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

J Pathol. 2015 May;236(1):103-15. doi: 10.1002/path.4505. Epub 2015 Feb 2.


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.

Keywords: SIRT1; TLX; nuclear receptor; oncogene-induced senescence; p21; prostate cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation / genetics
  • Cell Proliferation / physiology
  • Cell Transformation, Neoplastic / genetics
  • Cellular Senescence / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / physiology
  • Humans
  • Male
  • Mice, SCID
  • Orphan Nuclear Receptors
  • PTEN Phosphohydrolase / metabolism
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism*


  • CDKN1A protein, human
  • Cdkn1a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p21
  • NR2E1 protein, human
  • Nr2e1 protein, mouse
  • Orphan Nuclear Receptors
  • Receptors, Cytoplasmic and Nuclear
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • SIRT1 protein, human
  • Sirt1 protein, mouse
  • Sirtuin 1