Loss of the deubiquitylase BAP1 alters class I histone deacetylase expression and sensitivity of mesothelioma cells to HDAC inhibitors

Abstract

Histone deacetylases are important targets for cancer therapeutics, but their regulation is poorly understood. Our data show coordinated transcription of HDAC1 and HDAC2 in lung cancer cell lines, but suggest HDAC2 protein expression is cell-context specific. Through an unbiased siRNA screen we found that BRCA1-associated protein 1 (BAP1) regulates their expression, with HDAC2 reduced and HDAC1 increased in BAP1 depleted cells. BAP1 loss-of-function is increasingly reported in cancers including thoracic malignancies, with frequent mutation in malignant pleural mesothelioma. Endogenous HDAC2 directly correlates with BAP1 across a panel of lung cancer cell lines, and is downregulated in mesothelioma cell lines with genetic BAP1 inactivation. We find that BAP1 regulates HDAC2 by increasing transcript abundance, rather than opposing its ubiquitylation. Importantly, although total cellular HDAC activity is unaffected by transient depletion of HDAC2 or of BAP1 due to HDAC1 compensation, this isoenzyme imbalance sensitizes MSTO-211H cells to HDAC inhibitors. However, other established mesothelioma cell lines with low endogenous HDAC2 have adapted to become more resistant to HDAC inhibition. Our work establishes a mechanism by which BAP1 loss alters sensitivity of cancer cells to HDAC inhibitors. Assessment of BAP1 and HDAC expression may ultimately help identify patients likely to respond to HDAC inhibitors.

BAP1, a tumor suppressor gene driving malignant mesothelioma

“…The authors demonstrated that BAP1 can transcriptionally promote the expression of HDAC2. BAP1 knockdown led to a decrease in HDAC2 but an increase in HDAC1 expression (60). Interestingly, this altered HDAC imbalance led to an increase in MM cell sensitivity to vorinostat and other HDAC inhibitors.…”

“…Unfortunately, no improvements in overall survival resulted from vorinostat treatment (59). A recent study of MM cells and HDAC expression may have provided a reason for this disappointing clinical study result (60). The authors demonstrated that BAP1 can transcriptionally promote the expression of HDAC2.…”

BAP1 Loss Predicts Therapeutic Vulnerability in Malignant Peritoneal Mesothelioma

“…Recent in-vitro experiments demonstrated BAP1 loss altered sensitivity of PM as well as uveal melanoma (UM) cells to HDAC inhibition [28,29].…”

Malignant Mesothelioma: Time to Translate?

“…BAP1 seems also to indirectly control other important aspects of epigenetic regulation of gene transcription, such as histone acetylation and methylation. Indeed, BAP1 might regulate the expression of histone deacetylases (HDACs), suggesting a potential window of opportunity for clinically available HDAC-inhibitors in BAP1-mutated tumors [37]. BAP1 loss is also associated to increased trimethylated histone H3 lysine 27 (H3K27me3), and elevated levels of EZH2 (enhancer of zeste homolog 2), a Polycomb repressive complex 2 subunit [38].…”