Tumor suppressor ASXL1 is essential for the activation of INK4B expression in response to oncogene activity and anti-proliferative signals

• Published in: Cell research 2015-11, Vol.25 (11), p.1205-1218
• Main Authors: Wu, Xudong, Bekker-Jensen, Ida Holst, Christensen, Jesper, Rasmussen, Kasper Dindler, Sidoli, Simone, Qi, Yan, Kong, Yu, Wang, Xi, Cui, Yajuan, Xiao, Zhijian, Xu, Guogang, Williams, Kristine, Rappsilber, Juri, Sønderby, Casper Kaae, Winther, Ole, Jensen, Ole N, Helin, Kristian
• Format: Article
• Language: English
• Subjects: 631/67/581; 631/80/474/582; 692/420/755; Animals; Biomedical and Life Sciences; Bone marrow; Cell Biology; Cell Line; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p15 - metabolism; Histones - metabolism; Humans; Life Sciences; Mice; Mutation; Original; original-article; Polycomb-Group Proteins - metabolism; Promoter Regions, Genetic; Repressor Proteins - metabolism; Tumor Suppressor Proteins - metabolism; Ubiquitin Thiolesterase - metabolism; Ubiquitin-Specific Proteases - metabolism; 信号; 基因活性; 增殖; 活化作用; 肿瘤抑制; 致癌; 诱导表达; 转录激活
• ISSN: 1001-0602; 1748-7838; 1748-7838
• DOI: 10.1038/cr.2015.121

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.