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

Song Sun ,Bohan Xu,Hui Zhao,Fang Zhang,Lei Zhang,Jianfeng Cui,Yaoqin Gong,Xiaochen Liu,Changshun Shao,Chenxi Liang,Miaomiao Xu ,Yangyang Xia,Qinzhou Wang,Fei Tian,Haifeng Wei,Shujie Zhou,Xiaojie Zhang,Gaolin Wu ,Guo-Jiao Yang ,Yongxin Zou

doi:10.1038/s41419-019-1510-8

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.

Highlights

Psoriasis is a common chronic, recurring, and immunemediated inflammatory skin disease, with a worldwide incidence of ~0.09–5.1% and seriously impairs the life quality of the patients[1,2,3]
The molecular mechanisms involved in the pathogenesis of psoriasis are complex, growing evidence suggests that the activator of transcriptions 1 and 3 (STAT1 and STAT3), and nuclear factor-κB (NF-κB) is pivotal in the transcriptome network involved in the mechanism of psoriasis
The analysis showed that expression of CDC6 mRNA is similar in healthy normal and nonlesional skins of psoriasis patients, while it was significantly increased in lesional regions of psoriasis patients (Fig. 1a)

Summary

Introduction

Psoriasis is a common chronic, recurring, and immunemediated inflammatory skin disease, with a worldwide incidence of ~0.09–5.1% and seriously impairs the life quality of the patients[1,2,3]. Sun et al Cell Death and Disease (2019)10:274 pathways can be used as effective therapies against psoriasis. STAT3 is an essential player to be responsible for the antibacterial/fungal type 3 (Th17) immune response and is considered to function as a central player in psoriasis pathogenesis[9,10]. STAT3 was reported to be active in psoriatic lesions, and suppression of STAT3 could inhibit proliferation and induce apoptosis of psoriatic keratinocytes[11]. Expression of constitutively active STAT3 (STAT3C) in keratinocytes leads to the spontaneous development of psoriasis in transgenic mice[12,13]. The targeting STAT3 pathway has been a promising target for the development of psoriasis therapies. It was reported that STAT3 inhibitor inhibited the development of psoriasiform lesions in K5.Stat3C mice and improved psoriatic lesions in psoriasis patients[14]

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Conclusion