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ZFX Mediates Non-canonical Oncogenic Functions of the Androgen Receptor Splice Variant 7 in Castrate-Resistant Prostate Cancer.
Cai, Ling; Tsai, Yi-Hsuan; Wang, Ping; Wang, Jun; Li, Dongxu; Fan, Huitao; Zhao, Yilin; Bareja, Rohan; Lu, Rui; Wilson, Elizabeth M; Sboner, Andrea; Whang, Young E; Zheng, Deyou; Parker, Joel S; Earp, H Shelton; Wang, Gang Greg.
Afiliação
  • Cai L; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA; Department of Genetics, Universit
  • Tsai YH; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
  • Wang P; Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  • Wang J; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
  • Li D; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
  • Fan H; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
  • Zhao Y; Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  • Bareja R; Meyer Cancer Center and Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
  • Lu R; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
  • Wilson EM; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
  • Sboner A; Meyer Cancer Center and Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
  • Whang YE; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA; Department of Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
  • Zheng D; Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Neurology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  • Parker JS; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
  • Earp HS; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA; Department of Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Caro
  • Wang GG; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA. Electronic address: greg_wang@med
Mol Cell ; 72(2): 341-354.e6, 2018 10 18.
Article em En | MEDLINE | ID: mdl-30270106
ABSTRACT
Androgen receptor splice variant 7 (AR-V7) is crucial for prostate cancer progression and therapeutic resistance. We show that, independent of ligand, AR-V7 binds both androgen-responsive elements (AREs) and non-canonical sites distinct from full-length AR (AR-FL) targets. Consequently, AR-V7 not only recapitulates AR-FL's partial functions but also regulates an additional gene expression program uniquely via binding to gene promoters rather than ARE enhancers. AR-V7 binding and AR-V7-mediated activation at these unique targets do not require FOXA1 but rely on ZFX and BRD4. Knockdown of ZFX or select unique targets of AR-V7/ZFX, or BRD4 inhibition, suppresses growth of castration-resistant prostate cancer cells. We also define an AR-V7 direct target gene signature that correlates with AR-V7 expression in primary tumors, differentiates metastatic prostate cancer from normal, and predicts poor prognosis. Thus, AR-V7 has both ARE/FOXA1 canonical and ZFX-directed non-canonical regulatory functions in the evolution of anti-androgen therapeutic resistance, providing information to guide effective therapeutic strategies.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Oncogenes / Receptores Androgênicos / Processamento Alternativo / Fatores de Transcrição Kruppel-Like / Neoplasias de Próstata Resistentes à Castração / Carcinogênese Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2018 Tipo de documento: Article
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Oncogenes / Receptores Androgênicos / Processamento Alternativo / Fatores de Transcrição Kruppel-Like / Neoplasias de Próstata Resistentes à Castração / Carcinogênese Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2018 Tipo de documento: Article