Histone methyltransferase SETD2 modulates alternative splicing to inhibit intestinal tumorigenesis
文献类型：期刊论文
| 作者 | Yuan, Huairui2; Li, Ni2; Ren, Jiale2; Liu, Yongfeng2; Jiang, Min2; Pan, Qiang2; Han, Ying2; Qin, Jun2; Fu, Da3; Hui, Jingyi6 |
| 刊名 | JOURNAL OF CLINICAL INVESTIGATION
 |
| 出版日期 | 2017 |
| 卷号 | 127期号:9页码:3381-3397 |
| ISSN号 | 0021-9738 |
| DOI | 10.1172/JCI94292 |
| 文献子类 | Article |
| 英文摘要 | 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. |
| 学科主题 | Research & Experimental Medicine |
| WOS关键词 | STEM-CELL NICHE ; COLORECTAL-CANCER ; WNT/BETA-CATENIN ; BETA-CATENIN ; COLON-CANCER ; LRP6 PHOSPHORYLATION ; TUMOR-SUPPRESSOR ; WNT ACTIVITY ; IN-VIVO ; CHROMATIN |
| 语种 | 英语 |
| WOS记录号 | WOS:000408842300019 |
| 出版者 | AMER SOC CLINICAL INVESTIGATION INC |
| 版本 | 出版稿 |
| 源URL | [http://202.127.25.144/handle/331004/1059]  |
| 专题 | 中国科学院上海生命科学研究院营养科学研究所 |
| 作者单位 | 1.Sichuan Univ, West China Univ Hosp 2, Key Lab Birth Defects & Related Dis Women & Child, Dept Obstet Gynecol & Pediat,Minist Educ, Chengdu, Sichuan, Peoples R China; 2.Univ Chinese Acad Sci, Shanghai Jiao Tong Univ,Chinese Acad Sci, Key Lab Stem Cell Biol,CAS Ctr Excellence Mol Cel, Inst Hlth Sci,Shanghai Inst Biol Sci,Sch Med, Shanghai, Peoples R China; 3.Tongji Univ, Shanghai Peoples Hosp 10, Cent Lab Med Res, Sch Med, Shanghai, Peoples R China; 4.Fudan Univ, Dept Colorectal Surg, Shanghai Canc Ctr, Shanghai, Peoples R China; 5.Nanjing Med Univ, Dept Immunol, Nanjing, Jiangsu, Peoples R China, 6.Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, State Key Lab Mol Biol,CAS Ctr Excellence Mol Cel, Shanghai, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Yuan, Huairui,Li, Ni,Ren, Jiale,et al. Histone methyltransferase SETD2 modulates alternative splicing to inhibit intestinal tumorigenesis[J]. JOURNAL OF CLINICAL INVESTIGATION,2017,127(9):3381-3397. |
| APA | Yuan, Huairui.,Li, Ni.,Ren, Jiale.,Liu, Yongfeng.,Jiang, Min.,...&,.(2017).Histone methyltransferase SETD2 modulates alternative splicing to inhibit intestinal tumorigenesis.JOURNAL OF CLINICAL INVESTIGATION,127(9),3381-3397. |
| MLA | Yuan, Huairui,et al."Histone methyltransferase SETD2 modulates alternative splicing to inhibit intestinal tumorigenesis".JOURNAL OF CLINICAL INVESTIGATION 127.9(2017):3381-3397. |
入库方式： OAI收割
来源：上海营养与健康研究所
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