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Id2 gene-targeted crosstalk between Wnt and retinoid signaling regulates proliferation in human keratinocytes

Oncogene volume 26, pages 5038–5045 (2007)Cite this article

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-β-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.

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Acknowledgements

We thank Professor NE Fusenig (German Cancer Research Center, Heidelberg, Germany) for a kind gift of HaCaT cells, and members of the Department of Nuclear Signaling for discussions and advice. This work was supported in part by the Program for Promotion of Basic Research Activities for Innovative Biosciences (PROBRAIN) and priority areas from the Ministry of Education, Culture, Sports, Science and Technology (SK), and by the Kato Nuclear Complex Project grant from the Exploratory Research for Advanced Technology (ERATO), Japan Science and Technology Agency (JST).

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Authors and Affiliations

  1. Department of Nuclear Signaling, Institute of Molecular and Cellular Biosciences, University of Tokyo, Bunkyo-ku, Tokyo, Japan,

    A Memezawa, I Takada, K Takeyama, M Igarashi, S Ito, S Kato & A P Kouzmenko

  2. Department of Dermatology, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan,

    A Memezawa & S Aiba

  3. ERATO, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan,

    S Kato & A P Kouzmenko

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  1. A Memezawa
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  2. I Takada
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Correspondence to S Kato or A P Kouzmenko.

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Memezawa, A., Takada, I., Takeyama, K. et al. Id2 gene-targeted crosstalk between Wnt and retinoid signaling regulates proliferation in human keratinocytes. Oncogene 26, 5038–5045 (2007). https://doi.org/10.1038/sj.onc.1210320

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