Targeting a Single Alternative Polyadenylation Site Coordinately Blocks Expression of Androgen Receptor mRNA Splice Variants in Prostate Cancer.

Autor:	Van Etten JL; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota., Nyquist M; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.; Graduate Program in Molecular, Cellular, and Developmental Biology and Genetics, University of Minnesota, Minneapolis, Minnesota., Li Y; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota., Yang R; Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, Minnesota., Ho Y; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota., Johnson R; College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota., Ondigi O; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota., Voytas DF; Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota., Henzler C; Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, Minnesota., Dehm SM; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota. dehm@umn.edu.; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota.; Department of Urology, University of Minnesota, Minneapolis, Minnesota.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2017 Oct 01; Vol. 77 (19), pp. 5228-5235. Date of Electronic Publication: 2017 Aug 15.
DOI:	10.1158/0008-5472.CAN-17-0320
Abstrakt:	Prostate cancer is the second leading cause of male cancer deaths due to disease progression to castration-resistant prostate cancer (CRPC). Androgen receptor (AR) splice variants including AR-V7 function as constitutively active transcription factors in CRPC cells, thereby promoting resistance to AR-targeted therapies. To date, there are no AR variant-specific treatments for CRPC. Here we report that the splicing of AR variants AR-V7 as well as AR-V1 and AR-V9 is regulated coordinately by a single polyadenylation signal in AR intron 3. Blocking this signal with morpholino technology or silencing of the polyadenylation factor CPSF1 caused a splice switch that inhibited expression of AR variants and blocked androgen-independent growth of CRPC cells. Our findings support the development of new therapies targeting the polyadenylation signal in AR intron 3 as a strategy to prevent expression of a broad array of AR variants in CRPC. Cancer Res; 77(19); 5228-35. ©2017 AACR . (©2017 American Association for Cancer Research.)
Databáze:	MEDLINE
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