HMGA2 and Smads Co-regulate SNAIL1 Expression during Induction of Epithelial-to-Mesenchymal Transition

Ludwig Institute for Cancer Research, Box 595 Biomedical Center, Uppsala University, SE-751 24 Uppsala, Sweden.
Journal of Biological Chemistry (Impact Factor: 4.57). 11/2008; 283(48):33437-46. DOI: 10.1074/jbc.M802016200
Source: PubMed


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.

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    • "The so-called EMT transcription factors (EMT-TFs) are zinc finger proteins, such as the transcriptional repressors Snail (SNAI1) [25] [26] and Slug (SNAI2) [27] [28]; zinc finger and homeobox domain proteins, such as δEF1/ZEB1 [29] and SIP1/ZEB2 [30]; basic helix–loop–helix (bHLH) proteins such as E47 [31] and Twist1 [32] transcription factors. In addition, the chromatin protein high-mobility group A2 (HMGA2) integrates EMT signals downstream of TGFβ in breast cancer cell lines, and coordinates the transcriptional induction of Snail, Slug, Twist1 and the repression of the inhibitor of differentiation ID2 [33] [34] [35]. The molecular networks that coordinate the expression and function of the EMT-TFs in breast cancer are being understood at increasingly deeper levels [36], and specific examples will be listed below under the action of TGFβ. "
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    ABSTRACT: Background The progression of cancer through stages that guide a benign hyperplastic epithelial tissue towards a fully malignant and metastatic carcinoma, is driven by genetic and microenvironmental factors that remodel the tissue architecture. The concept of epithelial-mesenchymal transition (EMT) has evolved to emphasize the importance of plastic changes in tissue architecture, and the cross-communication of tumor cells with various cells in the stroma and with specific molecules in the extracellular matrix (ECM). Scope of the review Among the multitude of ECM-embedded cytokines and the regulatory potential of ECM molecules, this article focuses on the cytokine transforming growth factor β (TGFβ) and the glycosaminoglycan hyaluronan, and their roles in cancer biology and EMT. For brevity, we concentrate our effort on breast cancer. Major conclusions Both normal and abnormal TGFβ signaling can be detected in carcinoma and stromal cells, and TGFβ-induced EMT requires the expression of hyaluronan synthase 2 (HAS2). Correspondingly, hyaluronan is a major constituent of tumor ECM and aberrant levels of both hyaluronan and TGFβ are thought to promote a wounding reaction to the local tissue homeostasis. The link between EMT and metastasis also involves the mesenchymal-epithelial transition (MET). ECM components, signaling networks, regulatory non-coding RNAs and epigenetic mechanisms form the network of regulation during EMT-MET. General significance Understanding the mechanism that control epithelial plasticity in the mammary gland promises the development of valuable biomarkers for the prognosis of breast cancer progression and even provides new ideas for a more integrative therapeutic approach against disease. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties.
    Biochimica et Biophysica Acta (BBA) - General Subjects 08/2014; 1840(8). DOI:10.1016/j.bbagen.2014.02.004 · 4.38 Impact Factor
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    • "Based on reports above mentioned, we found that E-cadherin, N-cadherin, and Snail were changed as reported after K-Ras was transiently silenced using specific siRNA. Tan and colleagues made serial discoveries that HMGA2 can regulate important transcription factor Twist [24] and Snail [25] in a single or combinational with Smads in the induction of EMT. Therefore, based on findings of our own as well as other peer findings, results suggest that reexpression of let-7g could suppress the EMT process via downregulation of K-Ras/ERK1/2 signaling pathway. "
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    ABSTRACT: Let-7 family microRNAs have been reported to be downregulated in human hepatocellular carcinoma in comparison with normal hepatic tissues. Among them, let-7g was identified as the lowest expression using real-time RT-PCR. However, the mechanism by which let-7g works in hepatocellular carcinoma remains unknown. Here, in our present study, we have had let-7g reexpressed in vitro in hepatocellular carcinoma cell lines MHCC97-H and HCCLM3 via transfection. The proliferation after reexpression of let-7g was assayed using MTT method; the migration and invasion after restoration were detected by wound-healing and Transwell assay, respectively. We found using Western-blotting that let-7g can regulate epithelial-mesenchymal transition (EMT) by downregulating K-Ras and HMGA2A after reexpresssion. Xenografted nude mice were used to observe whether or not reexpression of let-7g could have potential therapeutic ability. In vivo, to observe the association with let-7g expression and overall prognosis, 40 paired cases of hepatocellular carcinoma were analyzed using in situ hybridization (ISH). It was found that reexpression of let-7g can inhibit the proliferation, migration, and invasion significantly, and that low expression of let-7g was significantly associated with poorer overall survival. Taken together, let-7g could be used as a promising therapeutic agent in vivo in the treatment of hepatocellular carcinoma at the earlier stage.
    03/2014; 2014(3):742417. DOI:10.1155/2014/742417
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    • "HMGA2 is predominantly expressed at invasive front oral carcinoma cells showing the EMT and in the patients with worse prognosis (Miyazawa et al, 2004), and MALT1 expression rapidly declines at the invasive front carcinoma cells (Chiba et al, 2009). HMGA2 represses CDH1 expression through SNAI2, ZEB2, and TWIST1 (Li et al, 1997; Thuault et al, 2008), which were downregulated in wtMALT1HSC2 cells. As numbers of previous studies established a fact that inactivation of E-cadherin (CDH1) expression is a critical determinant for aggressive carcinomas (Hanahan and Weinberg, 2011; Hashimoto et al, 2012), expression status of MALT1 may have a great impact on oral carcinoma progression. "
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    ABSTRACT: Background: Expression of mucosa-associated lymphoid tissue 1 (MALT1) is inactivated in oral carcinoma patients with worse prognosis. However, the role in carcinoma progression is unknown. Unveiling genes under the control of MALT1 is necessary to understand the pathology of carcinomas. Methods: Gene data set differentially transcribed in MALT1-stably expressing and -marginally expressing oral carcinoma cells was profiled by the microarray analysis and subjected to the pathway analysis. Migratory abilities of cells in response to MALT1 were determined by wound-healing assay and time-lapse analysis. Results: Totally, 2933 genes upregulated or downregulated in MALT1-expressing cells were identified. The subsequent pathway analysis implicated the inhibition of epidermal growth factor and transforming growth factor-β signalling gene expression, and highlighted the involvement in the cellular movement. Wound closure was suppressed by wild-type MALT1 (66.4%) and accelerated by dominant-negative MALT1 (218.6%), and the velocities of cell migration were increased 0.2-fold and 3.0-fold by wild-type and dominant-negative MALT1, respectively. Conclusion: These observations demonstrate that MALT1 represses genes activating the aggressive phenotype of carcinoma cells, and suggest that MALT1 acts as a tumour suppressor and that the loss of expression stimulates oral carcinoma progression.
    British Journal of Cancer 06/2013; 109(1). DOI:10.1038/bjc.2013.307 · 4.84 Impact Factor
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