title: Orphan nuclear receptor TLX functions as a potent suppressor of oncogene-induced senescence in prostate cancer via its transcriptional co-regulation of the CDKN1A (p21(WAF1) (/) (CIP1) ) and SIRT1 genes.
abstract: 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 TLX (NR2E1) 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 in vitro and in vivo, 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(G12V) or knockdown of tumour suppressor PTEN, via a mechanism of direct but differential transcriptional regulation of two senescence-associated genes, repression of CDKN1A and transactivation of SIRT1. 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.
authors.affiliation: School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, People's Republic of China.
authors.forename: Dinglan
authors.initials: D
authors.lastname: Wu
authors.forename: Shan
authors.initials: S
authors.lastname: Yu
authors.forename: Lin
authors.initials: L
authors.lastname: Jia
authors.forename: Chang
authors.initials: C
authors.lastname: Zou
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Xu
authors.forename: Lijia
authors.initials: L
authors.lastname: Xiao
authors.forename: Kam-Bo
authors.initials: KB
authors.lastname: Wong
authors.forename: Chi-Fai
authors.initials: CF
authors.lastname: Ng
authors.forename: Franky L
authors.initials: FL
authors.lastname: Chan
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D006801:Humans; D008297:Male; D016513:Mice, SCID; D057093:Orphan Nuclear Receptors; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; C088601:NR2E1 protein, human; C490258:Nr2e1 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: SIRT1; TLX; nuclear receptor; oncogene-induced senescence; p21; prostate cancer