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

Chelsey D Kline; Madeleine Anderson; John W Bassett; Gail Kent; Rachel Berryman; Matthew Honeggar; Shosuke Ito; Kazumasa Wakamatsu; Arup K Indra; Philip J Moos; Sancy A Leachman; Pamela B Cassidy

doi:10.3390/cancers14205011

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

Cancers (Basel). 2022 Oct 13;14(20):5011. doi: 10.3390/cancers14205011.

Authors

Affiliations

¹ Department of Dermatology, Oregon Health & Science University, Portland, OR 97239, USA.
² Institute for Melanin Chemistry, Fujita Health University, Toyoake 470-1192, Japan.
³ Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA.
⁴ Department of Dermatology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
⁵ Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112, USA.

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 (TR1^low) 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.

Keywords: MITF; glutathione; peroxiredoxin; redox signaling; thioredoxin reductase 1.

Grants and funding

This research was funded by the National Cancer Institute of the National Institutes of Health grants number R01 CA166710 (to PBC) and T32CA106195 (to CDK) and seed funding from the OHSU Knight Cancer Institute NCI Cancer Center Support Grant P30CA069533 (to PBC and AKI). RNAseq analysis was performed by the Massively Parallel Sequencing Shared Resource with funding provided by the OHSU School of Medicine Innovation Award to PBC.