Orphan nuclear receptor TLX functions as a potent suppressor of oncogene‐induced senescence in prostate cancer via its transcriptional co‐regulation of the CDKN1A (p21WAF1/CIP1) and SIRT1 genes. Issue 1 (2nd February 2015)

• Record Type: Journal Article
• Authors: Wu, Dinglan; Yu, Shan; Jia, Lin; Zou, Chang; Xu, Zhenyu; Xiao, Lijia; Wong, Kam‐Bo; Ng, Chi‐Fai; Chan, Franky L
• Is Part Of: Journal of pathology. Volume 236:Issue 1(2015)
• Page Start: 103
• Page End: 115
• Publication Date: 2015-02-02
• Subjects: Pathology -- Periodicals; 616.07
• DOI: 10.1002/path.4505
• Languages: English
• ISSNs: 0022-3417

Abstract

<abstract abstract-type="main" id="path4505-abs-0001"> <title>Abstract</title> <p id="path4505-para-0001">Oncogene‐induced senescence is an important tumour‐suppressing mechanism to prevent both premalignant transformation and cancer progression. Overcoming this process is a critical step in early cancer development. The druggable orphan nuclear receptor <italic>TLX</italic> (<italic>NR2E1</italic>) is characterized as an important regulator of neural stem cells and is also implicated in the development of some brain tumours. However, its exact functional roles in cancer growth regulation still remain unclear. Here we report that TLX can act as a promoter of tumourigenesis in prostate cancer by suppressing oncogene‐induced senescence. We determined that TLX exhibited an increased expression in high‐grade prostate cancer tissues and many prostate cancer cell lines. Functional studies revealed that TLX could perform an oncogenic function in prostate cancer cells, as its knockdown triggered cellular senescence and cell growth arrest <italic>in vitro</italic> and <italic>in vivo</italic>, whereas its over‐expression promoted the malignant growth of prostate cancer cells. Furthermore, enhancement of TLX activity, by either ectopic expression or ligand stimulation, could potently prevent doxorubicin‐induced senescence in prostate cancer cells and also allow prostatic epithelial cells to escape oncogene‐induced senescence induced either by activated oncogene H‐Ras<sup>G12V</sup> or knockdown of tumour suppressor <italic>PTEN</italic>, via a mechanism of direct but differential transcriptional regulation of two senescence‐associated genes, repression of <italic>CDKN1A</italic> and transactivation of <italic>SIRT1</italic>. Together, our present study shows, for the first time, that TLX may play an important role in prostate carcinogenesis through its suppression of oncogene‐induced senescence, and also suggests that targeting the senescence‐regulatory TLX is of potential therapeutic significance in prostate cancer. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</p> </abstract>