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.
Highlights
These authors contributed : Lin Jia, Dinglan Wu, Yuliang Wang.Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.The initial and advanced growth of prostate cancer is critically dependent on androgens
Expression analyses of TLX in VCaP-castration-resistant prostate cancer (CRPC) xenograft tumors revealed that both messenger RNA levels and immunosignals of TLX exhibited significant increased expression in castration-relapse VCaP-CRPC xenograft tumors grown in castrated mice as compared to precastration VCaP tumors grown in intact mice (Fig. 1a, b). Quantitative real-time polymerase chain reaction (qRT-PCR) analysis of TLX expression in a panel of LNCaPand VCaP-derived prostate cancer cell lines showed that TLX transcripts were significantly increased in androgenindependent LNCaP sublines (104R1, abl) established by long-term androgen deprivation [34, 35] and bicalutamideresistant LNCaP-BC and VCaP-BC cells [36], as compared to their parental cells (Supplementary Figure S1a)
The current view on the persistent and reactivated androgen receptor (AR) signaling in CRPC, that forms the basis of targeting the ARaxis signaling in androgendeprivation therapy (ADT), is largely based on the facts of positive AR expression detected in clinical CRPC tumor tissues [11, 41], persistent AR activity and intraprostatic androgen levels in primary prostate tumors from androgen deprivation-treated patients [42], recurrent serum PSA levels and the persistent AR activity as shown in experimental xenograft models of CRPC [43,44,45,46,47]
Summary
The initial and advanced growth of prostate cancer is critically dependent on androgens. Hormone or androgendeprivation therapy (ADT), which acts to suppress the androgen receptor (AR) signaling by androgen depletion or AR antagonists, is still the principal treatment option for locally advanced and metastatic prostate cancers. Patients inevitably develop resistance to treatment and relapse with a more aggressive form of castration-resistant prostate cancer (CRPC) within 2–3 years. Most studies on CRPC suggest that the advanced disease progression involves multiple and interrelating AR-dependent mechanisms, including (1) overexpression of AR and its co-regulators, (2) AR point mutations, (3) AR activation by growth factors-mediated signal transduction pathways, (4) AR-mediated activation of oncogenic fusion genes, (5) constitutively active AR splice variants, and (6) intratumoral production of androgens by either conversion from adrenal androgens or de novo androgen biosynthesis from cholesterol via overexpressed steroidogenic enzymes, that leading to persistent and reactivated AR signaling and altered androgen metabolism [1, 2]. Altered AR signaling is still the current research focus in CRPC
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