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

Abstract

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.

Sex and Gender Disparities in Melanoma

“…Many reports demonstrated AR involvement in melanoma growth and invasion in vitro [44,76] and in vivo (Figure 1, right), eventually involving immune response blockage [59]. A recent work conducted on a small number of patients correlated AR-positive melanoma patients with worse survival when compared to those AR negative [58]. In this study, AR was shown to induce miR-539-3p expression that, targeting ubiquitin-specific peptidase 13 (USP13), abolished its de-ubiquitination activity on the microphthalmia-associated transcription factor (MITF) and determined the induction of the receptor tyrosine kinase AXL, with a consequent increase in metastases [58].…”

“…Oral administration of TAM [56] and EDX [57] exert inhibitory effects on tumor metastatization into the mouse lungs. (Right) AR action is responsible for the increased number of lung metastases through the miR-539-3p/USP13/MITF/AXL axis [58], whereas AR blockade mediates an increase in the immune response [59]. T loss in castrated male mice causes a decrease in the anti-tumor neutrophil function [60].…”

miR-337 can be a key negative regulator in melanoma

“…MiR-155 expression is upregulated in lung cancer, and it is positively correlated with the prognosis. [8][9][10][11][12][13][14][15] Therefore, it is speculated that miRNA is likely to be associated with some human tumors, a variety of miRNA expression abnormalities in malignant tumors, but most of the relationship between miRNA and cancer remains to be further studied.…”

Identification of Genes under Purifying Selection in Human Cancers

“…Describing 599/927 genes in these sets, we found many known pathways involved in melanoma growth and survival, such as the sonic hedgehog, WNT, NFκB, PI3K, EGFR, and INFγ pathways, and the proteasome (Rubinfeld et al 1997;Ueda and Richmond 2006;Boone et al 2011;Yaguchi et al 2012;Jalili et al 2013;Selimovic et al 2013;Webster and Weeraratna 2013;Gross et al 2015). We also found a pathway required for immune suppression in melanomas, TNFα (Wang et al 2016). Importantly, genes under increased purifying selection in melanomas are less likely to be generally essential for cell viability when compared to genes under purifying selection in all tumors ( Figure 4D).…”