The CDK4/6-EZH2 pathway is a potential therapeutic target for psoriasis
Anne Müller1, Antje Dickmanns2, Claudia Resch1
1Interfaculty Institute for Biochemistry, University of Tübingen, Tübingen, Germany.
The Journal of Clinical Investigation
|July 24, 2020
Summary
Researchers discovered a new inflammatory pathway involving CDK4/6 and EZH2 in psoriasis. Inhibiting this pathway, particularly with topical treatments, shows promise for preventing psoriasis development.
Area of Science:
- Dermatology
- Molecular Biology
- Immunology
Background:
- Psoriasis is a common inflammatory skin condition.
- It involves keratinocyte hyperproliferation and immune cell infiltration.
- Current therapies aim to manage symptoms but novel targets are needed.
Purpose of the Study:
- To identify and characterize a novel proinflammatory signaling pathway in psoriasis.
- To evaluate the therapeutic potential of targeting this pathway.
- To investigate the role of CDK4/6, EZH2, STAT3, and IκBζ in psoriasis pathogenesis.
Main Methods:
- Pathway analysis in keratinocytes.
- Pharmacological and genetic inhibition of CDK4/6 and EZH2.
- Topical drug application in mouse models of psoriasis.
- Analysis of human and mouse psoriatic skin lesions.
Main Results:
- A novel pathway involving CDK4/6-mediated phosphorylation of EZH2, leading to STAT3 activation and IκBζ induction, was identified.
- Inhibition of CDK4/6 or EZH2 suppressed psoriasis-related gene expression by blocking IκBζ.
- Topical inhibitors of CDK4/6 or EZH2 prevented psoriasis development in mouse models.
- The CDK4/6-EZH2 pathway was hyperactivated in human and mouse psoriatic lesions.
Conclusions:
- The CDK4/6-EZH2-STAT3-IκBζ pathway is a key driver of inflammation in psoriasis.
- Targeting this pathway with CDK4/6 or EZH2 inhibitors offers a potential new therapeutic strategy.
- Repurposing existing inhibitors for topical psoriasis treatment is a promising avenue.
Related Concept Videos
02:15M-Cdk Drives Transition Into Mitosis
6.1K
Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or halt it in problematic ones. This regulation is known as the cell cycle control system.
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
6.1K
02:34Inhibition of Cdk Activity
5.4K
The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
5.4K
02:39Positive Regulator Molecules
6.4K
Mitotic cell division results in daughter cells that exactly resemble the parent cell. However, errors in the DNA replication or distribution of genetic material may lead to genetic mutations that may be passed down to every new cell formed from the resulting abnormal cell. Propagation of such mutant cells is restricted through checkpoint mechanisms present at different stages of the cell cycle. These checkpoints involve regulator molecules that either promote or demote cell cycle events.
6.4K
02:38Mitogens and the Cell Cycle
7.5K
Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
7.5K
01:22iPS Cell Differentiation
3.0K
The ability of induced pluripotent stem cells or iPSCs to differentiate into most body cell types has stimulated repair and regenerative medicine research over the past few decades. iPSC-derived blood cells, hepatocytes, beta islet cells, cardiomyocytes, neurons, and other cell types can repair injuries or regenerate damaged tissue in diseases such as diabetes and neurodegenerative disorders.
3.0K
01:20The JAK-STAT Signaling Pathway
11.3K
Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as SH2...
11.3K