Androgen receptor promotes melanoma metastasis via altering the miRNA-539-3p/USP13/MITF/AXL signals

• Published in: Oncogene 2017-03, Vol.36 (12), p.1644-1654
• Main Authors: Wang, Y, Ou, Z, Sun, Y, Yeh, S, Wang, X, Long, J, Chang, C
• Format: Article
• Language: English
• Subjects: 13; 13/106; 13/109; 13/51; 38; 38/77; 631/67/395; 631/80/304; 82; 82/1; Androgen receptors; Androgens; Animals; Apoptosis; Axl protein; Cancer metastasis; Cell Biology; Cell Line, Tumor; Cell lines; Cell Movement - genetics; Cluster Analysis; Comparative analysis; Development and progression; Disease Models, Animal; Endopeptidases - genetics; Female; Gene Expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Heterografts; Human Genetics; Humans; Internal Medicine; Male; Medicine; Medicine & Public Health; Melanoma; Melanoma - genetics; Melanoma - metabolism; Melanoma - mortality; Melanoma - pathology; Metastases; Metastasis; Mice; Microphthalmia-associated transcription factor; Microphthalmia-Associated Transcription Factor - metabolism; MicroRNA; MicroRNAs - genetics; Middle Aged; miRNA; Neoplasm Invasiveness; Oncology; original-article; Physiological aspects; Prognosis; Proto-Oncogene Proteins - metabolism; Receptor Protein-Tyrosine Kinases - metabolism; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Ribonucleic acid; RNA; RNA Interference; Signal Transduction; Tumor Burden; Ubiquitination
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2016.330

Early studies demonstrated that male melanoma patients have worse survival than female patients, yet the detailed mechanisms for this gender difference remain unclear. We analyzed around 100 cases of human melanoma and found that androgen receptor (AR) positive melanoma patients have worse survival outcomes compared with AR-negative melanoma patients. Here we report that AR can have positive roles to increase melanoma cell invasion in multiple cell lines in vitro and a mouse model in vivo . Mechanism dissection suggest that AR increases melanoma cell invasion via modulating the MITF-AXL signals via altering the miRNA-539-3p/USP13 signaling to increase MITF protein degradation through a reduction of de-ubiquitination. Restoring MITF can reverse AR-enhanced melanoma cell invasion. Together, our results demonstrate that AR can promote melanoma metastasis via altering the miRNA-539-3p/USP13/MITF/AXL signal and targeting this newly identified signal with AR degradation enhancer ASC-J9 may help us to better suppress the melanoma metastasis.