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

Our plain-English summary of BAP1 forms a trimer with HMGB1 and HDAC1 that modulates gene × environment interaction with asbestos, by F. Novelli, A. Bononi, Q. Wang, et al (Proceedings of the National Academy of Sciences of the United States of America, 2021).

The study

• Authors: F. Novelli, A. Bononi, Q. Wang, F. Bai, S. Patergnani, F. Kricek, E. Haglund, J.S. Suarez, M. Tanji, R. Xu, Y. Takanishi, M. Minaai, S. Pastorino, P. Morris, G. Sakamoto, H.I. Pass, H. Barbour, G. Gaudino, C. Giorgi, P. Pinton, J.N. Onuchic, H. Yang, M. Carbone
• Journal: Proceedings of the National Academy of Sciences of the United States of America
• Published: 2021;118(48)
• Cited by: 32 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

In plain English

This laboratory study combined molecular and cell experiments with a mouse carcinogenesis experiment and computational modelling to ask how heterozygous germline BAP1 mutations (BAP1+/-) interact with asbestos. In skin fibroblasts from BAP1+/- carriers of the Louisiana and Wisconsin families and matched BAP1 wild-type relatives, the authors detected BAP1-HMGB1 binding mainly in the nucleus, with fewer interaction signals in BAP1+/- cells; extranuclear HMGB1 was increased (P less than 0.001) and nuclear HMGB1 decreased (P less than 0.001) in BAP1+/- fibroblasts, and conditioned media from BAP1+/- fibroblasts contained more HMGB1, with increased acetyl-Lys12 HMGB1 shown in pairs of fibroblasts from Louisiana family members. BAP1+/- fibroblasts had reduced HDAC1 protein and HDAC activity, and BAP1 deubiquitylated HDAC1 in vitro. Surface plasmon resonance gave BAP1-HMGB1 affinity 3.8 plus or minus 1.5 nM and BAP1-HDAC1 17.1 plus or minus 7.7 nM. Silencing BAP1 increased transformation of human mesothelial cells exposed to crocidolite in the presence of TNFalpha, which BoxA, ethyl pyruvate and aspirin reduced. In crocidolite-injected Bap1+/- mice, mesothelioma occurred in 25 of 65 aspirin-treated versus 39 of 63 untreated mice (P = 0.0130).

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: human cell and protein experiments (proximity ligation, co-immunoprecipitation, ELISA, immunoblot, ubiquitylation and transformation assays, surface plasmon resonance), computational modelling, plus an in vivo asbestos-injection experiment in Bap1 mutant mice
• Who was studied: Primary skin fibroblasts and serum from BAP1+/- carriers and age- and gender-matched BAP1 wild-type members of the Louisiana and Wisconsin mesothelioma families; primary human mesothelial cells, THP-differentiated macrophages, HEK293 cells, mesothelioma cell lines HP-3 and H2373; 150 Bap1+/- mice (two groups of 75)
• Exposure: Crocidolite asbestos: 5 micrograms per square centimetre with TNFalpha in the cell transformation assay; in mice ten weekly 0.05-mg intraperitoneal injections (0.5 mg total), with or without aspirin chow (400 ppm)
• Main results:
  • BAP1 and HMGB1 interacted mainly in the nucleus, with significantly fewer PLA signals per cell in BAP1+/- fibroblasts than in BAP1 wild-type fibroblasts
  • In co-immunoprecipitation, full-length BAP1 and the catalytically inactive BAP1(C91S) bound HMGB1, while the truncated BAP1(L) and BAP1(W) mutants did not
  • Extranuclear HMGB1 was increased (P less than 0.001) and nuclear HMGB1 decreased (P less than 0.001) in fibroblasts from BAP1+/- carriers compared with BAP1 wild-type fibroblasts
  • In pairs of fibroblasts from Louisiana family members, conditioned media from BAP1+/- cells contained increased acetyl-Lys12 HMGB1 and HMGB1 compared with BAP1 wild-type cells
  • Serum HMGB1 and acetylated HMGB1 were slightly higher in BAP1+/- carriers than in BAP1 wild-type family members, with a large increase in one carrier at mesothelioma relapse
  • BAP1+/- fibroblasts had reduced HDAC1 protein, with no difference in HDAC4, and reduced nuclear HDAC activity
  • Surface plasmon resonance affinities: BAP1 to HMGB1 3.8 plus or minus 1.5 nM; BAP1 to HDAC1 17.1 plus or minus 7.7 nM; HMGB1 to HDAC1 24.1 plus or minus 14.4 nM
  • A preformed BAP1-HDAC1 complex bound immobilized HMGB1 with 1.2 plus or minus 0.7 nM affinity
  • In human mesothelial cells, BAP1 silencing with exposure to TNFalpha and crocidolite increased foci formation compared with controls
  • BoxA, ethyl pyruvate or aspirin reduced foci formation in BAP1-silenced human mesothelial cells
  • Among crocidolite-injected Bap1+/- mice, 38% (25 of 65) of aspirin-treated mice developed mesothelioma versus 62% (39 of 63) of untreated mice, P = 0.0130
  • Mesothelioma-specific survival was higher in aspirin-treated Bap1+/- mice (P = 0.0452, log-rank)
• The authors' conclusion: The authors concluded that their findings give a mechanistic explanation for the gene by environment interaction between BAP1 mutations, asbestos-induced chronic inflammation and carcinogenesis, and that interfering with these mechanisms reduced mesothelioma incidence in Bap1 mutant mice exposed to asbestos, a strategy they suggest might be effective in human carriers
• Limitations the authors state:
  • The authors state human specimens were limited, prompting validation in the mouse model
  • The authors note aspirin has other anti-inflammatory activities that may contribute to the mouse results
  • Mice were excluded from the analysis when death was unrelated to asbestos exposure

Topics

Medical terms in this study, explained in our Lexicon: BAP1, High Mobility Group Box 1 (HMGB1), BAP1 Tumor Predisposition Syndrome, Carcinogenesis, Mesothelioma, Discovery, Mesothelial Cells.

Related studies

• BAP1 regulates IP3R3-mediated Ca2+ flux to mitochondria suppressing cell transformation — A. Bononi, C. Giorgi, et al. (2017)
• Asbestos induces mesothelial cell transformation via HMGB1-driven autophagy — J. Xue, S. Patergnani, et al. (2020)
• Germline BARD1 variants predispose to mesothelioma by impairing DNA repair and calcium signaling — F. Novelli, Y. Yoshikawa, et al. (2024)
• HMGB1 released by mesothelial cells drives the development of asbestos-induced mesothelioma — J.S. Suarez, F. Novelli, et al. (2023)
• Germline BAP1 mutations induce a Warburg effect — A. Bononi, H. Yang, et al. (2017)
• Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma — A. Napolitano, L. Pellegrini, et al. (2016)

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