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) entry (SOCE) for melanoma and other cancers because malignant cells exhibit a strong dependence on Ca 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 flux through the endoplasmic reticulum Ca 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 flux and impaired IP3R function, which inhibited cell proliferation, invasion, and migration. Ca-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. 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.