1. The CDK4/6-EZH2 pathway is a potential therapeutic target for psoriasis.
- Author
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Müller, Anne, Dickmanns, Antje, Resch, Claudia, Schäkel, Knut, Hailfinger, Stephan, Dobbelstein, Matthias, Schulze-Osthoff, Klaus, and Kramer, Daniela
- Subjects
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PSORIASIS , *SKIN diseases , *TRANSCRIPTION factors , *GENE expression , *DNA methyltransferases , *METHYLTRANSFERASES - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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