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.

Cheng-Lung Hsu ¹, Jai-Shin Liu ², Po-Long Wu ³, Hong-Hsiang Guan ⁴, Yuh-Ling Chen ⁵, An-Chi Lin ⁶, Huei-Ju Ting ⁷, See-Tong Pang ⁸, Shauh-Der Yeh ⁷, Wen-Lung Ma ⁹, Chung-Jung Chen ⁴, Wen-Guey Wu ¹⁰, Chawnshang Chang ¹¹

Affiliations

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].

PMID: 25091737 DOI: 10.1016/j.molonc.2014.06.009

Abstract

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.

Keywords

Androgen receptor; Anti-androgen withdrawal syndrome; BUD31; Crystallography; FxxLF.

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