Progression of prostate cancer from castration-sensitive to castration-resistant disease is a complex process, which likely involves multiple genetic and epigenetic alterations. Here we report a novel mechanism where MYB acts as a novel binding partner of AR enabling its ligand-independent activation to support castration resistance in prostate cancer. MYB and AR interact and co-localize with each other predominantly in the nuclei. Androgen-depletion or enzalutamide treatment does not interfere with MYB-AR interaction, and MYB-overexpressing prostate cancer cells retain AR in the nucleus even when cultured under androgen-deprived condition. Transcriptional activity of KLK3 (an androgen-responsive gene encoding PSA) promoter is increased in MYB-overexpressing cells, while sustained under androgen-depleted condition. In silico analysis identifies a MYB-binding region in KLK3 promoter in close proximity to the AR binding site, and MYB is shown to cooperatively promote AR binding to the KLK3 promoter. MYB-overexpressing prostate cancer cells exhibit greater tumorigenicity when implanted orthotopically and quickly regain growth following castration leading to the poorer survival of mice, compared to those carrying low MYB-expressing prostate tumors. Together, these findings establish a novel and significant role of MYB-AR cross-talk in prostate cancer, which could be exploited for its therapeutic management.
Citation Format: Sanjeev Kumar Srivastava, Haseeb Zubair, Girijesh K. Patel, Mohammad Aslam Khan, Sachin Kumar Deshmukh, Seema Sing, Joel Andrews, Bin Wang, James E. Carter, Ajay Pratap Singh. A novel MYB-AR cross-talk promoting castration-resistance in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2609.
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