ZFX Mediates Non-canonical Oncogenic Functions of the Androgen Receptor Splice Variant 7 in Castrate-Resistant Prostate Cancer

Ling Cai; Yi-Hsuan Tsai; Ping Wang; Jun Wang; Dongxu Li; Huitao Fan; Yilin Zhao; Rohan Bareja; Rui Lu; Elizabeth M Wilson; Andrea Sboner; Young E Whang; Deyou Zheng; Joel S Parker; H Shelton Earp; Gang Greg Wang

doi:10.1016/j.molcel.2018.08.029

ZFX Mediates Non-canonical Oncogenic Functions of the Androgen Receptor Splice Variant 7 in Castrate-Resistant Prostate Cancer

Mol Cell. 2018 Oct 18;72(2):341-354.e6. doi: 10.1016/j.molcel.2018.08.029. Epub 2018 Sep 27.

Authors

Ling Cai¹, Yi-Hsuan Tsai², Ping Wang³, Jun Wang⁴, Dongxu Li⁴, Huitao Fan⁴, Yilin Zhao³, Rohan Bareja⁵, Rui Lu⁴, Elizabeth M Wilson⁴, Andrea Sboner⁵, Young E Whang⁶, Deyou Zheng⁷, Joel S Parker⁸, H Shelton Earp⁹, Gang Greg Wang¹⁰

Affiliations

¹ 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, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
² Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
³ Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
⁴ 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.
⁵ 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.
⁶ 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.
⁷ 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.
⁸ 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.
⁹ 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 Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA. Electronic address: hse@med.unc.edu.
¹⁰ 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.unc.edu.

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.

Keywords: AR-V7; BRD4; Enzalutamide; MDV3100; ZFX; androgen receptor; bromodomain inhibitor; castration resistance; prostate cancer; therapy resistance.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Alternative Splicing / genetics*
Animals
Carcinogenesis / genetics*
Cell Differentiation / genetics
Cell Line
Cell Line, Tumor
Drug Resistance, Neoplasm / genetics
Gene Expression Regulation, Neoplastic / genetics
HEK293 Cells
Hepatocyte Nuclear Factor 3-alpha / genetics
Humans
Kruppel-Like Transcription Factors / genetics*
Male
Mice
Mice, Inbred NOD
Mice, SCID
Nuclear Proteins / genetics
Oncogenes / genetics*
Promoter Regions, Genetic / genetics
Prostatic Neoplasms, Castration-Resistant / genetics*
Receptors, Androgen / genetics*

Substances

Hepatocyte Nuclear Factor 3-alpha
Kruppel-Like Transcription Factors
Nuclear Proteins
Receptors, Androgen
zinc finger protein, X-linked

Abstract

Publication types

MeSH terms

Substances

Grants and funding