPOSURE; RELEASE; MICE;

D O I：

10.1073/pnas.2111946118

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：11

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