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Cell Death Dis. 2019 Mar 20;10(4):274. doi: 10.1038/s41419-019-1510-8.

Berberine downregulates CDC6 and inhibits proliferation via targeting JAK-STAT3 signaling in keratinocytes.

Author information

1
Department of Dermatology, The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Shandong Provincial Hospital of Traditional Chinese Medicine, Jinan, 250011, Shandong, China.
2
The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University, School of Basic Medical Sciences, Jinan, 250012, Shandong, China.
3
Department of Urology, Qilu Hospital, Shandong University, Jinan, 250012, Shandong, China.
4
Department of Neurology, Qilu Hospital, Shandong University, Jinan, 250012, Shandong, China.
5
Department of Immunology and Key Laboratory of Infection and Immunity of Shandong Province, Shandong University, School of Basic Medical Sciences, Jinan, 250012, Shandong, China.
6
The First Affiliated Hospital of Soochow University and State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University, Suzhou, 215123, Jiangsu, China.
7
The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University, School of Basic Medical Sciences, Jinan, 250012, Shandong, China. zouyongxin@sdu.edu.cn.

Abstract

Psoriasis is a chronic skin disease characterized by hyperproliferation and impaired differentiation of epidermal keratinocytes accompanied by increased inflammation, suggesting that molecules with antiproliferation and anti-inflammatory abilities may be effective for its treatment. One of the key steps in regulating cell proliferation is DNA replication initiation, which relies on prereplication complex (pre-RC) assembly on chromatin. CDC6 is an essential regulator of pre-RC assembly and DNA replication in eukaryotic cells, but its role in proliferation of keratinocytes and psoriasis is unknown. Here we examined CDC6 expression in psoriatic skin and evaluated its function in the proliferation of human keratinocytes. CDC6 expression is upregulated in epidermal cells in psoriatic lesions and it could be induced by IL-22/STAT3 signaling, a key signaling pathway involved in the pathogenesis of psoriasis, in keratinocytes. Depletion of CDC6 leads to decreased proliferation of keratinocytes. We also revealed that berberine (BBR) could inhibit CDK4/6-RB-CDC6 signaling in keratinocytes, leading to reduced proliferation of keratinocytes. The mechanism of antiproliferation effects of BBR is through the repression of JAK1, JAK2, and TYK2, which in turn inhibits activation of STAT3. Finally, we demonstrated that BBR could inhibit imiquimod-induced psoriasis-like skin lesions and upregulation of CDC6 and p-STAT3 in mice. Collectively, our findings indicate that BBR inhibits CDC6 expression and proliferation in human keratinocytes by interfering the JAK-STAT3 signaling pathway. Thus, BBR may serve as a potential therapeutic option for patients with psoriasis.

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