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Theranostics 2019; 9(3):646-660. doi:10.7150/thno.30276 This issue Cite

Research Paper

Nuclear Entry of CRTC1 as Druggable Target of Acquired Pigmentary Disorder

Cheong-Yong Yun^1,*, Seung Deok Hong^1,*, Young Hee Lee², Jiyeon Lee¹, Da-Eun Jung¹, Ga Hyun Kim¹, Song-Hee Kim¹, Jae-Kyung Jung¹, Ki Ho Kim³, Heesoon Lee¹, Jin Tae Hong¹, Sang-Bae Han¹, Youngsoo Kim^1✉

1. College of Pharmacy, Chungbuk National University, Cheongju 28160, Korea
2. Samjin Pharmaceutical Company, Seoul 04054, Korea
3. Kihobio Company, Cheongju 28160, Korea
* C.-Y.Y. and S.D.H. equally contributed to this study.

✉ Corresponding author: Youngsoo Kim, Ph.D. & Professor. College of Pharmacy, Chungbuk National University, Cheongju 28160, Korea. E-mail: youngsooac.kr. Tel: +82-43-261-2823. Fax: +82-43-268-2732

Abstract

Rationale: SOX10 (SRY-related HMG-box 10) and MITF-M (microphthalmia-associated transcription factor M) restrict the expression of melanogenic genes, such as TYR (tyrosinase), in melanocytes. DACE (diacetylcaffeic acid cyclohexyl ester) inhibits melanin production in α-MSH (α-melanocyte stimulating hormone)-activated B16-F0 melanoma cells. In this study, we evaluated the antimelanogenic activity of DACE in vivo and elucidated the molecular basis of its action.

Methods: We employed melanocyte cultures and hyperpigmented skin samples for pigmentation assays, and applied chromatin immunoprecipitation, immunoblotting, RT-PCR or siRNA-based knockdown for mechanistic analyses.

Results: Topical treatment with DACE mitigated UV-B-induced hyperpigmentation in the skin with attenuated expression of MITF-M and TYR. DACE also inhibited melanin production in α-MSH- or ET-1 (endothelin 1)-activated melanocyte cultures. As a mechanism, DACE blocked the nuclear import of CRTC1 (CREB-regulated co-activator 1) in melanocytes. DACE resultantly inhibited SOX10 induction, and suppressed the transcriptional abilities of CREB/CRTC1 heterodimer and SOX10 at MITF-M promoter, thereby ameliorating facultative melanogenesis. Furthermore, this study unveiled new issues in melanocyte biology that i) KPNA1 (Impα5) escorted CRTC1 as a cargo across the nuclear envelope, ii) SOX10 was inducible in the melanogenic process, and iii) CRTC1 could direct SOX10 induction at the transcription level.

Conclusion: We propose the targeting of CRTC1 as a unique strategy in the treatment of acquired pigmentary disorders.

Keywords: diacetylcaffeic acid cyclohexyl ester, CRTC1, SOX10, MITF-M, facultative melanogenesis

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