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

Abstract

// Joseph J. Sacco 1 , Jenna Kenyani 1 , Zohra Butt 1 , Rachel Carter 1 , Hui Yi Chew 1, 2 , Liam P. Cheeseman 1, 3 , Sarah Darling 1 , Michael Denny 1 , Sylvie Urbé 1 , Michael J. Clague 1 , Judy M. Coulson 1 1 Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK 2 Current address: Cancer Stem Cell Biology, Agency for Science Technology and Research, Genome Institute of Singapore, Singapore 3 Current address: MRC Laboratory of Molecular Biology, Cambridge, UK Correspondence to: Judy M. Coulson, e-mail: j.m.coulson@liv.ac.uk Keywords: histone deacetylase 2, BRCA1-associated protein 1, MPM, vorinostat, stratified medicine Received: October 31, 2014      Accepted: April 10, 2015      Published: April 24, 2015 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.