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 Yun1,*, Seung Deok Hong1,*, 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 Kim1✉

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.

Citation:
Yun CY, Hong SD, Lee YH, Lee J, Jung DE, Kim GH, Kim SH, Jung JK, Kim KH, Lee H, Hong JT, Han SB, Kim Y. Nuclear Entry of CRTC1 as Druggable Target of Acquired Pigmentary Disorder. Theranostics 2019; 9(3):646-660. doi:10.7150/thno.30276. https://www.thno.org/v09p0646.htm
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Abstract

Graphic 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


Citation styles

APA
Yun, C.Y., Hong, S.D., Lee, Y.H., Lee, J., Jung, D.E., Kim, G.H., Kim, S.H., Jung, J.K., Kim, K.H., Lee, H., Hong, J.T., Han, S.B., Kim, Y. (2019). Nuclear Entry of CRTC1 as Druggable Target of Acquired Pigmentary Disorder. Theranostics, 9(3), 646-660. https://doi.org/10.7150/thno.30276.

ACS
Yun, C.Y.; Hong, S.D.; Lee, Y.H.; Lee, J.; Jung, D.E.; Kim, G.H.; Kim, S.H.; Jung, J.K.; Kim, K.H.; Lee, H.; Hong, J.T.; Han, S.B.; Kim, Y. Nuclear Entry of CRTC1 as Druggable Target of Acquired Pigmentary Disorder. Theranostics 2019, 9 (3), 646-660. DOI: 10.7150/thno.30276.

NLM
Yun CY, Hong SD, Lee YH, Lee J, Jung DE, Kim GH, Kim SH, Jung JK, Kim KH, Lee H, Hong JT, Han SB, Kim Y. Nuclear Entry of CRTC1 as Druggable Target of Acquired Pigmentary Disorder. Theranostics 2019; 9(3):646-660. doi:10.7150/thno.30276. https://www.thno.org/v09p0646.htm

CSE
Yun CY, Hong SD, Lee YH, Lee J, Jung DE, Kim GH, Kim SH, Jung JK, Kim KH, Lee H, Hong JT, Han SB, Kim Y. 2019. Nuclear Entry of CRTC1 as Druggable Target of Acquired Pigmentary Disorder. Theranostics. 9(3):646-660.

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