Data from Selenoprotein O Promotes Melanoma Metastasis and Regulates Mitochondrial Complex II Activity

Evolutionarily conserved selenoprotein O (SELENOO) catalyzes a posttranslational 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 affect metastatic potential. However, further work is needed to elucidate the substrates and functional relevance of the mammalian homolog of SELENOO. In this study, 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.

Significance: SELENOO alters mitochondrial function and supports metastasis in melanoma, highlighting the impact of SELENOO-mediated posttranslational modification of mitochondrial substrates and selenoproteins in cancer progression.