Preventive and therapeutic opportunities: targeting BAP1 and/or HMGB1 pathways to diminish the burden of mesothelioma

Abstract

Mesothelioma is a cancer typically caused by asbestos. Mechanistically, asbestos carcinogenesis has been linked to the asbestos-induced release of HMGB1 from the nucleus to the cytoplasm, where HMGB1 promotes autophagy and cell survival, and to the extracellular space where HMGB1 promotes chronic inflammation and mesothelioma growth. Targeting HMGB1 inhibited asbestos carcinogenesis and the growth of mesothelioma. It is hoped that targeting HMGB1 will be a novel therapeutic strategy that benefits mesothelioma patients. Severe restrictions and/or a complete ban on the use of asbestos were introduced in the 80 and early 90s in the Western world. These measures have proven effective as the incidence of mesothelioma/per 100,000 persons is decreasing in these countries. However, the overall number of mesotheliomas in the Western world has not significantly decreased. There are several reasons for that which are discussed here: (1) the presence of asbestos in old constructions; (2) the development of rural areas containing asbestos or other carcinogenic mineral fibers in the terrain; (3) the discovery of an increasing fraction of mesotheliomas caused by germline genetic mutations of BAP1 and other tumor suppressor genes; (4) mesotheliomas caused by radiation therapy; (5) the overall increase in the population and of the fraction of older people who are much more susceptible to develop all types of cancers, including mesothelioma. In summary, the epidemiology of mesothelioma is changing, the ban on asbestos worked, there are opportunities to help mesothelioma patients especially those who develop in a background of germline mutations and there is the opportunity to prevent a mesothelioma epidemic in the developing world, where the use of asbestos is increasing exponentially. We hope that restrictive measures similar to those introduced in the Western world will soon be introduced in developing countries to prevent a mesothelioma epidemic.

Fig. 1

Diagram showing the regulation of chronic inflammation and cell transformation by the BAP1, HDAC1, and HMGB1 trimer. Asbestos causes mesothelial cell death that in turn leads to the release of HMGB1 from the nucleus to the extracellular space, where HMGB1 acts as a DAMP recruiting macrophages and other inflammatory cells. Macrophages actively secrete HMGB1 and TNF-α propagating inflammation around asbestos deposits in tissue, a process that over time can cause malignant transformation and mesothelioma. A similar process takes place in mesothelial cells carrying germline BAP1 mutations (BAP1^+/−), depicted at the bottom of the figure, even in the absence of asbestos exposure. In BAP1 wild-type (WT) cells, nuclear BAP1 deubiquitylates and stabilizes HDAC1, which deacetylates HMGB1: deacetylated HMGB1 remains in the nucleus. In BAP1^+/− cells, the reduced BAP1 levels cause HDAC1 ubiquitylation and degradation. This, in turn, causes increased acetylation of HMGB1. Acetylated HMGB1 moves to the cytoplasm where it activates autophagy, and from there to the extracellular space where HMGB1 propagates chronic information that favors malignant transformation and mesothelioma growth. The combination of asbestos exposure and BAP1 germline mutations can cooperate in propagating chronic inflammation and malignant transformation [21]. Created with BioRender.com

Fig. 2

BAP1 regulation of HIF-1α. HIF-1α is a key regulator of the adaptive response to a hypoxic environment and tumor cell invasion. HIF-1α is ubiquitylated in normoxia and it is degraded via an oxygen-dependent mechanism mediated by VHL. In the nucleus BAP1 binds, deubiquitylates, and stabilizes HIF-1α. In BAP1^+/− carriers during hypoxia, the lack or reduced presence of BAP1 is accompanied by a significant reduction of HIF-1α which may contribute to the reduced aggressiveness of tumors. Created with BioRender.com