title: Loss of BAP1 function leads to EZH2-dependent transformation.
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.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Gerstner Sloan Kettering School of Biomedical Sciences, New York, New York, USA.
authors.forename: Lindsay M
authors.initials: LM
authors.lastname: LaFave
authors.affiliation: Department of Hematology/Oncology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Béguelin
authors.affiliation: The Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Koche
authors.affiliation: Department of Hematology/Oncology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Matt
authors.initials: M
authors.lastname: Teater
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Spitzer
authors.affiliation: The Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Chramiec
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Efthymia
authors.initials: E
authors.lastname: Papalexi
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Keller
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Hricik
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Katerina
authors.initials: K
authors.lastname: Konstantinoff
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Micol
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Durham
authors.affiliation: Epizyme, Inc., Cambridge, Massachusetts, USA.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Knutson
authors.affiliation: Epizyme, Inc., Cambridge, Massachusetts, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Campbell
authors.affiliation: Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York.|Tri-Institutional Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Gil
authors.initials: G
authors.lastname: Blum
authors.affiliation: Chemical Synthesis Core, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Xinxu
authors.initials: X
authors.lastname: Shi
authors.affiliation: Proteomics Center of Excellence, Northwestern University, Evanston, Illinois, USA.
authors.forename: Emma H
authors.initials: EH
authors.lastname: Doud
authors.affiliation: The Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Krivtsov
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Young Rock
authors.initials: YR
authors.lastname: Chung
authors.affiliation: Anti-Tumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Inna
authors.initials: I
authors.lastname: Khodos
authors.affiliation: Anti-Tumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Elisa
authors.initials: E
authors.lastname: de Stanchina
authors.affiliation: Chemical Synthesis Core, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Ouathek
authors.initials: O
authors.lastname: Ouerfelli
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Prasad S
authors.identifier: http://orcid.org/0000-0002-1699-2046
authors.initials: PS
authors.lastname: Adusumilli
authors.affiliation: Proteomics Center of Excellence, Northwestern University, Evanston, Illinois, USA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Thomas
authors.affiliation: Proteomics Center of Excellence, Northwestern University, Evanston, Illinois, USA.
authors.forename: Neil L
authors.initials: NL
authors.lastname: Kelleher
authors.affiliation: Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Minkui
authors.initials: M
authors.lastname: Luo
authors.affiliation: Epizyme, Inc., Cambridge, Massachusetts, USA.
authors.forename: Heike
authors.initials: H
authors.lastname: Keilhack
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
authors.affiliation: Department of Hematology/Oncology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.affiliation: The Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Armstrong
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|The Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D042421:Histone Code; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D007938:Leukemia / Q000235:genetics; D008654:Mesothelioma / Q000235:genetics; D008745:Methylation; D051379:Mice; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics* / Q000378:metabolism
chemical_list: C473949:ASXL1 protein, human; C510915:Asxl1 protein, mouse; C400134:BAP1 protein, human; C575444:BAP1 protein, mouse; D006657:Histones; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D011495:Histone-Lysine N-Methyltransferase; C470730:KMT5A protein, human; D063151:Polycomb Repressive Complex 2; D043222:Ubiquitin Thiolesterase