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Functional analysis of androgen receptor N-terminal and ligand binding domain interacting coregulators in prostate
1George Whipple Laboratory for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and Cancer Center, University of Rochester, Rochester, NY 14642, USA.
Abstract:
Several new androgen receptor (AR) coregulators, including ARA70, ARA55, ARA54, ARA160 and ARA24, associated with the N-terminal or the ligand-binding domain (LBD) of AR, have been identified by our group. We first identified the AR-LBD coregulators ARA70, ARA55, and ARA54. Our previous reports suggest that ARA70 can enhance the androgenic activity of 17 beta-estradiol (E2) and antiandrogens toward AR. It is of interest to compare and determine if the specificity of sex hormones and antiandrogens can be modulated by different coregulators. Our results indicate that, ARA70 is the best coregulator for increasing the androgenic activity of E2. Only ARA70 and ARA55 were able to significantly increase the androgenic activity of hydroxyflutamide, the active metabolite of a widely-used antiandrogen for the treatment of prostate cancer. Furthermore, our results suggest that among the LBD coregulators, ARA70 has a relatively high specificity for AR in the human prostate cancer cell line DU145. Together, our data suggest that the androgenic activity of some sex hormones and antiandrogens can be modulated by selective AR coactivators. In addition to the AR-LBD associated proteins, ARA24 and ARA160 have been identified as AR coregulators, interacting with the AR N-terminal instead of the LBD. Functional analysis revealed that the AR N-terminal coregulator ARA160 could cooperate with the AR LBD-associated coregulator ARA70. Our data indicate that ARA24 could also interact with AR, and that this binding is decreased by an expanding poly-glutamine (Q) length within AR. The length of the poly-Q stretch in the AR N-terminal domain is inversely correlated with the transcriptional activity of AR. Our data suggest that optimal AR transactivation may require interaction of AR with AR coregulators. The identification of factors or peptides that can interrupt androgen-mediated AR-ARA interactions may be useful in the development of better antiandrogens for treating androgen-related diseases, such as prostate cancer.
Insights
New androgen receptor (AR) coregulators modulate hormone and anti-androgen activity. Specific coregulators like ARA70 enhance androgenic activity, offering potential for new prostate cancer treatments.
Area of Science:
- Molecular Endocrinology
- Cancer Biology
- Signal Transduction
Background:
- Androgen receptor (AR) signaling is crucial in prostate cancer.
- AR activity is modulated by various coregulator proteins.
- Identifying specific AR coregulators can reveal new therapeutic targets.
Purpose of the Study:
- To identify and characterize novel AR coregulators.
- To investigate the role of different AR coregulators in modulating the activity of sex hormones and anti-androgens.
- To explore the potential of AR coregulators in developing treatments for prostate cancer.
Main Methods:
- Identification of AR-interacting proteins (coregulators).
- Functional assays to assess the impact of coregulators on AR activity.
- Cell-based studies using human prostate cancer cell lines (DU145).
Main Results:
- Several AR coregulators (ARA70, ARA55, ARA54, ARA160, ARA24) were identified, interacting with either the N-terminal or ligand-binding domain (LBD) of AR.
- ARA70 significantly enhanced the activity of 17 beta-estradiol (E2) and hydroxyflutamide.
- ARA70 and ARA55 selectively enhanced hydroxyflutamide activity, a key metabolite in prostate cancer treatment.
- ARA160 (N-terminal) cooperated with ARA70 (LBD).
- ARA24 binding to AR decreased with increasing poly-glutamine (Q) length, inversely correlating with AR activity.
Conclusions:
- Selective AR coactivators can modulate the androgenic activity of sex hormones and anti-androgens.
- AR coregulator interactions are essential for optimal AR transactivation.
- Targeting AR-coregulator interactions may lead to improved anti-androgen therapies for prostate cancer.