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Updated: Jul 16, 2026
Evaluation of Keratinocyte Proliferation on Two- and Three-dimensional Type I Collagen Substrates
Published on: April 22, 2019
Id2 gene-targeted crosstalk between Wnt and retinoid signaling regulates proliferation in human keratinocytes
A Memezawa1, I Takada, K Takeyama
1Department of Nuclear Signaling, Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo, Japan.
Abstract:
We investigated the effect of all-trans-retinoic acid (atRA) on proliferation in several human skin cell lines and found that antiproliferative potency of atRA correlated with the endogenous activity of canonical Wnt signaling. In HaCaT keratinocytes, we found that atRA significantly suppressed the expression of Id2, a member of the inhibitor of differentiation family of transcription factors that regulate cell growth and differentiation. However, no apparent change in the expression of other Wnt targets, like c-Myc or cyclin D1, was observed. Retinoid-induced Id2 gene suppression was associated with decreased levels of histone H3 and H4 acetylation and histone H3 Lys-4 methylation, and with recruitment of the LSD1 demethylase at the Wnt-response element (WRE) (TCF/LEF-binding site), in the Id2 gene promoter. None of such changes was detected at the WRE of c-Myc and cyclin D1 gene promoters. Inhibition of Id2 by short interfering RNA (siRNA) had a similar effect on the proliferation of HaCaT cells as exposure to atRA, whereas anti-beta-catenin siRNA significantly inhibited its antiproliferative effect. These data suggest that downregulation of Id2 gene expression through transcriptional convergence between Wnt and retinoid signaling pathways underlies the antiproliferative effect of retinoids in keratinocytes, and provide evidence of gene-targeted crosstalk between signaling pathways.
Insights
All-trans-retinoic acid (atRA) inhibits skin cell proliferation by suppressing Id2 expression. This occurs through Wnt signaling pathway crosstalk, impacting gene transcription and cell growth.
Area of Science:
- Dermatology
- Molecular Biology
- Epigenetics
Background:
- Skin cell proliferation is crucial for tissue homeostasis and is dysregulated in various skin conditions.
- Canonical Wnt signaling plays a significant role in regulating cell growth and differentiation.
- All-trans-retinoic acid (atRA) is a derivative of Vitamin A known for its effects on skin cell behavior.
Purpose of the Study:
- To investigate the antiproliferative effects of atRA on human skin cells.
- To elucidate the molecular mechanisms underlying atRA's action, particularly its interaction with Wnt signaling.
- To determine the role of Id2 gene expression in retinoid-induced growth inhibition.
Main Methods:
- Utilized human skin cell lines (HaCaT keratinocytes).
- Assessed gene expression changes (Id2, c-Myc, cyclin D1) following atRA treatment.
- Analyzed epigenetic modifications (histone acetylation, H3 Lys-4 methylation) at target gene promoters.
- Employed short interfering RNA (siRNA) to inhibit Id2 and beta-catenin expression.
Main Results:
- atRA suppressed Id2 expression in HaCaT cells, correlating with antiproliferative effects.
- atRA treatment led to decreased histone acetylation and H3 Lys-4 methylation at the Id2 promoter, with LSD1 recruitment.
- No significant changes were observed in c-Myc or cyclin D1 expression or their promoter regions.
- siRNA-mediated inhibition of Id2 mimicked atRA's antiproliferative effect, while anti-beta-catenin siRNA blocked it.
Conclusions:
- Downregulation of Id2 gene expression is a key mechanism for the antiproliferative effect of atRA in keratinocytes.
- Transcriptional convergence between Wnt and retinoid signaling pathways mediates this effect.
- Provides evidence for gene-targeted crosstalk between these signaling pathways in skin cells.
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