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

// Michael P. Marciel 1 , Vedbar S. Khadka 2 , Youping Deng 2 , Pascal Kilicaslan 3 , Andrew Pham 1 , Pietro Bertino 1 , Katie Lee 1 , Suzie Chen 4 , Natalija Glibetic 5 , FuKun W. Hoffmann 1 , Michelle L. Matter 5 and Peter R. Hoffmann 1 1 Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, U.S.A. 2 Bioinformatics Core in the Department of Complementary and Integrative Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, U.S.A. 3 Biotechnology Department, University of Applied Sciences Mannheim, Mannheim, Germany 4 Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey, U.S.A. 5 The University of Hawaii Cancer Center, Honolulu, Hawaii, U.S.A. Correspondence to: Peter R. Hoffmann, email: peterrh@hawaii.edu Keywords: selenium; migration; inositol 1,4,5-triphosphate receptor; calcium channel; palmitoylation Received: October 07, 2017      Accepted: January 23, 2018      Published: February 03, 2018 ABSTRACT 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.