1. The CDK4/6-EZH2 pathway is a potential therapeutic target for psoriasis
- Author
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Muller, Anne, Dickmanns, Antje, Resch, Claudia, Schakel, Knut, Hailfinger, Stephan, Dobbelstein, Matthias, Schulze-Osthoff, Klaus, and Kramer, Daniela
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Inflammation -- Development and progression -- Genetic aspects ,Protein kinases -- Genetic aspects -- Health aspects ,Psoriasis -- Development and progression -- Genetic aspects -- Care and treatment ,Cellular signal transduction -- Health aspects -- Genetic aspects ,Health care industry - 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 cydin- 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 I[kappa]B[zeta], 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 I[kappa]B[zeta] 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 I[kappa]B[zeta] 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., Introduction Psoriasis is a mixed autoimmune and autoinflammatory skin disease, affecting 2% to 3% of the population worldwide. Psoriatic skin lesions are characterized by keratinocyte hyperproliferation and a massive infiltration [...]
- Published
- 2020
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