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

Cheng Lung Hsu, Jai Shin Liu, Po Long Wu, Hong Hsiang Guan, Yuh Ling Chen, An Chi Lin, Huei Ju Ting, See Tong Pang, Shauh Der Yeh, Wen Lung Ma, Chung Jung Chen, Wen Guey Wu, Chawnshang Chang

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1575-1587
Number of pages13
JournalMolecular Oncology
Volume8
Issue number8
DOIs
Publication statusPublished - Dec 1 2014
Externally publishedYes

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Keywords

  • Androgen receptor
  • Anti-androgen withdrawal syndrome
  • BUD31
  • Crystallography
  • FxxLF

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Medicine

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