Abstract 2324: Phospho-MED1 mediates the transcriptional regulation of AR splice variants in castration-resistant prostate cancer

• Published in: Cancer research (Chicago, Ill.) Vol. 74; no. 19_Supplement; p. 2324
• Main Authors: Liu, Gang, Sprenger, Cynthia, Wu, Pin-Jou, Sun, Shihua, Uo, Takuma, Haugk, Kathleen, Epilepsia, Kathryn Soriano, Plymate, Stephen
• Format: Journal Article
• Language: English
• Published: 01.10.2014
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2014-2324

Abstract The appearance of constitutively active androgen receptor splice variants (AR-Vs) has been proposed as one of the causes of castration-resistant prostate cancer (CRPC). Prior to treatment with enzalutamide or abiraterone, around 20-30% of CRPC patients already have high levels of AR-Vs in their metastases, especially ARv567es, and this portends a rapid progression and shorter survival. However, the underlying mechanism of AR-Vs in CRPC transcriptional regulation still remains unclear. A distinct transcriptome enriched with cell cycle genes (like UBE2C) has been associated with AR-Vs, which indicates the possibility of a different transcriptional mechanism than that of wild type AR. In our study, we performed co-immunoprecipitation, ChIP and luciferase reporter assays to explore the components involved in ARv567es activated UBE2C transcription. We found that (i) MED1 is necessary for ARv567es induced UBE2C up-regulation and subsequent prostate cancer cell growth; (ii) p-MED1 is recruited to ARv567es independent of full-length AR; (iii) p-MED1 has higher recruitment to UBE2C promoter and enhancer regions in the presence of ARv567es, (iv) ARv567es enhanced UBE2C transcription could be blocked by silencing MED1; (v) ARv567es/p-MED1 signaling cross talks with the PI3K-AKT pathway but not the MAPK pathway, and (vi) FoxA1 and histone methylation are involved in ARv567es/p-MED1 induced UBE2C long range chromatin interactions. In summary, these data indicate that p-MED1 serves as a key mediator in ARv567es transcriptional regulation and suggests a mechanism by which AR-Vs promote the development and progression of CRPC. Citation Format: Gang Liu, Cynthia Sprenger, Pin-Jou Wu, Shihua Sun, Takuma Uo, Kathleen Haugk, Kathryn Soriano Epilepsia, Stephen Plymate. Phospho-MED1 mediates the transcriptional regulation of AR splice variants in castration-resistant prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2324. doi:10.1158/1538-7445.AM2014-2324