Theranostics 2020; 10(1):340-352. doi:10.7150/thno.39066

Research Paper

Stem Cell Factor-Inducible MITF-M Expression in Therapeutics for Acquired Skin Hyperpigmentation

Cheong-Yong Yun1*, Eunmiri Roh1*, Song-Hee Kim1, Jinhe Han2, Jiyeon Lee1, Da-Eun Jung1, Ga Hyeon Kim1, Sang-Hun Jung3, Won-Jea Cho2, Sang-Bae Han1, Youngsoo Kim1✉

1. College of Pharmacy, Chungbuk National University, Cheongju 28160, Korea.
2. College of Pharmacy, Chonnam National University, Gwangju 61186, Korea.
3. College of Pharmacy, Chungnam National University, Daejeon 34134, Korea.
*C.-Y.Y. and E.R. equally contributed to this study.

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Citation:
Yun CY, Roh E, Kim SH, Han J, Lee J, Jung DE, Kim GH, Jung SH, Cho WJ, Han SB, Kim Y. Stem Cell Factor-Inducible MITF-M Expression in Therapeutics for Acquired Skin Hyperpigmentation. Theranostics 2020; 10(1):340-352. doi:10.7150/thno.39066. Available from http://www.thno.org/v10p0340.htm

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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.

Keywords: Stem cell factor, KIT, MITF-M activity, epidermal melanocyte, skin pigmentation, chemical inhibition