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Cancer Res. 2015 Sep 1;75(17):3663-71. doi: 10.1158/0008-5472.CAN-15-0381. Epub 2015 Jun 9.

Androgen Receptor Splice Variants Dimerize to Transactivate Target Genes.

Author information

1
College of Life Sciences, Jilin University, Changchun, China. Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana. School of Nursing, Jilin University, Changchun, China.
2
Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana.
3
College of Life Sciences, Jilin University, Changchun, China. Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana.
4
McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wisconsin.
5
Bio-X Program and Department of Radiology, Stanford University School of Medicine, Stanford, California.
6
Department of Pathology, New York University School of Medicine, New York, New York.
7
Department of Urology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana. Department of Medicine, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana.
8
Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana.
9
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana.
10
College of Life Sciences, Jilin University, Changchun, China. Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana. National Engineering Laboratory for AIDS Vaccine, Jilin University, Changchun, China. ydong@tulane.edu.

Abstract

Constitutively active androgen receptor splice variants (AR-V) lacking the ligand-binding domain have been implicated in the pathogenesis of castration-resistant prostate cancer and in mediating resistance to newer drugs that target the androgen axis. AR-V regulates expression of both canonical AR targets and a unique set of cancer-specific targets that are enriched for cell-cycle functions. However, little is known about how AR-V controls gene expression. Here, we report that two major AR-Vs, termed AR-V7 and AR(v567es), not only homodimerize and heterodimerize with each other but also heterodimerize with full-length androgen receptor (AR-FL) in an androgen-independent manner. We found that heterodimerization of AR-V and AR-FL was mediated by N- and C-terminal interactions and by the DNA-binding domain of each molecule, whereas AR-V homodimerization was mediated only by DNA-binding domain interactions. Notably, AR-V dimerization was required to transactivate target genes and to confer castration-resistant cell growth. Our results clarify the mechanism by which AR-Vs mediate gene regulation and provide a pivotal pathway for rational drug design to disrupt AR-V signaling as a rational strategy for the effective treatment of advanced prostate cancer.

PMID:
26060018
PMCID:
PMC4558376
DOI:
10.1158/0008-5472.CAN-15-0381
[Indexed for MEDLINE]
Free PMC Article

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