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| Content Provider | PubMed Central |
|---|---|
| Author | Savoy, Rosalinda M. Chen, Liqun Siddiqui, Salma Melgoza, Frank U. Blythe, Durbin-johnson Drake, Christiana Jathal, Maitreyee K. Bose, Swagata Steele, Thomas M. Mooso, Benjamin A. D’abronzo, Leandro S. Fry, William H. Carraway, Kermit L. Maria, Mudryj Ghosh, Paramita M. |
| Abstract | Prostate cancer (PCa) progression is regulated by the androgen receptor (AR); however, patients undergoing androgen deprivation therapy (ADT) for disseminated PCa eventually develop castration resistant PCa (CRPC). Studies showed that AR, a transcription factor, occupies distinct genomic loci in CRPC compared to hormone-naïve PCa; however, the cause for this distinction was unknown. The E3 ubiquitin ligase Nrdp1 is a model AR target modulated by androgens in hormone-naïve PCa but not in CRPC. Using Nrdp1, we investigated how AR switches transcription programs during CRPC progression. The proximal Nrdp1 promoter contains an androgen response element (ARE); we demonstrated AR binding to this ARE in androgen-sensitive PCa. Analysis of hormone-naive human prostatectomy specimens revealed correlation between Nrdp1 and AR expression, supporting AR regulation of Nrdp1 levels in androgen-sensitive tissue. However, despite sustained AR levels, AR binding to the Nrdp1 promoter and Nrdp1 expression were suppressed in CRPC. Elucidation of the suppression mechanism demonstrated correlation of Nrdp1 levels with nuclear localization of the scaffolding protein Filamin A (FlnA) which, as we previously showed, is itself repressed following ADT in many CRPC tumors. Restoration of nuclear FlnA in CRPC stimulated AR binding to Nrdp1 ARE, increased its transcription, and augmented Nrdp1 protein expression and responsiveness to ADT, indicating that nuclear FlnA controls AR-mediated androgen-sensitive Nrdp1 transcription. Expressions of other AR-regulated genes lost in CRPC were also re-established by nuclear FlnA. Thus our data demonstrate that nuclear FlnA promotes androgen-dependent AR-regulated transcription in PCa, while loss of nuclear FlnA in CRPC alters the AR-regulated transcription program. |
| Related Links | http://dx.doi.org/10.1530/erc-15-0021 |
| Ending Page | 386 |
| Page Count | 18 |
| Starting Page | 369 |
| File Format | |
| ISSN | 13510088 |
| e-ISSN | 14796821 |
| Journal | Endocrine-related cancer |
| Issue Number | 3 |
| Volume Number | 22 |
| Language | English |
| Publisher Date | 2015-05-13 |
| Access Restriction | Open |
| Subject Keyword | Cancer Research Oncology Endocrinology, Diabetes and Metabolism Endocrinology Research in Higher Education |
| Content Type | Text |
| Resource Type | Article |
| Subject | Endocrinology, Diabetes and Metabolism Cancer Research Endocrinology Oncology |
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