Nonclassical testosterone signaling through ZIP9 renders melanoma more aggressive in males than in females

Melanoma and most other cancers occur more frequently, and have worse prognosis, in males vs. females. Though sex steroids are thought to be involved, melanoma lacks classical androgen and estrogen receptors. Here we show that testosterone promotes melanoma proliferation by activating ZIP9/SLC39A9, a zinc channel that is not intentionally targeted by any available therapeutics. Testosterone9s pro-tumorigenic activity requires zinc influx, MAPK activation and YAP1 nuclear translocation. We demonstrate that inhibitors of the classical androgen receptor (AR), also inhibit ZIP9, and thereby antagonize the pro-tumorigenic effects of testosterone in melanoma. In male mice, AR inhibitors suppressed growth of ZIP9 expressing melanomas, but had no effect on isogenic melanomas lacking ZIP9, nor on melanomas in females. These data suggest that ZIP9 might be effectively targeted in melanoma and other cancers by repurposing modern AR inhibitors, which are currently approved only for prostate cancer.