Id2 gene-targeted crosstalk between Wnt and retinoid signaling regulates proliferation in human keratinocytes
Id2 gene-targeted crosstalk between Wnt and retinoid signaling regulates proliferation in human keratinocytes
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DOI：
10.1038/sj.onc.1210320
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发表时间：
2007-08-02
期刊：
影响因子：
8
通讯作者：
Kouzmenko, A. P.
中科院分区：
文献类型：
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作者：
Memezawa, A.;Takada, I.;Kouzmenko, A. P.
我们研究了全反式维甲酸（atRA）对几种人皮肤细胞系增殖的影响，发现atRA的抗增殖效力与经典Wnt信号的内源性活性相关。在HaCaT角质形成细胞中，我们发现atRA显著抑制了Id 2的表达，Id 2是调节细胞生长和分化的转录因子的分化抑制因子家族的成员。然而，没有观察到其他Wnt靶点（如c-Myc或细胞周期蛋白D1）的表达发生明显变化。类维生素A诱导的Id 2基因抑制与组蛋白H3和H4乙酰化和组蛋白H3 Lys-4甲基化水平降低以及Id 2基因启动子中Wnt反应元件（WRE）（TCF/LEF结合位点）LSD 1去甲基化酶的募集相关。在c-Myc和cyclin D1基因启动子的WRE上没有检测到这种变化。通过短干扰RNA（siRNA）抑制Id 2对HaCaT细胞的增殖具有与暴露于atRA类似的效果，而抗β-连环蛋白siRNA显著抑制其抗增殖作用。这些数据表明，通过Wnt和类维生素A信号通路之间的转录会聚下调Id 2基因表达是类维生素A在角质形成细胞中的抗增殖作用的基础，并提供了信号通路之间的基因靶向串扰的证据。
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.