Abstract
Melanoma and most other cancers occur more frequently, and have worse prognosis, in males compared with 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 transporter that is not intentionally targeted by available therapeutics. This activity requires zinc influx, MAPK activation and YAP1 nuclear translocation. We demonstrate that inhibitors of the classical androgen receptor, also inhibit ZIP9, and thereby antagonize the pro-tumorigenic effects of testosterone in melanoma. In male mice, androgen receptor 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 androgen receptor inhibitors that are currently approved only for prostate cancer.
Summary Androgen receptor inhibitors for prostate cancer also block the zinc transporter ZIP9, and thereby inhibit melanoma in males.
Competing Interest Statement
C.A.P., C.A.N., and T.W.R., and are inventors on a provisional patent held by the University of Pennsylvania related to this work.
Footnotes
Clarified text and added new data.