Interest has emerged in the therapeutic potential of inhibiting store operated calcium (Ca²⁺) entry (SOCE) for melanoma and other cancers because malignant cells exhibit a strong dependence on Ca²⁺ 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 Ca²⁺ flux through the endoplasmic reticulum Ca²⁺ 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 Ca²⁺ flux and impaired IP3R function, which inhibited cell proliferation, invasion, and migration. Ca²⁺-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.

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