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The CDK4/6-EZH2 pathway is a potential therapeutic target for psoriasis
Anne Müller, … , Klaus Schulze-Osthoff, Daniela Kramer
Anne Müller, … , Klaus Schulze-Osthoff, Daniela Kramer
Published July 23, 2020
Citation Information: J Clin Invest. 2020;130(11):5765-5781. https://doi.org/10.1172/JCI134217.
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Research Article Dermatology Article has an altmetric score of 6

The CDK4/6-EZH2 pathway is a potential therapeutic target for psoriasis

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Abstract

Psoriasis is a frequent, inflammatory skin disease characterized by keratinocyte hyperproliferation and a disease-related infiltration of immune cells. Here, we identified a novel proinflammatory signaling pathway driven by cyclin-dependent kinase 4 (CDK4) and CDK6 and the methyltransferase EZH2 as a valid target for psoriasis therapy. Delineation of the pathway revealed that CDK4/6 phosphorylated EZH2 in keratinocytes, thereby triggering a methylation-induced activation of STAT3. Subsequently, active STAT3 resulted in the induction of IκBζ, which is a key proinflammatory transcription factor required for cytokine synthesis in psoriasis. Pharmacological or genetic inhibition of CDK4/6 or EZH2 abrogated psoriasis-related proinflammatory gene expression by suppressing IκBζ induction in keratinocytes. Importantly, topical application of CDK4/6 or EZH2 inhibitors on the skin was sufficient to fully prevent the development of psoriasis in various mouse models by suppressing STAT3-mediated IκBζ expression. Moreover, we found a hyperactivation of the CDK4/6-EZH2 pathway in human and mouse psoriatic skin lesions. Thus, this study not only identifies a novel psoriasis-relevant proinflammatory pathway, but also proposes the repurposing of CDK4/6 or EZH2 inhibitors as a new therapeutic option for patients with psoriasis.

Authors

Anne Müller, Antje Dickmanns, Claudia Resch, Knut Schäkel, Stephan Hailfinger, Matthias Dobbelstein, Klaus Schulze-Osthoff, Daniela Kramer

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Figure 7

CDK4/6 and EZH2 inhibitors attenuate established psoriasis-like skin lesions in vivo.

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CDK4/6 and EZH2 inhibitors attenuate established psoriasis-like skin les...
All analyses were performed with n = 6 mice per group ± SEM. (A) Treatment scheme for the therapy using the IMQ mouse model. To explore whether CDK4/6 and EZH2 inhibitors suppress already-established psoriasis-like skin inflammation, mice were first treated with IMQ, followed by the application of 2% abemaciclib or 5% CPI-169 solution starting at the third IMQ application. (B) Ear thickness measurements during treatment. (C) H&E staining of untreated (Ctrl), IMQ-, IMQ and Abe–, or IMQ and CPI–treated ears. H&E staining shows the prevalence of psoriasis-like symptoms at IMQ day 2 when the inhibitors were applied for the first time. Scale bars: 100 μm. (D) Quantification of infiltrating immune cells in mouse ears at day 6. Immune cell subpopulations were quantified as in Figure 6D. n = 3 mice per group ± SEM. (E) Protein levels in untreated (Ctrl) and IMQ-treated mouse skin tissue in the presence or absence of abemaciclib or CPI-169 at day 6. Mice were treated as in A. FOXM1 and H3K27me3 were analyzed as positive controls for drug action. (F) Treatment scheme in the IL-36–induced psoriasis mouse model. IL-36–mediated psoriasis-like dermatitis was induced by administration of 1 μg IL-36α at every second day. Control mice received PBS. Starting from day 4 of IL-36α injection, ethanol as Vehicle (Veh), 2% abemaciclib, or 5% CPI-169 were daily applied by topical administration. (G) Ear thickness measurements during IL-36α treatment. (H) H&E staining of PBS- or IL-36α–treated ears at day 9. Scale bars: 100 μm. (I) Immunoblot analysis in IL-36α–treated mouse skin tissue at day 9. Significance was calculated using a 1-way ANOVA for multiple groups and a 2-tailed Student’s t test for comparing 2 groups: *P < 0.05; **P < 0.01; ***P < 0.001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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