Zhu Jin, Yang Dong-Rong, Sun Yin, Qiu Xiaofu, Chang Hong-Chiang, Li Gonghui, Shan Yuxi, Chang Chawnshang
Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, China. George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York.
George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York.
Mol Cancer Ther. 2015 Jun;14(6):1445-53. doi: 10.1158/1535-7163.MCT-14-0971. Epub 2015 Apr 1.
The testicular nuclear receptor 4 (TR4) is a member of the nuclear receptor superfamily that mediates various biologic functions with key impacts on metabolic disorders and tumor progression. Here, we demonstrate that TR4 may play a positive role in prostate cancer CD133(+) stem/progenitor (S/P) cell invasion. Targeting TR4 with lentiviral silencing RNA significantly suppressed prostate cancer CD133(+) S/P cell invasion both in vitro and in vivo. Mechanism dissection found that TR4 transcriptionally regulates the oncogene EZH2 via binding to its 5' promoter region. The consequences of targeting TR4 to suppress EZH2 expression may then suppress the expression of its downstream key metastasis-related genes, including NOTCH1, TGFβ1, SLUG, and MMP9. Rescue approaches via adding the EZH2 reversed the TR4-mediated prostate cancer S/P cell invasion. Together, these results suggest that the TR4→EZH2 signaling may play a critical role in the prostate cancer S/P cell invasion and may allow us to develop a better therapy to battle the prostate cancer metastasis.
睾丸核受体4（TR4）是核受体超家族的成员，介导各种生物学功能，对代谢紊乱和肿瘤进展具有关键影响。在此，我们证明TR4可能在前列腺癌CD133（+）干/祖细胞（S/P）侵袭中发挥积极作用。用慢病毒沉默RNA靶向TR4可在体外和体内显著抑制前列腺癌CD133（+）S/P细胞侵袭。机制剖析发现，TR4通过与其5'启动子区域结合转录调控癌基因EZH2。靶向TR4抑制EZH2表达的结果可能会抑制其下游关键转移相关基因的表达，包括NOTCH1、TGFβ1、SLUG和MMP9。通过添加EZH2的挽救方法逆转了TR4介导的前列腺癌S/P细胞侵袭。总之，这些结果表明TR4→EZH2信号通路可能在前列腺癌S/P细胞侵袭中起关键作用，并可能使我们开发出更好的治疗方法来对抗前列腺癌转移。
