PRPF6 promotes androgen receptor/androgen receptor-variant 7 actions in castration-resistant prostate cancer cells
Wei LiuChunyu WangShengli WangKai ZengShan WeiNing SunGe SunManlin WangRenlong ZouWensu LiuLin LinHuijuan SongZining JinYue Zhao
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Androgen receptor (AR) and its variants play vital roles in development and progression of prostate cancer. To clarify the mechanisms involved in the enhancement of their actions would be crucial for understanding the process in prostate cancer and castration-resistant prostate cancer transformation. Here, we provided the evidence to show that pre-mRNA processing factor 6 (PRPF6) acts as a key regulator for action of both AR full length (AR-FL) and AR variant 7 (AR-V7), thereby participating in the enhancement of AR-FL and AR-V7-induced transactivation in prostate cancer. In addition, PRPF6 is recruited toKeywords:
Androgen Receptor Antagonists
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Androgen receptor (AR) is one of the large superfamily of nuclear hormone receptors. AR consists of distinct domains including an N-terminal DNA-binding domain and a C-terminal ligand-binding domain (LBD). Regulation of AR nuclear import and subsequent transactivation activity represent essential steps in androgen action. Mutations in the AR gene are known to cause different degrees of androgen insensitivity syndrome (AIS). This study aimed to identify the possible contribution of LBD of AR to cellular distribution, ligand binding, and transactivation activities using mutant AR clone lacking the entire LBD that we previously observed in an AIS patient. Subcellular distribution was assessed by green fluorescence protein-tagged vector and transcriptional activity was analyzed by luciferase assay. Wild-type AR had ligand-dependent transcriptional activation and nuclear import activities. On the other hand, mutant AR had no transcriptional activity regardless of the presence of ligand, 5-α-dihydroxytestosterone (DHT). These mutants were presented predominantly in the nucleus even without DHT. The observation of no transactivation in the mutant receptor must be due to the loss of complex formation between androgen and AR protein. The C-terminal domain has the critical role in the cellular localization and transactivation as well as on the ligand binding.
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The androgen receptor (AR) acting as a transcription factor plays a pivotal role in the occurrence and progression of prostate cancer (CaP). Several AR-related factors or modulators have been reported to influence AR activity. Whether and how these factors cooperatively modulate the AR activity has not been well defined. In the present study, the combined effect of p160 coactivators, short CAG length (encoding a short polyQ tract), and AR mutations on AR transactivation in a yeast system was evaluated. It was found that the short polyQ tract can upregulate the transactivation of the wild-type (WT) AR and partial-function (PF) AR mutants in response to a physiological level (10−9 M) of dihydrotestosterone. Addition of a p160 coactivator (SRC-1 or TIF2) to the above systems resulted in a significant increase in the ligand-stimulated transactivation. Although the androgen antagonist bicalutamide could suppress the activity of androgen-activated WT or PF ARs, it was unable to do so for gain-of-function AR mutants. A combination of the short polyQ tract and coactivator TIF2 acted cooperatively on the WT AR and PF AR mutants to enhance their transactivation in response to either a low level of dihydrotestosterone (10−10 M) or adrenal dehydroepiandrosterone. Taken together, this finding suggests that the modulated AR activity may involve early in the carcinogenesis of CaP. Additionally, these data support the concept that a given CaP in which the AR activity is modulated by multiple AR modulators may progress more readily to castrate resistance.
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Early reports showed that androgen receptor (AR) NH2- and COOH-terminal (N-C) interaction was important for full AR function. However, the influence of these interactions on the AR in vivo effects remains unclear. Here we tested some AR-associated peptides and coregulators to determine their influences on AR N-C interaction, AR transactivation, and AR coregulator function. The results showed that AR coactivators such as ARA70N, gelsolin, ARA54, and SRC-1 can enhance AR transactivation but showed differential influences on the N-C interaction. In contrast, AR corepressors ARA67 and Rad9 can suppress AR transactivation, with ARA67 enhancing and Rad9 suppressing AR N-C interaction. Furthermore, liganded AR C terminus-associated peptides can block AR N-C interaction, but only selective peptides can block AR transactivation and coregulator function. We found all the tested peptides can suppress prostate cancer LNCaP cell growth at different levels in the presence of 5alpha-dihydrotestosterone, but only the tested FXXLF-containing peptides, not FXXMF-containing peptides, can suppress prostate cancer CWR22R cell growth. Together, these results suggest that the effects of AR N-C interactions may not always correlate with similar effects on AR-mediated transactivation and/or AR-mediated cell growth. Therefore, drugs designed by targeting AR N-C interaction as a therapeutic intervention for prostate cancer treatment may face unpredictable in vivo effects.
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The proto-oncoprotein c-Jun forms as a heterodimer with c-Fos, the transcription factor AP-1. AP-1 regulates transcription through transactivation, a process requiring DNA binding. Here we report an indirect mechanism by which c-Jun can regulate transcription via the androgen receptor. In this process, c-Jun is able to support androgen receptor-mediated transactivation in the absence of an interaction with c-Fos or any apparent DNA binding. This positive effect of c-Jun was dose-dependent. Both exogenously added and endogenously induced c-Jun are able to act on the androgen receptor. Transactivation by the androgen receptor can undergo self-squelching, and this was relieved by transfected c-Jun. Using a time-course experiment, we provide evidence that the c-Jun effect is primary. c-Fos is able to block human androgen receptor activity in both the absence and presence of transfected c-Jun. Using a modified form of the yeast two-hybrid system, we show in Cos cells that c-Jun can interact with the DNA binding domain/hinge region (CD regions) of the androgen receptor. Therefore, we propose that c-Jun functions as a mediator for androgen receptor-induced transactivation. The proto-oncoprotein c-Jun forms as a heterodimer with c-Fos, the transcription factor AP-1. AP-1 regulates transcription through transactivation, a process requiring DNA binding. Here we report an indirect mechanism by which c-Jun can regulate transcription via the androgen receptor. In this process, c-Jun is able to support androgen receptor-mediated transactivation in the absence of an interaction with c-Fos or any apparent DNA binding. This positive effect of c-Jun was dose-dependent. Both exogenously added and endogenously induced c-Jun are able to act on the androgen receptor. Transactivation by the androgen receptor can undergo self-squelching, and this was relieved by transfected c-Jun. Using a time-course experiment, we provide evidence that the c-Jun effect is primary. c-Fos is able to block human androgen receptor activity in both the absence and presence of transfected c-Jun. Using a modified form of the yeast two-hybrid system, we show in Cos cells that c-Jun can interact with the DNA binding domain/hinge region (CD regions) of the androgen receptor. Therefore, we propose that c-Jun functions as a mediator for androgen receptor-induced transactivation.
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<p>S5: UT-155 prevents nuclear localization of AR and AR v567es. S6: UT-155 binds to AR AF-1 domain. S7: Results from microarray with SARDs.S8: UT-155 inhibits transactivation of AD1 and D567es AR transactivation. Metabolism properties of SARDs.</p>
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