Loss of BAP1 function leads to EZH2-dependent transformation

Our plain-English summary of Loss of BAP1 function leads to EZH2-dependent transformation, by L.M. LaFave, W. Béguelin, R. Koche, et al (Nature Medicine, 2015).

The study

• Authors: L.M. LaFave, W. Béguelin, R. Koche, M. Teater, B. Spitzer, A. Chramiec, E. Papalexi, M.D. Keller, T. Hricik, K. Konstantinoff, J.B. Micol, B. Durham, S.K. Knutson, J.E. Campbell, G. Blum, X. Shi, E.H. Doud, A.V. Krivtsov, Y.R. Chung, I. Khodos, E. de Stanchina, O. Ouerfelli, P.S. Adusumilli, P.M. Thomas, N.L. Kelleher, M. Luo, H. Keilhack, O. Abdel-Wahab, A. Melnick, S.A. Armstrong, R.L. Levine
• Journal: Nature Medicine
• Published: 2015;21(11):1344-9
• Cited by: 305 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The tumor suppressors BAP1 and ASXL1 interact to form a polycomb deubiquitinase complex that removes monoubiquitin from histone H2A lysine 119 (H2AK119Ub). However, BAP1 and ASXL1 are mutated in distinct cancer types, consistent with independent roles in regulating epigenetic state and malignant transformation. Here we demonstrate that Bap1 loss in mice results in increased trimethylated histone H3 lysine 27 (H3K27me3), elevated enhancer of zeste 2 polycomb repressive complex 2 subunit (Ezh2) expression, and enhanced repression of polycomb repressive complex 2 (PRC2) targets. These findings contrast with the reduction in H3K27me3 levels seen with Asxl1 loss. Conditional deletion of Bap1 and Ezh2 in vivo abrogates the myeloid progenitor expansion induced by Bap1 loss alone. Loss of BAP1 results in a marked decrease in H4K20 monomethylation (H4K20me1). Consistent with a role for H4K20me1 in the transcriptional regulation of EZH2, expression of SETD8-the H4K20me1 methyltransferase-reduces EZH2 expression and abrogates the proliferation of BAP1-mutant cells. Furthermore, mesothelioma cells that lack BAP1 are sensitive to EZH2 pharmacologic inhibition, suggesting a novel therapeutic approach for BAP1-mutant malignancies.

In plain English

This laboratory study examined the gene BAP1, often mutated in mesothelioma. Asbestos exposure was not studied. Mice whose Bap1 gene was switched off in blood-forming cells all developed a blood disorder (myeloproliferative disease) with an enlarged spleen. These cells also had more H3K27me3, a chemical mark on DNA-packaging proteins placed by a complex containing the enzyme EZH2. Also deleting the Ezh2 gene abrogated (did away with) the blood disorder caused by Bap1 loss. The drug EPZ011989, which blocks EZH2, decreased spleen enlargement and white blood cell counts in Bap1-deficient mice. The Bap1-deficient cells had much less of a second mark, H4K20me1. In BAP1-mutant human mesothelioma cell lines (H226, H2452), making the cells produce extra SETD8, which places H4K20me1, increased cell death and reduced growth. Silencing EZH2 also induced cell death in these lines. BAP1-normal lines (MSTO-211H, Meso10) were unaffected by SETD8 and kept growing when EZH2 was silenced. In mice with implanted mesothelioma tumors (6 per group), EPZ011989 reduced BAP1-mutant tumor size. BAP1-normal tumors responded less. The authors concluded that EZH2 represents a potential therapeutic target in BAP1-mutant cancer cells.

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 study: genetically engineered mice, human mesothelioma cell lines, and human tumor cells implanted into mice (xenografts), plus analysis of existing gene-expression data
• Who was studied: Mice with Bap1 deleted in blood-forming cells (Mx1-Cre Bap1f/f), with or without Ezh2 deletion. Unless otherwise indicated: 5 control, 5 Ezh2-KO, 8 Bap1-KO and 11 Bap1/Ezh2-KO mice. Human mesothelioma cell lines: BAP1 wild-type MSTO-211H and Meso10; BAP1-mutant H226 (homozygous BAP1 deletion) and H2452 (catalytic mutation). NOD-SCID mice implanted with these lines, 6 per group. TCGA mesothelioma patient data. Animals were housed at Memorial Sloan Kettering Cancer Center.
• Exposure: No asbestos exposure was studied. Interventions were genetic loss of Bap1, deletion of Ezh2, expression of SETD8, silencing of EZH2, and the EZH2 inhibitor EPZ011989 given orally twice daily at 500 mg per kg (16 days in Bap1-KO mice).
• Main results:
  • In mice, Bap1 loss in blood-forming cells led to myeloproliferative disease with an enlarged spleen in all affected mice (fully penetrant).
  • H3K27me3 levels were increased in Bap1-knockout mouse cells.
  • In mice, deleting Ezh2 together with Bap1 abrogated the myeloid malignancy caused by Bap1 loss.
  • In Bap1-knockout mice (5 per group), the EZH2 inhibitor EPZ011989 decreased H3K27me3, spleen enlargement and white blood cell counts compared with vehicle controls.
  • Bap1-knockout mouse cells showed a marked decrease in H4K20me1.
  • Expressing SETD8 in BAP1-mutant mesothelioma cell lines H226 and H2452 increased cell death (apoptosis) and reduced growth. The BAP1 wild-type lines were unaffected.
  • Silencing EZH2 induced cell death (apoptosis) in BAP1-mutant mesothelioma cell lines, while BAP1 wild-type cells continued to grow.
  • In TCGA data, EZH2 mRNA expression was higher in mesothelioma than in matched normal tissue.
  • In mice, silencing EZH2 stopped tumor formation by BAP1-mutant mesothelioma cell lines but not by BAP1 wild-type lines.
  • In mice implanted with mesothelioma cells (6 per group), EPZ011989 significantly reduced tumor size for BAP1-mutant tumors compared with vehicle. Wild-type tumors were less responsive.
  • EZH2 inhibition stopped spread to the lungs by a BAP1-mutant mesothelioma cell line with metastatic potential.
• The authors' conclusion: The authors concluded that EZH2 is a potential therapeutic target in BAP1-mutant cancer cells. They said that BAP1 loss creates a dependency on PRC2 that should be explored further in preclinical and clinical studies.

Topics

Medical terms in this study, explained in our Lexicon: BAP1, Malignant Transformation, Mesothelioma.

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