MITF Is Regulated by Redox Signals Controlled by the Selenoprotein Thioredoxin Reductase 1

Abstract

TR1 and other selenoproteins have paradoxical effects in melanocytes and melanomas. Increasing selenoprotein activity with supplemental selenium in a mouse model of UV-induced melanoma prevents oxidative damage to melanocytes and delays melanoma tumor formation. However, TR1 itself is positively associated with progression in human melanomas and facilitates metastasis in melanoma xenografts. Here, we report that melanocytes expressing a microRNA directed against TR1 (TR1low) grow more slowly than control cell lines and contain significantly less melanin. This phenotype is associated with lower tyrosinase (TYR) activity and reduced transcription of tyrosinase-like protein-1 (TYRP1). Melanoma cells in which the TR1 gene (TXNRD1) was disrupted using Crispr/Cas9 showed more dramatic effects including the complete loss of the melanocyte-specific isoform of MITF; other MITF isoforms were unaffected. We provide evidence that TR1 depletion results in 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.

The metabolism of melanin synthesis—From melanocytes to melanoma

“…TR1 levels are raised by UV‐induced and endogenous oxidative stress and the Trx/TR1 system responds by scavenging ROS and signaling to increase melanogenesis (Schallreuter, Lemke, et al., 1994), and when the oxidized form of Trx is present at high concentrations indicating decreased TR1 activity, Trx can inhibit TYR activity by binding the central copper (Lu et al., 2021). TR1 also prevents direct oxidation of melanogenic regulator MITF, ensuring stability and activation (Kline et al., 2022), showing further the integral role of this system in promoting melanin synthesis.…”