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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.

SUBMITTER: Jia L

PROVIDER: S-EPMC6013422 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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

Jia Lin L Wu Dinglan D Wang Yuliang Y You Wenxing W Wang Zhu Z Xiao Lijia L Cai Ganhui G Xu Zhenyu Z Zou Chang C Wang Fei F Teoh Jeremy Yuen-Chun JY Ng Chi-Fai CF Yu Shan S Chan Franky L FL

Oncogene 20180320 25

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 poorl ...[more]

PMID: 29555975

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Project description:Enhanced intratumoral androgen biosynthesis and persistent androgen receptor (AR) signaling are key factors responsible for the relapse growth of castration-resistant prostate cancer (CRPC). Residual intraprostatic androgens can be produced by de novo synthesis of androgens from cholesterol or conversion from adrenal androgens by steroidogenic enzymes expressed in prostate cancer cells via different steroidogenic pathways. However, the dysregulation of androgen biosynthetic enzymes in CRPC still remains poorly understood. This study aims to elucidate the role of the nuclear receptor, estrogen-related receptor alpha (ERRα, ESRRA), in the promotion of androgen biosynthesis in CRPC growth. Methods: ERRα expression in CRPC patients was analyzed using Gene Expression Omnibus (GEO) datasets and validated in established CRPC xenograft model. The roles of ERRα in the promotion of castration-resistant growth were elucidated by overexpression and knockdown studies and the intratumoral androgen levels were measured by UPLC-MS/MS. The effect of suppression of ERRα activity in the potentiation of sensitivity to androgen-deprivation was determined using an ERRα inverse agonist. Results: ERRα exhibited an increased expression in metastatic CRPC and CRPC xenograft model, could act to promote castration-resistant growth via direct transactivation of two key androgen synthesis enzymes CYP11A1 and AKR1C3, and hence enhance intraprostatic production of dihydrotestosterone (DHT) and activation of AR signaling in prostate cancer cells. Notably, inhibition of ERRα activity by an inverse agonist XCT790 could reduce the DHT production and suppress AR signaling in prostate cancer cells. Conclusion: Our study reveals a new role of ERRα in the intratumoral androgen biosynthesis in CRPC via its transcriptional control of steroidogenic enzymes, and also provides a novel insight that targeting ERRα could be a potential androgen-deprivation strategy for the management of CRPC.

Dataset Information

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

Publications

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

Similar Datasets

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