Selenoprotein K deficiency inhibits melanoma by reducing calcium flux required for tumor growth and metastasis

Interest has emerged in the therapeutic potential of inhibiting store operated calcium (Ca(2+)) entry (SOCE) for melanoma and other cancers because malignant cells exhibit a strong dependence on Ca(2+) flux for disease progression. We investigated the effects of deleting Selenoprotein K (SELENOK) in melanoma since previous work in immune cells showed SELENOK was required for efficient Ca(2+) flux through the endoplasmic reticulum Ca(2+) channel protein, inositol 1,4,5-trisphosphate receptor (IP3R), which is due to the role SELENOK plays in palmitoylating and stabilizing the expression of IP3R. CRISPR/Cas9 was used to generate SELENOK-deficiency in human melanoma cells and this led to reduced Ca(2+) flux and impaired IP3R function, which inhibited cell proliferation, invasion, and migration. Ca(2+)-dependent signaling through calcineurin was inhibited with SELENOK-deficiency, and gene array analyses together with evaluation of transcript and protein levels showed altered transcriptional programs that ultimately disrupted stemness and pro-growth properties. In vivo investigations were conducted using the Grm1-Tg transgenic mouse strain that develops spontaneous metastatic melanoma, which was crossed with SELENOK(−/−) mice to generate the following littermates: Grm1-Tg/SELENOK(−/−), Grm1-Tg/SELENOK(−/+), Grm1-Tg/SELENOK(+/+). SELENOK-deficiency in Grm1-Tg/SELENOK(−/−) male and female mice inhibited primary tumor growth on tails and ears and reduced metastasis to draining lymph nodes down to levels equivalent to non-tumor control mice. Cancer stem cell pools were also decreased in Grm1-Tg/SELENOK(−/−) mice compared to littermates. These results suggest that melanoma requires SELENOK expression for IP3R dependent maintenance of stemness, tumor growth and metastasic potential, thus revealing a new potential therapeutic target for treating melanoma and possibly other cancers.