Orphan nuclear receptor TLX contributes to androgen insensitivity in castration-resistant prostate cancer via its repression of androgen receptor transcription.

Abstract

The metastatic castration-resistant prostate cancer (CRPC) is a lethal form of prostate cancer, in which the expression of androgen receptor (AR) is highly heterogeneous. Indeed, lower AR expression and attenuated AR signature activity is shown in CRPC tissues, especially in the subset of neuroendocrine prostate cancer (NEPC) and prostate cancer stem-like cells (PCSCs). However, the significance of AR downregulation in androgen insensitivity and de-differentiation of tumor cells in CRPC is poorly understood and much neglected. Our previous study shows that the orphan nuclear receptor TLX (NR2E1), which is upregulated in prostate cancer, plays an oncogenic role in prostate carcinogenesis by suppressing oncogene-induced senescence. In the present study, we further established that TLX exhibited an increased expression in metastatic CRPC. Further analyses showed that overexpression of TLX could confer resistance to androgen deprivation and anti-androgen in androgen-dependent prostate cancer cells in vitro and in vivo, whereas knockdown of endogenous TLX could potentiate the sensitivity to androgen deprivation and anti-androgen in prostate cancer cells. Our study revealed that the TLX-induced resistance to androgen deprivation and anti-androgen was mediated through its direct suppression of AR gene transcription and signaling in both androgen-stimulated and -unstimulated prostate cancer cells. We also characterized that TLX could bind directly to AR promoter and repress AR transcription by recruitment of histone modifiers, including HDAC1, HDAC3, and LSD1. Together, our present study shows, for the first time, that TLX can contribute to androgen insensitivity in CRPC via repression of AR gene transcription and signaling, and also implicates that targeting the druggable TLX may have a potential therapeutic significance in CRPC management, particularly in NEPC and PCSCs.

• Authors: Lin Jia, Dinglan Wu, Yuliang Wang, Wenxing You, Zhu Wang, Lijia Xiao, Ganhui Cai, Zhenyu Xu, Chang Zou, Fei Wang, Jeremy Yuen-Chun Teoh, Chi-Fai Ng, Shan Yu, Franky L Chan
• Journal: Oncogene (Oncogene) Vol. 37 Issue 25 Pg. 3340-3355 (06 2018) ISSN: 1476-5594 [Electronic] England
• PMID: 29555975 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AR protein, human
• Androgen Antagonists
• Biomarkers, Tumor
• NR2E1 protein, human
• Orphan Nuclear Receptors
• Receptors, Androgen
• Receptors, Cytoplasmic and Nuclear

Topics

• Androgen Antagonists (pharmacology)
• Animals
• Apoptosis
• Biomarkers, Tumor (genetics, metabolism)
• Cell Proliferation
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Mice
• Mice, SCID
• Orphan Nuclear Receptors
• Prognosis
• Prostatic Neoplasms, Castration-Resistant (drug therapy, genetics, pathology)
• Receptors, Androgen (chemistry, genetics, metabolism)
• Receptors, Cytoplasmic and Nuclear (genetics, metabolism)
• Transcription, Genetic
• Transcriptional Activation
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays