1. A positive role of c-Myc in regulating androgen receptor and its splice variants in prostate cancer.
- Author
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Bai S, Cao S, Jin L, Kobelski M, Schouest B, Wang X, Ungerleider N, Baddoo M, Zhang W, Corey E, Vessella RL, Dong X, Zhang K, Yu X, Flemington EK, and Dong Y
- Subjects
- Adenocarcinoma pathology, Alternative Splicing genetics, Animals, Cells, Cultured, Gene Expression Regulation, Neoplastic, HEK293 Cells, Humans, Male, Mice, Mice, Inbred C57BL, Mice, SCID, Prostatic Neoplasms, Castration-Resistant pathology, Protein Isoforms genetics, Adenocarcinoma genetics, Prostatic Neoplasms, Castration-Resistant genetics, Proto-Oncogene Proteins c-myc physiology, Receptors, Androgen genetics
- Abstract
Increased expression of the full-length androgen receptor (AR-FL) and AR splice variants (AR-Vs) drives the progression of castration-resistant prostate cancer (CRPC). The levels of AR-FL and AR-V transcripts are often tightly correlated in individual CRPC samples, yet our understanding of how their expression is co-regulated is limited. Here, we report a role of c-Myc in accounting for coordinated AR-FL and AR-V expression. Analysis of gene-expression data from 159 metastatic CRPC samples and 2142 primary prostate tumors showed that the level of c-Myc is positively correlated with that of individual AR isoforms. A striking positive correlation also exists between the activity of the c-Myc pathway and the level of individual AR isoforms, between the level of c-Myc and the activity of the AR pathway, and between the activities of the two pathways. Moreover, the c-Myc signature is highly enriched in tumors expressing high levels of AR, as is the AR signature in c-Myc-high-expressing tumors. Using shRNA knockdown, we confirmed c-Myc regulation of expression and activity of AR-FL and AR-Vs in cell models and a patient-derived xenograft model. Mechanistically, c-Myc promotes the transcription of the AR gene and enhances the stability of the AR-FL and AR-V proteins without altering AR RNA splicing. Importantly, inhibiting c-Myc sensitizes enzalutamide-resistant cells to growth inhibition by enzalutamide. Overall, this study highlights a critical role of c-Myc in regulating the coordinated expression of AR-FL and AR-Vs that is commonly observed in CRPC and suggests the utility of targeting c-Myc as an adjuvant to AR-directed therapy.
- Published
- 2019
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