Transgelin functions as a suppressor via inhibition of ARA54-enhanced androgen receptor transactivation and prostate cancer cell growth

Zhiming Yang, Yu Jia Chang, Hiroshi Miyamoto, Jing Ni, Yuanjie Niu, Zhaodian Chen, Yuh Ling Chen, Jorge L. Yao, P. Anthony Di Sant'Agnese, Chawnshang Chang

Research output: Contribution to journalArticle

70 Citations (Scopus)

Abstract

The androgen receptor (AR) requires coregulators for its optimal function. However, whether AR co-regulators further need interacting protein(s) for their proper function remains unclear. Here we describe transgelin as the first ARA54-associated negative modulator for AR. Transgelin suppressed ARA54-enhanced AR function in ARA54-positive, but not in ARA54-negative, cells. Transgelin suppressed AR transactivation via interruption of ARA54 homodimerization and AR-ARA54 heterodimerization, resulting in the cytoplasmic retention of AR and ARA54. Stable transfection of transgelin in LNCaP cells suppressed AR-mediated cell growth and prostate-specific antigen expression, whereas this suppressive effect was abolished by the addition of ARA54-small interfering RNA. Results from tissue surveys showing decreased expression of transgelin in prostate cancer specimens further strengthened the suppressor role of transgelin. Our findings reveal the novel mechanisms of how transgelin functions as a suppressor to inhibit prostate cancer cell growth. They also demonstrate that AR coregulators, like ARA54, might have dual in vivo roles functioning as both a direct coactivator and as an indirect mediator in AR function. The finding that a protein can modulate AR function without direct interaction with AR might provide a new therapeutic approach, with fewer side effects, to battle prostate cancer by targeting AR indirectly.

Original languageEnglish
Pages (from-to)343-358
Number of pages16
JournalMolecular Endocrinology
Volume21
Issue number2
DOIs
Publication statusPublished - Feb 2007

Fingerprint

Androgen Receptors
Transcriptional Activation
Prostatic Neoplasms
Growth
transgelin
Prostate-Specific Antigen
Small Interfering RNA
Transfection
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism

Cite this

Transgelin functions as a suppressor via inhibition of ARA54-enhanced androgen receptor transactivation and prostate cancer cell growth. / Yang, Zhiming; Chang, Yu Jia; Miyamoto, Hiroshi; Ni, Jing; Niu, Yuanjie; Chen, Zhaodian; Chen, Yuh Ling; Yao, Jorge L.; Di Sant'Agnese, P. Anthony; Chang, Chawnshang.

In: Molecular Endocrinology, Vol. 21, No. 2, 02.2007, p. 343-358.

Research output: Contribution to journalArticle

Yang, Zhiming ; Chang, Yu Jia ; Miyamoto, Hiroshi ; Ni, Jing ; Niu, Yuanjie ; Chen, Zhaodian ; Chen, Yuh Ling ; Yao, Jorge L. ; Di Sant'Agnese, P. Anthony ; Chang, Chawnshang. / Transgelin functions as a suppressor via inhibition of ARA54-enhanced androgen receptor transactivation and prostate cancer cell growth. In: Molecular Endocrinology. 2007 ; Vol. 21, No. 2. pp. 343-358.
@article{ea1f70fd6cfc4233a31259fb25a97f8b,
title = "Transgelin functions as a suppressor via inhibition of ARA54-enhanced androgen receptor transactivation and prostate cancer cell growth",
abstract = "The androgen receptor (AR) requires coregulators for its optimal function. However, whether AR co-regulators further need interacting protein(s) for their proper function remains unclear. Here we describe transgelin as the first ARA54-associated negative modulator for AR. Transgelin suppressed ARA54-enhanced AR function in ARA54-positive, but not in ARA54-negative, cells. Transgelin suppressed AR transactivation via interruption of ARA54 homodimerization and AR-ARA54 heterodimerization, resulting in the cytoplasmic retention of AR and ARA54. Stable transfection of transgelin in LNCaP cells suppressed AR-mediated cell growth and prostate-specific antigen expression, whereas this suppressive effect was abolished by the addition of ARA54-small interfering RNA. Results from tissue surveys showing decreased expression of transgelin in prostate cancer specimens further strengthened the suppressor role of transgelin. Our findings reveal the novel mechanisms of how transgelin functions as a suppressor to inhibit prostate cancer cell growth. They also demonstrate that AR coregulators, like ARA54, might have dual in vivo roles functioning as both a direct coactivator and as an indirect mediator in AR function. The finding that a protein can modulate AR function without direct interaction with AR might provide a new therapeutic approach, with fewer side effects, to battle prostate cancer by targeting AR indirectly.",
author = "Zhiming Yang and Chang, {Yu Jia} and Hiroshi Miyamoto and Jing Ni and Yuanjie Niu and Zhaodian Chen and Chen, {Yuh Ling} and Yao, {Jorge L.} and {Di Sant'Agnese}, {P. Anthony} and Chawnshang Chang",
year = "2007",
month = "2",
doi = "10.1210/me.2006-0104",
language = "English",
volume = "21",
pages = "343--358",
journal = "Molecular Endocrinology",
issn = "0888-8809",
publisher = "The Endocrine Society",
number = "2",

