Tumor suppressor ASXL1 is essential for the activation of INK4B expression in response to oncogene activity and anti-proliferative signals
ASXL1 mutations are frequently found in hematological tumors, and loss of Asxll promotes myeloid transforma- tion in mice. Here we present data supporting a role for an ASXL1-BAP1 complex in the deubiquitylation of mono-ubiquitinylated lysine 119 on Histone H2A （H2AK119ubl） in vivo. The Polycomb gro...
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| Published in | Cell research Vol. 25; no. 11; pp. 1205 - 1218 |
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| Main Authors | , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
London
Nature Publishing Group UK
01.11.2015
Nature Publishing Group |
| Subjects | |
| Online Access | Get full text |
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| Summary: | ASXL1 mutations are frequently found in hematological tumors, and loss of Asxll promotes myeloid transforma- tion in mice. Here we present data supporting a role for an ASXL1-BAP1 complex in the deubiquitylation of mono-ubiquitinylated lysine 119 on Histone H2A （H2AK119ubl） in vivo. The Polycomb group proteins control the expression of the INK4B-ARF-INK4A locus during normal development, in part through catalyzing mono-ubiquit- inylation of H2AK119. Since the activation of the locus INK4B-ARF-INK4A plays a fail-safe mechanism protecting against tumorigenesis, we investigated whether ASXLl-dependent H2A deubiquitylation plays a role in its activation. Interestingly, we found that ASXL1 is specifically required for the increased expression of p15INa4n 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/BAPl-mediated deubiqui- tylation of H2AK119ubl. Consistently, our results show that ASXL1 mutations are associated with lower expression levels of p151NK4B 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 ASXLl-mediated H2A deubiquitylation and transcriptional activation of INK4B expression to its tumor sup- pressor functions. |
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| Bibliography: | 31-1568 ASXL1 mutations are frequently found in hematological tumors, and loss of Asxll promotes myeloid transforma- tion in mice. Here we present data supporting a role for an ASXL1-BAP1 complex in the deubiquitylation of mono-ubiquitinylated lysine 119 on Histone H2A （H2AK119ubl） in vivo. The Polycomb group proteins control the expression of the INK4B-ARF-INK4A locus during normal development, in part through catalyzing mono-ubiquit- inylation of H2AK119. Since the activation of the locus INK4B-ARF-INK4A plays a fail-safe mechanism protecting against tumorigenesis, we investigated whether ASXLl-dependent H2A deubiquitylation plays a role in its activation. Interestingly, we found that ASXL1 is specifically required for the increased expression of p15INa4n 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/BAPl-mediated deubiqui- tylation of H2AK119ubl. Consistently, our results show that ASXL1 mutations are associated with lower expression levels of p151NK4B 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 ASXLl-mediated H2A deubiquitylation and transcriptional activation of INK4B expression to its tumor sup- pressor functions. tumor suppressor; Polycomb; INK4A; INK4B; H2A ubiquitylation Xudong Wu, Ida Holst Bekker-Jensen, Jesper Christensen, Kasper Dindler Rasmussen, Simone Sidoli, Yan Qi, Yu Kong, Xi Wang, Yajuan Cui, Zhijian Xiao, Guogang Xu, Kristine Williams, Juri Rappsilber, Casper Kaae Sonderby, Ole Winther, Ole N Jensens, Kristian Helin（1.Department of Cell Biology, Hanjin Medical University, Qixiangtai Road 22, Tianjin 300070, China; 2 Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, 2200 Copenhagen, Denmark,3 Centre for Epigenetics, University of Copenhagen, Ole Maaloes Vej 5, 2200 Copenhagen, Denmark,4 The Danish Stem Cell Center （Danstem）, University of Copen- hagen, Blegdamsvej 3, 2200 Copenhagen, Denmark, 5Centre for Epigenetics, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark, 6 MDS and MPN Centre, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences ＆ Peking Union Medical College, Tianjin 300020, China; 7 The Second Affiliated Hospital to Nanchang University, 1 Minde Road, Nanchang, Jiangxi 330006, China; 8 Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3BF, UK; 9 Department of Bioanalytics, Institute of BiotechnoIogy, Tech- nische Universitdt Berlin, 13355 Berlin, Germany; 10 Cognitive Systems, DTU Compute, Technical University of Denmark, 2800 Lyngby, Denmark,11 Bioinformatics Centre, University of Copenhagen, Ole Maaloes Vej 5, 2200 Copenhagen, Denmark;12 Epigenetics Program, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA, USA; 13 The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark） ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
| ISSN: | 1001-0602 1748-7838 1748-7838 |
| DOI: | 10.1038/cr.2015.121 |