AKT-mediated stabilization of histone methyltransferase WHSC1 promotes prostate cancer metastasis
文献类型：期刊论文
| 作者 | Li, Ni7,8; Yuan, Huairui7,8; Dong, Baijun7,9; Ding, Yufeng7,8; Liu, Yongfeng7,8; Jiang, Min7,8; Kan, Shan7,8; Sun, Tongyu7,8; Li, Xiang7,8; Qin, Jun7,8 |
| 刊名 | JOURNAL OF CLINICAL INVESTIGATION
 |
| 出版日期 | 2017 |
| 卷号 | 127期号:4页码:1284-1302 |
| 关键词 | cancer stem cells sphere colon cancer fenretinide cell cycle cell stress |
| ISSN号 | 0021-9738 |
| DOI | 10.1172/JCI91144 |
| 文献子类 | Article |
| 英文摘要 | Loss of phosphatase and tensin homolog (PTEN) and activation of the PI3K/AKT signaling pathway are hallmarks of prostate cancer (PCa). However, these alterations alone are insufficient for cells to acquire metastatic traits. Here, we have shown that the histone dimethyl transferase WHSC1 critically drives indolent PTEN-null tumors to become metastatic PCa. In a PTEN-null murine PCa model, WHSC1 overexpression in prostate epithelium cooperated with Pten deletion to produce a metastasis-prone tumor. Conversely, genetic ablation of Whsc1 prevented tumor progression in PTEN-null mice. Molecular characterization revealed that increased AKT activity due to PTEN loss directly phosphorylates WHSC1 at S172, preventing WHSC1 degradation by CRL4(Cdt2) E3 ligase. Increased WHSC1 expression transcriptionally upregulates expression of RICTOR, a pivotal component of mTOR complex 2 (mTORC2), to further enhance AKT activity. Therefore, the AKT/WHSC1/mTORC2 signaling cascade represents a vicious feedback loop that elicits unrestrained AKT signaling. Furthermore, we determined that WHSC1 positively regulates Rac1 transcription to increase tumor cell motility. The biological importance of a WHSC1-mediated signaling cascade is substantiated by patient sample analysis in which WHSC1 signaling is tightly correlated with disease progression and recurrence. Taken together, our findings highlight a pivotal link between an epigenetic regulator, WHSC1, and key intracellular signaling molecules, AKT, RICTOR, and Rac1, to drive PCa metastasis. |
| 学科主题 | Research & Experimental Medicine |
| WOS关键词 | WOLF-HIRSCHHORN-SYNDROME ; MULTIPLE-MYELOMA ; PTEN LOSS ; LYSINE 36 ; PROGRESSION ; GENE ; ACTIVATION ; EXPRESSION ; EZH2 ; MMSET |
| 语种 | 英语 |
| WOS记录号 | WOS:000398183300020 |
| 出版者 | AMER SOC CLINICAL INVESTIGATION INC |
| 版本 | 出版稿 |
| 源URL | [http://202.127.25.144/handle/331004/878]  |
| 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.Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Hlth Sci, Shanghai, Peoples R China; 3.Third Mil Med Univ, Inst Pathol, Southwest Hosp, Chongqing, Peoples R China; 4.Third Mil Med Univ, Southwest Canc Ctr, Southwest Hosp, Chongqing, Peoples R China; 5.Nanjing Med Univ, Dept Immunol, Nanjing, Jiangsu, Peoples R China; 6.Sichuan Univ, West China Univ Hosp 2, Key Lab Birth Defects & Related Dis Women & Child, Minist Educ, Chengdu, Peoples R China, 7.Chinese Acad Sci, Shanghai Inst Biol Sci, Ctr Excellence Mol Cell Sci, Key Lab Stem Cell Biol,Inst Hlth Sci, 320 Yue Yang Rd, Shanghai 200031, Peoples R China; 8.Shanghai Jiao Tong Univ, Sch Med, Univ Chinese Acad Sci, Shanghai, Peoples R China; 9.Shanghai Jiao Tong Univ, Ren Ji Hosp, Dept Urol, Shanghai, Peoples R China; 10.Shanghai Jiao Tong Univ, Inst Hlth Sci, Sch Med, Shanghai, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Li, Ni,Yuan, Huairui,Dong, Baijun,et al. AKT-mediated stabilization of histone methyltransferase WHSC1 promotes prostate cancer metastasis[J]. JOURNAL OF CLINICAL INVESTIGATION,2017,127(4):1284-1302. |
| APA | Li, Ni.,Yuan, Huairui.,Dong, Baijun.,Ding, Yufeng.,Liu, Yongfeng.,...&,.(2017).AKT-mediated stabilization of histone methyltransferase WHSC1 promotes prostate cancer metastasis.JOURNAL OF CLINICAL INVESTIGATION,127(4),1284-1302. |
| MLA | Li, Ni,et al."AKT-mediated stabilization of histone methyltransferase WHSC1 promotes prostate cancer metastasis".JOURNAL OF CLINICAL INVESTIGATION 127.4(2017):1284-1302. |
入库方式： OAI收割
来源：上海营养与健康研究所
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