The CDK4/6-EZH2 pathway is a potential therapeutic target for psoriasis
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...
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| Main Authors: | , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
July 23, 2020
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| In: |
The journal of clinical investigation
Year: 2020, Volume: 130, Issue: 11, Pages: 5765-5781 |
| ISSN: | 1558-8238 |
| DOI: | 10.1172/JCI134217 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1172/JCI134217 Verlag, lizenzpflichtig, Volltext: https://www.jci.org/articles/view/134217 
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| Author Notes: | Anne Müller, Antje Dickmanns, Claudia Resch, Knut Schäkel, Stephan Hailfinger, Matthias Dobbelstein, Klaus Schulze-Osthoff, and Daniela Kramer |
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| 520 | |a 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. | ||
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