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.
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We are grateful to Dr. Alan Meeker at Johns Hopkins University for providing LNCaP95 cells, to Dr. Donald Vander Griend at the University of Illinois at Chicago for providing CWR-R1-EnzR cells, and to Dr. Robert Matusik at Vanderbilt School of Medicine for providing the ARR3-luc construct. We appreciate the support from the Tulane Cancer Next Generation Sequence Analysis core for utilization of resources and expertise for this work.
Conflict of interest
This work was supported by the following grants: the National Institutes of Health grants R01CA188609, R01AI101046, R01AI106676, P01CA214091, RCMI 2G12MD007595, and P20GM103518; Department of Defense grants W81XWH-15-1-0439, W81XWH-16-1-0317, W81XWH-16-1-0318, and W81XWH-14-1-0485; National Natural Science Foundation of China Project 81430087. The Richard M. Lucas Foundation supported the development of the LuCaP 35CR model. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.
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Bai, S., Cao, S., Jin, L. et al. A positive role of c-Myc in regulating androgen receptor and its splice variants in prostate cancer. Oncogene 38, 4977–4989 (2019). https://doi.org/10.1038/s41388-019-0768-8
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