Targeting a Single Alternative Polyadenylation Site Coordinately Blocks Expression of Androgen Receptor mRNA Splice Variants in Prostate Cancer
| Autor: | Scott M. Dehm, Michael D. Nyquist, Daniel F. Voytas, Jamie L. Van Etten, Rendong Yang, Olivia Ondigi, Yeung Ho, Christine Henzler, Yingming Li, Rachel M. Gibbons Johnson |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Cancer Research Morpholino Polyadenylation Apoptosis Biology urologic and male genital diseases Article 03 medical and health sciences Prostate cancer Tumor Cells Cultured medicine Humans Gene silencing RNA Messenger Transcription factor Cell Proliferation Alternative splicing Cancer medicine.disease Molecular biology Gene Expression Regulation Neoplastic Androgen receptor Alternative Splicing Prostatic Neoplasms Castration-Resistant 030104 developmental biology Oncology Receptors Androgen Cancer research |
| Zdroj: | Cancer Research. 77:5228-5235 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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