The selenoprotein thioredoxin reductase 1 and redox modification(s) of MITF

We have discovered that redox signaling downstream of the selenoprotein thioredoxin reductase 1 (TR1) impacts the function of MITF, the master regulator of the melanocyte that plays a critical role in melanoma. In earlier studies, we showed that TR1 and other selenoproteins have paradoxical effects in melanocytes and melanomas. Increasing selenoprotein activity with supplemental selenium prevented oxidative damage to melanocytes and delayed melanoma tumor formation, yet TR1 itself was positively associated with progression in human melanomas and facilitated metastasis in a mouse melanoma model. Here we report that melanocytes expressing a microRNA directed against TR1 (TR1lo) grow more slowly than control cell lines and contain significantly less melanin. This phenotype is associated with lower tyrosinase activity and reduced transcription of tyrosinase-like protein-1 and tyrosinase. Melanoma cells in which the TR1 gene (TXNRD1) was disrupted using Crispr/Cas9 showed more dramatic effects include the complete loss of the melanocyte-specific isoform of MITF; other MITF isoforms were unaffected. We provide evidence that TR1 depletion results in activation of peroxiredoxin 1 (PRX1), a member of the TR1 redox signaling pathway, and oxidation of MITF itself. This newly-discovered mechanism for redox modification of MITF has profound implications for controlling both pigmentation and tumorigenesis in cells of the melanocyte lineage.