Targeting a single alternative polyadenylation site coordinately blocks expression of androgen receptor mRNA splice variants in prostate cancer

Jamie L. Van Etten, Michael Nyquist, Yingming Li, Rendong Yang, Yeung Ho, Rachel Johnson, Olivia Ondigi, Daniel F. Voytas, Christine Henzler, Scott M. Dehm

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5228-5235
Number of pages8
JournalCancer Research
Volume77
Issue number19
DOIs
StatePublished - Oct 1 2017

Bibliographical note

Funding Information:
This study was funded by a grant from the NIH (R01CA174777 to S. M. Dehm). J.L. Van Etten was supported by T32 CA009138. This work was also supported by a Prostate Cancer Foundation (PCF) Young Investigator Award to R. Yang and a PCF Challenge Grant to S.M. Dehm.

Publisher Copyright:
©2017 AACR.

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