Identification of a new androgen receptor (AR) co-regulator BUD31 and related peptides to suppress wild-type and mutated AR-mediated prostate cancer growth via peptide screening and X-ray structure analysis
- Mol Oncol. 2014 Dec;8(8):1575-87. doi: 10.1016/j.molonc.2014.06.009.
- 1. The George Whipple Lab for Cancer Research, Department of Pathology and Urology, University of Rochester Medical Center, Rochester, NY 14642, USA; Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan.
- 2. Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan; Department of Physics, Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 300, Taiwan.
- 3. National Synchrotron Radiation Center, Hsinchu 300, Taiwan.
- 4. National Synchrotron Radiation Center, Hsinchu 300, Taiwan; Department of Physics, Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 300, Taiwan.
- 5. The George Whipple Lab for Cancer Research, Department of Pathology and Urology, University of Rochester Medical Center, Rochester, NY 14642, USA; Institute of Oral Medicine, National Cheng Kung University, Tainan 701, Taiwan.
- 6. Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan.
- 7. The George Whipple Lab for Cancer Research, Department of Pathology and Urology, University of Rochester Medical Center, Rochester, NY 14642, USA.
- 8. Division of Urology, Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan.
- 9. The George Whipple Lab for Cancer Research, Department of Pathology and Urology, University of Rochester Medical Center, Rochester, NY 14642, USA; Sex Hormone Research Center, China Medical University/Hospital, Taichung 104, Taiwan.
- 10. National Synchrotron Radiation Center, Hsinchu 300, Taiwan; Department of Physics, Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 300, Taiwan. Electronic address: [email protected].
- 11. The George Whipple Lab for Cancer Research, Department of Pathology and Urology, University of Rochester Medical Center, Rochester, NY 14642, USA; Sex Hormone Research Center, China Medical University/Hospital, Taichung 104, Taiwan. Electronic address: [email protected].
Treatment with individual anti-androgens is associated with the development of hot-spot mutations in the Androgen Receptor (AR). Here, we found that anti-androgens-mt-ARs have similar binary structure to the 5α-dihydrotestosterone-wt-AR. Phage display revealed that these ARs bound to similar peptides, including BUD31, containing an Fxx(F/H/L/W/Y)Y motif cluster with Tyr in the +5 position. Structural analyses of the AR-LBD-BUD31 complex revealed formation of an extra hydrogen bond between the Tyr+5 residue of the peptide and the AR. Functional studies showed that BUD31-related peptides suppressed AR transactivation, interrupted AR N-C interaction, and suppressed AR-mediated cell growth. Combination of peptide screening and X-ray structure analysis may serve as a new strategy for developing anti-ARs that simultaneously suppress both wt and mutated AR function.