Review
The emerging roles of orphan nuclear receptors in prostate cancer

https://doi.org/10.1016/j.bbcan.2016.06.001Get rights and content

Highlights

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    Orphan NRs as valuable diagnostic or prognostic markers in prostate cancer

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    Emerging roles of orphan NRs in prostate cancer progression

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    Therapeutic potential of druggable orphan NRs in prostate cancer treatment

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    Interference of orphan NRs with androgen receptor signaling

Abstract

Orphan nuclear receptors are members of the nuclear receptor (NR) superfamily and are so named because their endogenous physiological ligands are either unknown or may not exist. Because of their important regulatory roles in many key physiological processes, dysregulation of signalings controlled by these receptors is associated with many diseases including cancer. Over years, studies of orphan NRs have become an area of great interest because their specific physiological and pathological roles have not been well-defined, and some of them are promising drug targets for diseases. The recently identified synthetic small molecule ligands, acting as agonists or antagonists, to these orphan NRs not only help to understand better their functional roles but also highlight that the signalings mediated by these ligand-independent NRs in diseases could be therapeutically intervened. This review is a summary of the recent advances in elucidating the emerging functional roles of orphan NRs in cancers, especially prostate cancer. In particular, some orphan NRs, RORγ, TR2, TR4, COUP-IFII, ERRα, DAX1 and SHP, exhibit crosstalk or interference with androgen receptor (AR) signaling in either normal or malignant prostatic cells, highlighting their involvement in prostate cancer progression as androgen and AR signaling pathway play critical roles in this process. We also propose that a better understanding of the mechanism of actions of these orphan NRs in prostate gland or prostate cancer could help to evaluate their potential value as therapeutic targets for prostate cancer.

Introduction

Prostate cancer is the most frequently diagnosed cancer among males in most economically developed countries. The American Cancer Society estimates that in 2016, there will be 180,890 newly diagnosed cases and 26,120 deaths due to prostate cancer in the United States, making it the second leading cause of cancer death in men [1]. Recent statistics indicates that its incidence rate is also rapidly increasing in China [2]. The majority of newly diagnosed (about 85%) prostate cancers are localized to prostate gland and treatment options for primary cancers include active surveillance, radical prostatectomy and external beam radiotherapy. However, the natural history of prostate cancer is threatening once it progresses to the fatal invasive or metastatic disease. Patients with metastatic or high-risk localized disease are commonly treated with hormone therapy (androgen-deprivation therapy ADT or androgen receptor/AR-axis-targeted therapy) targeting to AR signaling. Suppression of AR signaling can be achieved by means of surgical or chemical castration to reduce androgen levels using luteinizing hormone-releasing hormone agonists (LHRHa) or androgen biosynthesis inhibitor, and blocking of AR activity using antiandrogens. Although initial responses to ADT are highly favorable for most patients, it can only last for an average of 18–20 months after treatments. The disease inevitably becomes unresponsive to androgen blockade and progresses to the fatal metastatic castration-resistant prostate cancer (CRPC). Patients with metastatic CRPC have only a median survival period of about 1–2 years [3].

Section snippets

Nuclear receptors and orphan nuclear receptors

Nuclear receptors (NRs) constitute a superfamily of DNA-binding transcription factors, comprising the ligand-regulated (or hormone NRs) and ligand-independent members (orphan NRs), which can both activate and repress target gene expression by directly binding to specific genomic DNA sequences or indirectly via protein-protein interaction with other DNA-bound transcription factors, such as specificity proteins (Sp) and activating protein-1 (AP-1) [4]. Among the total 48 members of human NRs, 25

Orphan NRs in prostate cancer

Within the orphan NR subgroup, half of the members have been studied so far in prostate cancer.

Interaction of orphan NRs with AR signaling pathway

It is well characterized that androgen receptor (AR, NR3C4) plays critical roles in normal prostate development and also prostate cancer progression. In CRPC, most cancer cells maintain activated AR signaling and hormone sensitivity despite low levels of serum testosterone. Current findings suggest that multiple molecular mechanisms are involved in the progression of CRPC, including [1] AR hypersensitivity due to AR gene amplification and overexpression, AR mutations and expression of AR splice

Remarks and perspectives

Among the NR superfamily, AR has been extensively studied and represents the most established therapeutic target in prostate cancer. However, almost all patients receiving hormone therapies targeting to AR-axis signaling still inevitably develop therapy resistance. Therefore, targeting alternative signaling pathways may provide potential opportunities to prostate cancer treatment, especially its advanced metastatic castration-resistant disease. Over the years, studies on orphan NRs have gained

Declaration statement

The authors declare that they have no conflict of interest to disclose.

Acknowledgements

This work was supported by the Earmarked Research Grant (CUHK4411/06M), General Research Funds (461009, 14100914) from the Research Grants Council of Hong Kong and National Science Foundation of China (81502570).

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    Dinglan Wu and Alyson Cheung contributed equally to this article.

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