}

TY - JOUR

T1 - Transgelin functions as a suppressor via inhibition of ARA54-enhanced androgen receptor transactivation and prostate cancer cell growth

AU - Yang, Zhiming

AU - Chang, Yu Jia

AU - Miyamoto, Hiroshi

AU - Ni, Jing

AU - Niu, Yuanjie

AU - Chen, Zhaodian

AU - Chen, Yuh Ling

AU - Yao, Jorge L.

AU - Di Sant'Agnese, P. Anthony

AU - Chang, Chawnshang

PY - 2007/2

Y1 - 2007/2

N2 - The androgen receptor (AR) requires coregulators for its optimal function. However, whether AR co-regulators further need interacting protein(s) for their proper function remains unclear. Here we describe transgelin as the first ARA54-associated negative modulator for AR. Transgelin suppressed ARA54-enhanced AR function in ARA54-positive, but not in ARA54-negative, cells. Transgelin suppressed AR transactivation via interruption of ARA54 homodimerization and AR-ARA54 heterodimerization, resulting in the cytoplasmic retention of AR and ARA54. Stable transfection of transgelin in LNCaP cells suppressed AR-mediated cell growth and prostate-specific antigen expression, whereas this suppressive effect was abolished by the addition of ARA54-small interfering RNA. Results from tissue surveys showing decreased expression of transgelin in prostate cancer specimens further strengthened the suppressor role of transgelin. Our findings reveal the novel mechanisms of how transgelin functions as a suppressor to inhibit prostate cancer cell growth. They also demonstrate that AR coregulators, like ARA54, might have dual in vivo roles functioning as both a direct coactivator and as an indirect mediator in AR function. The finding that a protein can modulate AR function without direct interaction with AR might provide a new therapeutic approach, with fewer side effects, to battle prostate cancer by targeting AR indirectly.

AB - The androgen receptor (AR) requires coregulators for its optimal function. However, whether AR co-regulators further need interacting protein(s) for their proper function remains unclear. Here we describe transgelin as the first ARA54-associated negative modulator for AR. Transgelin suppressed ARA54-enhanced AR function in ARA54-positive, but not in ARA54-negative, cells. Transgelin suppressed AR transactivation via interruption of ARA54 homodimerization and AR-ARA54 heterodimerization, resulting in the cytoplasmic retention of AR and ARA54. Stable transfection of transgelin in LNCaP cells suppressed AR-mediated cell growth and prostate-specific antigen expression, whereas this suppressive effect was abolished by the addition of ARA54-small interfering RNA. Results from tissue surveys showing decreased expression of transgelin in prostate cancer specimens further strengthened the suppressor role of transgelin. Our findings reveal the novel mechanisms of how transgelin functions as a suppressor to inhibit prostate cancer cell growth. They also demonstrate that AR coregulators, like ARA54, might have dual in vivo roles functioning as both a direct coactivator and as an indirect mediator in AR function. The finding that a protein can modulate AR function without direct interaction with AR might provide a new therapeutic approach, with fewer side effects, to battle prostate cancer by targeting AR indirectly.

UR - http://www.scopus.com/inward/record.url?scp=33846642151&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33846642151&partnerID=8YFLogxK

U2 - 10.1210/me.2006-0104

DO - 10.1210/me.2006-0104

M3 - Article

VL - 21

SP - 343

EP - 358

JO - Molecular Endocrinology

JF - Molecular Endocrinology

SN - 0888-8809

IS - 2

ER -