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
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.
Cell Res. 2015 Nov;25(11):1205-18. doi: 10.1038/cr.2015.121. Epub 2015 Oct 16.
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.
ASXL1突变在血液系统肿瘤中经常被发现，并且Asxl1的缺失会促进小鼠的髓系转化。在此，我们提供的数据支持ASXL1 - BAP1复合物在体内对组蛋白H2A上单泛素化赖氨酸119（H2AK119ub1）去泛素化的作用。多梳蛋白家族在正常发育过程中控制INK4B - ARF - INK4A基因座的表达，部分是通过催化H2AK119的单泛素化来实现的。由于INK4B - ARF - INK4A基因座的激活发挥着防止肿瘤发生的故障安全机制，我们研究了ASXL1依赖的H2A去泛素化是否在其激活中起作用。有趣的是，我们发现ASXL1是响应致癌信号和外在抗增殖信号时p15(INK4B)表达增加所特别需要的。因为我们发现ASXL1和BAP1都在INK4B基因座富集，我们的结果表明INK4B基因座的激活需要ASXL1 / BAP1介导的H2AK119ub1去泛素化。一致地，我们的结果表明ASXL1突变与原代骨髓细胞中p15(INK4B)的低表达水平以及造血祖细胞的增殖优势相关，并且在多种细胞系中ASXL1的缺失导致对生长抑制信号的抗性。综上所述，本研究将ASXL1介导的H2A去泛素化和INK4B表达的转录激活与其肿瘤抑制功能联系起来。
