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

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.

Medical and Surgical Care of Patients With Mesothelioma and Their Relatives Carrying Germline BAP1 Mutations

“…Studies revealed significantly higher total and acetylated high-mobility group box 1 blood levels in patients with mesothelioma and in asbestos-exposed patients, compared with healthy controls, but this test relies on Western blotting, which is not suitable for screening, whereas validation of mass spectrometry and enzymelinked immunosorbent assay has proved difficult. 63 Fibulin-3, encoded by the SPP1 gene, is an extracellular glycoprotein expressed in most tissues in the early embryonic stage, and it is selectively elevated in patients with mesothelioma. Ongoing studies elucidated possible reasons for inconsistent readings depending on the tube that the blood is harvested owing to FBLN3 proteoloysis.…”

The Interplay of Hypoxia Signaling on Mitochondrial Dysfunction and Inflammation in Cardiovascular Diseases and Cancer: From Molecular Mechanisms to Therapeutic Approaches

“…High levels of HIF-1α protein increase the susceptibility to ferroptosis in renal carcinoma cells [ 231 , 232 ]. Notably, the tumor suppressor BRCA1-associated protein 1 (BAP1) is involved in apoptosis and ferroptosis in different cancer cells [ 233 , 234 ]. It has been demonstrated the role of BAP1 in attenuating cancer development by provoking the ferroptosis event via solute carrier family 7-member 11 (SLC7A11) inhibition [ 235 ].…”

Inflammation of the Pleural Cavity: A Review on Pathogenesis, Diagnosis and Implications in Tumor Pathophysiology

“…It is well-known that asbestos fibers induce mesothelial cell carcinogenesis through prolonged tissue damage, inflammation and repair, with various mechanisms being proposed as implicated in this carcinogenesis, including the induction of a pro-tumoral inflammation in the pleural cavity [82,96]. The high mobility group box 1 (HMGB1) protein released by mesothelial cells and macrophages after asbestos exposure promotes chronic inflammation [97] but also induces autophagy in mesothelial cells promoting their survival and malignant transformation [98]. Besides, carriers of the heterozygous germline BAP1 mutation can be affected by any cancer type, but they are mostly susceptible to asbestos carcinogenesis and develop mesotheliomas, a "preference" suggested to be attributed to the higher amounts of HMGB1 secreted by these mutant cells [97].…”

“…The high mobility group box 1 (HMGB1) protein released by mesothelial cells and macrophages after asbestos exposure promotes chronic inflammation [97] but also induces autophagy in mesothelial cells promoting their survival and malignant transformation [98]. Besides, carriers of the heterozygous germline BAP1 mutation can be affected by any cancer type, but they are mostly susceptible to asbestos carcinogenesis and develop mesotheliomas, a "preference" suggested to be attributed to the higher amounts of HMGB1 secreted by these mutant cells [97].…”