Yuan Huairui, Li Ni, Fu Da, Ren Jiale, Hui Jingyi, Peng Junjie, Liu Yongfeng, Qiu Tong, Jiang Min, Pan Qiang, Han Ying, Wang Xiaoming, Li Qintong, Qin Jun
The Key Laboratory of Stem Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine, University of Chinese Academy of Sciences, Shanghai, China.
Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
J Clin Invest. 2017 Sep 1;127(9):3375-3391. doi: 10.1172/JCI94292. Epub 2017 Aug 21.
The histone H3K36 methyltransferase SETD2 is frequently mutated or deleted in a variety of human tumors. Nevertheless, the role of SETD2 loss in oncogenesis remains largely undefined. Here, we found that SETD2 counteracts Wnt signaling and its inactivation promotes intestinal tumorigenesis in mouse models of colorectal cancer (CRC). SETD2 was not required for intestinal homeostasis under steady state; however, upon irradiation, genetic inactivation of Setd2 in mouse intestinal epithelium facilitated the self-renewal of intestinal stem/progenitor cells as well as tissue regeneration. Furthermore, depletion of SETD2 enhanced the susceptibility to tumorigenesis in the context of dysregulated Wnt signaling. Mechanistic characterizations indicated that SETD2 downregulation affects the alternative splicing of a subset of genes implicated in tumorigenesis. Importantly, we uncovered that SETD2 ablation reduces intron retention of dishevelled segment polarity protein 2 (DVL2) pre-mRNA, which would otherwise be degraded by nonsense-mediated decay, thereby augmenting Wnt signaling. The signaling cascades mediated by SETD2 were further substantiated by a CRC patient cohort analysis. Together, our studies highlight SETD2 as an integral regulator of Wnt signaling through epigenetic regulation of RNA processing during tissue regeneration and tumorigenesis.
组蛋白H3K36甲基转移酶SETD2在多种人类肿瘤中经常发生突变或缺失。然而，SETD2缺失在肿瘤发生中的作用仍 largely undefined。在这里，我们发现SETD2可对抗Wnt信号，其失活促进结直肠癌（CRC）小鼠模型中的肠道肿瘤发生。在稳态下，肠道稳态不需要SETD2；然而，照射后，小鼠肠上皮中Setd2的基因失活促进了肠道干/祖细胞的自我更新以及组织再生。此外，在Wnt信号失调的情况下，SETD2的缺失增强了肿瘤发生的易感性。机制表征表明，SETD2下调影响了与肿瘤发生相关的一部分基因的可变剪接。重要的是，我们发现SETD2缺失减少了散乱节段极性蛋白2（DVL2）前体mRNA的内含子保留，否则该前体mRNA将通过无义介导的衰变降解，从而增强Wnt信号。SETD2介导的信号级联通过CRC患者队列分析得到进一步证实。总之，我们的研究强调SETD2是通过在组织再生和肿瘤发生过程中对RNA加工进行表观遗传调控来作为Wnt信号的一个组成调节因子。
