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

doi:10.1016/j.molonc.2014.06.009

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

研究成果: 雜誌貢獻 › 文章 › 同行評審

43 引文斯高帕斯（Scopus）

摘要

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.

原文	英語
頁（從 - 到）	1575-1587
頁數	13
期刊	Molecular Oncology
卷	8
發行號	8
DOIs	https://doi.org/10.1016/j.molonc.2014.06.009
出版狀態	已發佈 - 12月 1 2014

ASJC Scopus subject areas

遺傳學
分子醫學
腫瘤科
癌症研究

UN SDG

此研究成果有助於以下永續發展目標

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10.1016/j.molonc.2014.06.009

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Link to publication in Scopus

引用此

Hsu, C. L., Liu, J. S., Wu, P. L., Guan, H. H., Chen, Y. L., Lin, A. C., Ting, H. J., Pang, S. T., Yeh, S. D., Ma, W. L., Chen, C. J., Wu, W. G., & Chang, C. (2014). 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. Molecular Oncology, 8(8), 1575-1587. https://doi.org/10.1016/j.molonc.2014.06.009

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. / Hsu, Cheng Lung; Liu, Jai Shin; Wu, Po Long 等.
於: Molecular Oncology, 卷 8, 編號 8, 01.12.2014, p. 1575-1587.

研究成果: 雜誌貢獻 › 文章 › 同行評審

Hsu, CL, Liu, JS, Wu, PL, Guan, HH, Chen, YL, Lin, AC, Ting, HJ, Pang, ST, Yeh, SD, Ma, WL, Chen, CJ, Wu, WG & Chang, C 2014, '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', Molecular Oncology, 卷 8, 編號 8, 頁 1575-1587. https://doi.org/10.1016/j.molonc.2014.06.009

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title = "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",

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",

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

note = "Funding Information: We thank Karen L. Wolf for proofreading. We also thank the staff at the National Synchrotron Radiation Research Center in Taiwan for access to the Beamline BL13B. Portions of this research were carried out at the National Synchrotron Radiation Research Center, a national user facility supported by the National Science Council of Taiwan, ROC. The Synchrotron Radiation Protein Crystallography Facility is supported by the National Core Facility Program for Biotechnology. Publisher Copyright: {\textcopyright} 2014 Federation of European Biochemical Societies.",

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doi = "10.1016/j.molonc.2014.06.009",

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T1 - 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

AU - Hsu, Cheng Lung

AU - Liu, Jai Shin

AU - Wu, Po Long

AU - Guan, Hong Hsiang

AU - Chen, Yuh Ling

AU - Lin, An Chi

AU - Ting, Huei Ju

AU - Pang, See Tong

AU - Yeh, Shauh Der

AU - Ma, Wen Lung

AU - Chen, Chung Jung

AU - Wu, Wen Guey

AU - Chang, Chawnshang

N1 - Funding Information: We thank Karen L. Wolf for proofreading. We also thank the staff at the National Synchrotron Radiation Research Center in Taiwan for access to the Beamline BL13B. Portions of this research were carried out at the National Synchrotron Radiation Research Center, a national user facility supported by the National Science Council of Taiwan, ROC. The Synchrotron Radiation Protein Crystallography Facility is supported by the National Core Facility Program for Biotechnology. Publisher Copyright: © 2014 Federation of European Biochemical Societies.

PY - 2014/12/1

Y1 - 2014/12/1

N2 - 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.

AB - 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.

KW - Androgen receptor

KW - Anti-androgen withdrawal syndrome

KW - BUD31

KW - Crystallography

KW - FxxLF

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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

摘要

ASJC Scopus subject areas

UN SDG

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