Stem cell factor-inducible MITF-M expression in therapeutics for acquired skin hyperpigmentation

Cheong Yong Yun, Eunmiri Roh, Song Hee Kim, Jinhe Han, Jiyeon Lee, Da Eun Jung, Ga Hyeon Kim, Sang Hun Jung, Won Jea Cho, Sang Bae Han, Youngsoo Kim

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1 Scopus citations

Abstract

Rationale: Microphthalmia-associated transcription factor M (MITF-M) plays important roles in the pigment production, differentiation and survival of melanocytes. Stem cell factor (SCF) and its receptor KIT stimulate MITF-M activity via phosphorylation at the post-translation level. However, the phosphorylation shortens half-life of MITF-M protein over the course of minutes. Here, we investigated novel hypotheses of (i) whether SCF/KIT can regulate MITF-M activity through gene expression as the alternative process, and (ii) whether chemical inhibition of KIT activity can mitigate the acquired pigmentation in skin by targeting the expression of MITF-M. Methods: We employed melanocyte cultures in vitro and pigmented skin samples in vivo, and applied immunoblotting, RT-PCR, siRNA-based gene knockdown and confocal microscopy. Results: The protein and mRNA levels of MITF-M in epidermal melanocytes and the promoter activity of MITF-M in B16-F0 melanoma cells demonstrated that SCF/KIT could trigger the expression of MITF-M de novo, following the phosphorylation-dependent proteolysis of pre-existing MITF-M protein. SCF/KIT regulated the transcription abilities of cAMP-responsive element-binding protein (CREB), CREB-regulated co-activator 1 (CRTC1) and SRY-related HMG-box 10 (SOX10) but not β-catenin at the MITF-M promoter. Meanwhile, chemical inhibition of KIT activity abolished SCF-induced melanin production in epidermal melanocyte cultures, as well as protected the skin from UV-B-induced hyperpigmentation in HRM2 mice or brownish guinea pigs, in which it down-regulated the expression of MITF-M de novo at the promoter level. Conclusion: We propose the targeting of SCF/KIT-inducible MITF-M expression as a strategy in the therapeutics for acquired pigmentary disorders.

Original languageEnglish (US)
Pages (from-to)340-352
Number of pages13
JournalTheranostics
Volume10
Issue number1
DOIs
StatePublished - 2020

Bibliographical note

Funding Information:
This study was financially supported by grants (2016R1A6A3A11933508, 2018R1D1A1B07045596) or MRC program (2017R1A5A2015541) from the National Research Foundation of Korea; a grant (WISET 2017-519) from the Korean Ministry of Science and ICT; and the foresting project of Osong academy-industry convergence from the Korean Ministry of Trade, Industry and Energy.

Publisher Copyright:
© The author(s).

Keywords

  • Chemical inhibition
  • Epidermal melanocyte
  • KIT
  • MITF-M activity
  • Skin pigmentation
  • Stem cell factor

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

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