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

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

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 4

CDK4/6-dependent, EZH2-mediated methylation of STAT3 at lysine 180 induces IκBζ expression in keratinocytes.

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CDK4/6-dependent, EZH2-mediated methylation of STAT3 at lysine 180 induc...
(A and B) Detection of methylated STAT3 by coimmunoprecipitation. EZH2 and STAT3 (A) or CDK6 and STAT3 (B) were transiently expressed in HEK293T cells. After 1 hour of treatment with (A) abemaciclib (Abe) or (B) EPZ6438 (EPZ), cell lysates were prepared and subjected to immunoprecipitation using a STAT3-specific antibody or control IgG. (C) NFKBIZ promoter-driven luciferase activity in HEK293T cells, transiently expressing CDK6 and EZH2, alone or in combination with WT (wt) STAT3 or methylation-defective STAT3 mutant (K180R). n = 3 ± SD. (D) Analysis of IκBζ and IκBζ target gene expression in STAT3 wt or STAT3 K180R-expressing HaCaT cells. STAT3 wt or STAT3 K180R constructs were transiently expressed in STAT3-KO HaCaT cells, followed by stimulation for 1 hour with IL-36α. n = 3 ± SD. (E) Chromatin immunoprecipitation (ChIP) of STAT3, EZH2, or IgG control in STAT3-KO HaCaT cells reconstituted with either STAT3 wt or STAT3 K180R after 30 minutes of stimulation with IL-36α. Fold enrichment at the NFKBIZ promoter or at the myoglobin genomic region (MB; as negative control) was calculated relative to the IgG control. n = 3 ± SD. (F) ChIP of STAT3, EZH2, CDK4, and CDK6 in IL-36α–stimulated HaCaT cells stimulated for 30 minutes with IL-36α. Shown is the fold enrichment over IgG control. n = 3 ± SD. 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.