title: Tumor suppressor ASXL1 is essential for the activation of INK4B expression in response to oncogene activity and anti-proliferative signals.
abstract: ASXL1 mutations are frequently found in hematological tumors, and loss of Asxl1 promotes myeloid transformation in mice. Here we present data supporting a role for an ASXL1-BAP1 complex in the deubiquitylation of mono-ubiquitylated lysine 119 on Histone H2A (H2AK119ub1) in vivo. The Polycomb group proteins control the expression of the INK4B-ARF-INK4A locus during normal development, in part through catalyzing mono-ubiquitylation of H2AK119. Since the activation of the locus INK4B-ARF-INK4A plays a fail-safe mechanism protecting against tumorigenesis, we investigated whether ASXL1-dependent H2A deubiquitylation plays a role in its activation. Interestingly, we found that ASXL1 is specifically required for the increased expression of p15(INK4B) in response to both oncogenic signaling and extrinsic anti-proliferative signals. Since we found that ASXL1 and BAP1 both are enriched at the INK4B locus, our results suggest that activation of the INK4B locus requires ASXL1/BAP1-mediated deubiquitylation of H2AK119ub1. Consistently, our results show that ASXL1 mutations are associated with lower expression levels of p15(INK4B) and a proliferative advantage of hematopoietic progenitors in primary bone marrow cells, and that depletion of ASXL1 in multiple cell lines results in resistance to growth inhibitory signals. Taken together, this study links ASXL1-mediated H2A deubiquitylation and transcriptional activation of INK4B expression to its tumor suppressor functions.
authors.affiliation: Department of Cell Biology, Tianjin Medical University, Qixiangtai Road 22, Tianjin 300070, China.|Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark.|Centre for Epigenetics, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark.
authors.forename: Xudong
authors.initials: X
authors.lastname: Wu
authors.affiliation: Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark.|Centre for Epigenetics, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark.
authors.forename: Ida Holst
authors.initials: IH
authors.lastname: Bekker-Jensen
authors.affiliation: Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark.|Centre for Epigenetics, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark.
authors.forename: Jesper
authors.initials: J
authors.lastname: Christensen
authors.affiliation: Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark.|Centre for Epigenetics, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark.|The Danish Stem Cell Center (Danstem), University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark.
authors.forename: Kasper Dindler
authors.initials: KD
authors.lastname: Rasmussen
authors.affiliation: Centre for Epigenetics, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark.|Present address: Epigenetics Program, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA, USA.
authors.forename: Simone
authors.initials: S
authors.lastname: Sidoli
authors.affiliation: Department of Cell Biology, Tianjin Medical University, Qixiangtai Road 22, Tianjin 300070, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Department of Cell Biology, Tianjin Medical University, Qixiangtai Road 22, Tianjin 300070, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Kong
authors.affiliation: Department of Cell Biology, Tianjin Medical University, Qixiangtai Road 22, Tianjin 300070, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.affiliation: MDS and MPN Centre, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.
authors.forename: Yajuan
authors.initials: Y
authors.lastname: Cui
authors.affiliation: MDS and MPN Centre, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Xiao
authors.affiliation: The Second Affiliated Hospital to Nanchang University, 1 Minde Road, Nanchang, Jiangxi 330006, China.
authors.forename: Guogang
authors.initials: G
authors.lastname: Xu
authors.affiliation: Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark.|Centre for Epigenetics, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark.|Present address: The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark.
authors.forename: Kristine
authors.initials: K
authors.lastname: Williams
authors.affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3BF, UK.|Department of Bioanalytics, Institute of Biotechnology, Technische Universität Berlin, 13355 Berlin, Germany.
authors.forename: Juri
authors.initials: J
authors.lastname: Rappsilber
authors.affiliation: Cognitive Systems, DTU Compute, Technical University of Denmark, 2800 Lyngby, Denmark.|Bioinformatics Centre, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark.
authors.forename: Casper Kaae
authors.initials: CK
authors.lastname: Sønderby
authors.affiliation: Cognitive Systems, DTU Compute, Technical University of Denmark, 2800 Lyngby, Denmark.|Bioinformatics Centre, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark.
authors.forename: Ole
authors.initials: O
authors.lastname: Winther
authors.affiliation: Centre for Epigenetics, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark.
authors.forename: Ole N
authors.initials: ON
authors.lastname: Jensen
authors.affiliation: Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark.|Centre for Epigenetics, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark.|The Danish Stem Cell Center (Danstem), University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark.
authors.forename: Kristian
authors.initials: K
authors.lastname: Helin
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009154:Mutation; D063146:Polycomb-Group Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000378:metabolism; D064570:Ubiquitin-Specific Proteases / Q000378:metabolism
chemical_list: C473949:ASXL1 protein, human; C400134:BAP1 protein, human; C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D006657:Histones; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases