Histone methyltransferase SETD2 modulates alternative splicing to inhibit intestinal tumorigenesis
Histone methyltransferase SETD2 modulates alternative splicing to inhibit intestinal tumorigenesis
复制标题
组蛋白甲基转移酶 SETD2 调节选择性剪接抑制肠道肿瘤发生
DOI：
10.1172/jci94292
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发表时间：
2017-09-01
影响因子：
15.9
通讯作者：
Qin, Jun
中科院分区：
文献类型：
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作者：
Yuan, Huairui;Li, Ni;Qin, Jun
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在很大程度上仍未明确。在这里，我们发现SETD2抵消Wnt信号，其失活促进结肠直肠癌（CRC）小鼠模型的肠道肿瘤发生。稳态下肠道稳态不需要SETD2；然而，照射后，小鼠肠上皮中Setd2基因失活促进了肠干/祖细胞的自我更新和组织再生。此外，在Wnt信号失调的情况下，SETD2的缺失增加了肿瘤发生的易感性。机制表征表明，SETD2下调影响与肿瘤发生有关的一个基因子集的选择性剪接。重要的是，我们发现SETD2消融减少了凌乱片段极性蛋白2 （DVL2）前mrna的内含子保留，否则它们会被无义介导的衰变降解，从而增强了Wnt信号。一项CRC患者队列分析进一步证实了SETD2介导的信号级联反应。总之，我们的研究强调了SETD2在组织再生和肿瘤发生过程中通过表观遗传调控RNA加工作为Wnt信号的整体调节剂。
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.