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

Area of Science:

• Oncology
• Molecular Biology
• Environmental Health

Background:

• Germline BAP1 mutations define BAP1 cancer syndrome, increasing cancer risk.
• Asbestos exposure is a known carcinogen, particularly for mesothelioma.
• Chronic inflammation and HMGB1 release are implicated in asbestos carcinogenesis.

Purpose of the Study:

• Investigate the mechanism by which BAP1 mutations cooperate with asbestos in carcinogenesis.
• Determine the role of HMGB1 in BAP1-associated asbestos susceptibility.
• Elucidate the molecular interaction between BAP1, HMGB1, and HDAC1.

Main Methods:

• Analysis of HMGB1 secretion in BAP1+/- cells.
• Detection of serum HMGB1 levels in BAP1+/- carriers and mesothelioma patients.
• Identification of a BAP1-HMGB1-HDAC1 protein complex.
• Assessment of HDAC1 stability and HMGB1 acetylation upon BAP1 reduction.

Main Results:

• BAP1+/- cells exhibit increased HMGB1 secretion.
• Elevated serum HMGB1, particularly acetylated forms, observed in BAP1+/- carriers and mesothelioma patients.
• BAP1 forms a complex with HMGB1 and HDAC1, regulating HMGB1 acetylation.
• Reduced BAP1 leads to HDAC1 degradation, increased HMGB1 acetylation, and enhanced secretion.

Conclusions:

• BAP1 deficiency promotes HMGB1 secretion via HDAC1 dysregulation.
• This mechanism explains the heightened susceptibility to asbestos-induced mesothelioma in BAP1 mutation carriers.
• Targeting the BAP1-HMGB1-HDAC1 axis may offer therapeutic strategies for BAP1 cancer syndrome.