HMGA2 and Smads Co-regulate SNAIL1 Expression during Induction of Epithelial-to-Mesenchymal Transition
HMGA2 and Smads Co-regulate SNAIL1 Expression during Induction of Epithelial-to-Mesenchymal Transition
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DOI：
10.1074/jbc.m802016200
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发表时间：
2008-11-28
影响因子：
4.8
通讯作者：
Moustakas, Aristidis
中科院分区：
文献类型：
--
作者：
Thuault, Sylvie;Tan, E-Jean;Moustakas, Aristidis
上皮-间充质转化(EMT)在胚胎细胞层运动和肿瘤细胞侵袭过程中起重要作用。EMT将黏附的上皮细胞转化为可移动的间充质细胞，在癌症进展的背景下有利于转移。转化生长因子-β(TGF-β)通过细胞内Smad转导和其他信号蛋白触发EMT。我们以前曾报道，高迁移率族A2(HMGA2)基因是转化生长因子-β诱导乳腺上皮细胞发生EMT所必需的。在本研究中，我们研究了HMGA2诱导EMT的分子机制。我们发现，HMGA2调节E-钙粘蛋白的许多重要抑制因子的表达。其中，我们详细分析了锌指转录因子SNAIL1，它在肿瘤进展和EMT中发挥关键作用。我们证明HMGA2直接与SNAIL1启动子结合，并作为SNAIL1表达的转录调节因子。此外，我们观察到HMGA2与转化生长因子-β/Smad途径在调节SNAIL1基因表达方面具有协同作用。这种合作背后的机制涉及这些因素之间的物理相互作用，导致Smads与SNAIL1启动子的结合增加。Snail1似乎在HMGA2下游扮演着诱导EMT的主效应子的角色，因为SNAIL1的下调部分逆转了HMGA2诱导的上皮分化的丧失。这些数据表明，HMGA2以基因特异性的方式协调EMT计划所需的转录网络。
Epithelial-mesenchymal transition (EMT) is important during embryonic cell layer movement and tumor cell invasiveness. EMT converts adherent epithelial cells to motile mesenchymal cells, favoring metastasis in the context of cancer progression. Transforming growth factor-beta (TGF-beta) triggers EMT via intracellular Smad transducers and other signaling proteins. We previously reported that the high mobility group A2 (HMGA2) gene is required for TGF-beta to elicit EMT in mammary epithelial cells. In the present study we investigated the molecular mechanisms by which HMGA2 induces EMT. We found that HMGA2 regulates expression of many important repressors of E-cadherin. Among these, we analyzed in detail the zinc-finger transcription factor SNAIL1, which plays key roles in tumor progression and EMT. We demonstrate that HMGA2 directly binds to the SNAIL1 promoter and acts as a transcriptional regulator of SNAIL1 expression. Furthermore, we observed that HMGA2 cooperates with the TGF-beta/Smad pathway in regulating SNAIL1 gene expression. The mechanism behind this cooperation involves physical interaction between these factors, leading to an increased binding of Smads to the SNAIL1 promoter. SNAIL1 seems to play the role of a master effector downstream of HMGA2 for induction of EMT, as SNAIL1 knock-down partially reverts HMGA2-induced loss of epithelial differentiation. The data propose that HMGA2 acts in a gene-specific manner to orchestrate the transcriptional network necessary for the EMT program.