Memezawa A, Takada I, Takeyama K, Igarashi M, Ito S, Aiba S, Kato S, Kouzmenko A P
Department of Nuclear Signaling, Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo, Japan.
Oncogene. 2007 Aug 2;26(35):5038-45. doi: 10.1038/sj.onc.1210320. Epub 2007 Feb 19.
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.
我们研究了全反式维甲酸（atRA）对几种人类皮肤细胞系增殖的影响，发现atRA的抗增殖能力与经典Wnt信号通路的内源性活性相关。在HaCaT角质形成细胞中，我们发现atRA显著抑制Id2的表达，Id2是调节细胞生长和分化的转录因子分化抑制家族的成员。然而，未观察到其他Wnt靶标如c-Myc或细胞周期蛋白D1的表达有明显变化。维甲酸诱导的Id2基因抑制与组蛋白H3和H4乙酰化水平降低以及组蛋白H3赖氨酸-4甲基化水平降低相关，并且与LSD1去甲基化酶在Id2基因启动子的Wnt反应元件（WRE）（TCF/LEF结合位点）处的募集有关。在c-Myc和细胞周期蛋白D1基因启动子的WRE处未检测到此类变化。用小干扰RNA（siRNA）抑制Id2对HaCaT细胞增殖的影响与暴露于atRA相似，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和维甲酸信号通路之间的转录汇聚下调Id2基因表达是维甲酸对角质形成细胞抗增殖作用的基础，并提供了信号通路之间基因靶向串扰的证据。
