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A positive role of c-Myc in regulating androgen receptor and its splice variants in prostate cancer.
- Source :
-
Oncogene [Oncogene] 2019 Jun; Vol. 38 (25), pp. 4977-4989. Date of Electronic Publication: 2019 Feb 28. - Publication Year :
- 2019
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5594
- Volume :
- 38
- Issue :
- 25
- Database :
- MEDLINE
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 30820039
- Full Text :
- https://doi.org/10.1038/s41388-019-0768-8