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Selenoprotein O Promotes Melanoma Metastasis and Regulates Mitochondrial Complex II Activity
Cancer Research ( IF 12.5 ) Pub Date : 2024-12-19 , DOI: 10.1158/0008-5472.can-23-2194 Luiza Martins. Nascentes Melo, Marie Sabatier, Vijayashree Ramesh, Krystina J. Szylo, Cameron S. Fraser, Alexandra Pon, Evann C. Mitchell, Kelly A. Servage, Gabriele Allies, Isa V. Westedt, Feyza Cansiz, Jonathan Krystkiewicz, Andrea Kutritz, Dirk Schadendorf, Sean J. Morrison, Jessalyn M. Ubellacker, Anju Sreelatha, Alpaslan Tasdogan
Cancer Research ( IF 12.5 ) Pub Date : 2024-12-19 , DOI: 10.1158/0008-5472.can-23-2194 Luiza Martins. Nascentes Melo, Marie Sabatier, Vijayashree Ramesh, Krystina J. Szylo, Cameron S. Fraser, Alexandra Pon, Evann C. Mitchell, Kelly A. Servage, Gabriele Allies, Isa V. Westedt, Feyza Cansiz, Jonathan Krystkiewicz, Andrea Kutritz, Dirk Schadendorf, Sean J. Morrison, Jessalyn M. Ubellacker, Anju Sreelatha, Alpaslan Tasdogan
Evolutionarily conserved selenoprotein O (SELENOO) catalyzes a post-translational protein modification known as AMPylation that is essential for the oxidative stress response in bacteria and yeast. Given that oxidative stress experienced in the blood limits survival of metastasizing melanoma cells, SELENOO might be able to impact metastatic potential. However, further work is needed to elucidate the substrates and functional relevance of the mammalian homologue of SELENOO. Here, we revealed that SELENOO promotes cancer metastasis and identified substrates of SELENOO in mammalian mitochondria. In patients with melanoma, high SELENOO expression was correlated with metastasis and poor overall survival. In a murine model of spontaneous melanoma metastasis, SELENOO deficiency significantly reduced metastasis to distant visceral organs, which could be rescued by treatment with the antioxidant N-acetylcysteine. Mechanistically, SELENOO AMPylated multiple mitochondrial substrates, including succinate dehydrogenase subunit A, one of the four key subunits of mitochondrial complex II. Consistently, SELENOO-deficient cells featured increased mitochondrial complex II activity. Together, these findings demonstrate that SELENOO deficiency limits melanoma metastasis by modulating mitochondrial function and oxidative stress.
更新日期：2024-12-19
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