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

Our plain-English summary of Loss of the deubiquitylase BAP1 alters class I histone deacetylase expression and sensitivity of mesothelioma cells to HDAC inhibitors, by J.J. Sacco, J. Kenyani, Z. Butt, et al (Oncotarget, 2015).

The study

• Authors: J.J. Sacco, J. Kenyani, Z. Butt, R. Carter, H.Y. Chew, L.P. Cheeseman, S. Darling, M. Denny, S. Urbé, M.J. Clague, J.M. Coulson
• Journal: Oncotarget
• Published: 2015;6(15):13757-71
• Cited by: 50 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This was a laboratory study of cancer cell lines from the University of Liverpool. It did not study patients or asbestos exposure. The authors used small RNA molecules (siRNA) to switch off each of 92 deubiquitylase enzymes in A549 lung cancer cells and measured two related proteins, HDAC1 and HDAC2. Switching off BAP1, which the authors describe as frequently mutated in malignant pleural mesothelioma, lowered HDAC2 and raised HDAC1. In mesothelioma cell lines, HDAC2 levels tracked BAP1 levels, and HDAC2 was low in lines lacking BAP1. One exception, NCI-H2052, kept BAP1 but had low HDAC2, likely due to lost HDAC2 gene copies. BAP1 appeared to act on HDAC2 messenger RNA levels rather than on protein breakdown. In MSTO-211H mesothelioma cells, temporarily removing BAP1 lowered the vorinostat LC50, the concentration that halved the estimated number of living cells, from 2.6 to 1.2 μM. However, mesothelioma lines with long-standing low HDAC2 were more resistant to the drug mocetinostat. The authors concluded that BAP1 loss alters HDAC2 and sensitivity to HDAC inhibitor drugs. They said their findings need confirming in other models.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) cell-line study, including an siRNA screen of deubiquitylase enzymes
• Who was studied: Human cell lines grown in the laboratory (University of Liverpool, UK). These were a panel of normal lung and lung cancer lines (three small cell, one carcinoid and six non-small cell lung cancer lines), the normal mesothelial line MeT-5A, and the mesothelioma lines MSTO-211H, NCI-H2052, NCI-H28, NCI-H226 and NCI-H2452. Study dates were not given.
• Exposure: No asbestos exposure was studied. The cells were exposed to siRNA depletion of BAP1, HDAC1 or HDAC2, and to the HDAC inhibitor drugs vorinostat, trichostatin A, mocetinostat and MC1568. In the cell-viability tests the drugs were used at their LC30 ('lethal concentration 30%', set using a viable-cell assay): 2.5 μM vorinostat, 1.25 μM mocetinostat and 20 μM MC1568.
• Main results:
  • In the screen in A549 lung cancer cells, switching off BAP1 (and USP27X) produced the largest decrease in the ratio of HDAC2 to HDAC1. For BAP1, this reflected both less HDAC2 and more HDAC1.
  • In the mesothelioma cell lines, HDAC2 was low in the lines lacking BAP1 and closely tracked BAP1 levels (linear regression R2 = 0.98 excluding NCI-H2052).
  • The NCI-H2052 mesothelioma line was an exception: it had BAP1 but low HDAC2, which the authors said was likely explained by its loss of HDAC2 copy number.
  • In MSTO-211H cells, switching off BAP1 markedly decreased HDAC2 messenger RNA. BAP1 did not appear to protect the HDAC2 protein from breakdown.
  • In MSTO-211H cells, switching off HDAC1, HDAC2 or BAP1 had no significant effect on total cellular HDAC activity.
  • In MSTO-211H cells, the reported vorinostat LC50 (the concentration that halved the estimated viable-cell number, measured by an ATP-based assay) fell from 2.6 μM in control cells to 1.3 μM with HDAC2 switched off and 1.2 μM with BAP1 switched off.
  • Mesothelioma lines with constitutively low HDAC2 were more resistant to mocetinostat. The LC50 was 4.0, 4.5 and 4.9 μM for NCI-H2052, NCI-H28 and NCI-H226, compared with 2.4 μM for MSTO-211H.
• The authors' conclusion: The authors concluded that loss of BAP1 in cell-line models of thoracic cancers alters HDAC2 expression, which in turn changes how sensitive the cells are to HDAC inhibitor drugs.
• Limitations the authors state:
  • Temporarily switching off BAP1 did not behave the same as long-term genetic loss of BAP1 in established cell lines. The authors cautioned that inferring clinical markers from temporary depletion might give misleading results.
  • The authors stated that the findings need to be confirmed in other models.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: BAP1, Mesothelioma, Lung Cancer, Pleural Mesothelioma.

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