Article

Suppression of the Epithelial-Mesenchymal Transition by Grainyhead-like-2

Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia 26506, USA.
Cancer Research (Impact Factor: 9.28). 03/2012; 72(9):2440-53. DOI: 10.1158/0008-5472.CAN-11-4038
Source: PubMed

ABSTRACT Grainyhead genes are involved in wound healing and developmental neural tube closure. In light of the high degree of similarity between the epithelial-mesenchymal transitions (EMT) occurring in wound-healing processes and the cancer stem cell-like compartment of tumors, including TGF-β dependence, we investigated the role of the Grainyhead gene, Grainyhead-like-2 (GRHL2) in oncogenic EMT. GRHL2 was downregulated specifically in the claudin-low subclass breast tumors and in basal-B subclass breast cancer cell lines. GRHL2 suppressed TGF-β-induced, Twist-induced or spontaneous EMT, enhanced anoikis sensitivity, and suppressed mammosphere generation in mammary epithelial cells. These effects were mediated in part by suppression of ZEB1 expression via direct repression of the ZEB1 promoter. GRHL2 also inhibited Smad-mediated transcription and it upregulated mir-200b/c as well as the TGF-β receptor antagonist, BMP2. Finally, ectopic expression of GRHL2 in MDA-MB-231 breast cancer cells triggered an MET and restored sensitivity to anoikis. Taken together, our findings define a major role for GRHL2 in the suppression of oncogenic EMT in breast cancer cells.

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    • "Reduced expression of GRHL2 in breast tumors has been associated with an EMT phenotype, increased cell survival, and migratory and invasive behaviour, which is reminiscent of a tumor suppressor gene [11] [12]. Conversely, high GRHL2 expression has been related to a poor prognosis for breast cancer metastasis [10] [11] [15] [17], although we are currently exploring the hypothesis that high expression of GRHL2 indicates a loss of function of this protein. Figure 5. GRHL2 expression at the mRNA level in cervical samples without lesions. "
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    • "We suspected that SALL4 regulates transcription factors involving in EMT, because SALL4 knockdown induces epithelial transition. In order to identify the factor(s), we used quantitative RT-PCR to screen the transcription factors, SNAI1, SNAI2, TWIST1, TWIST2, FOXC1, FOXC2, TGFB1, TCF3, GSC, GRHL2, ZEB1 and ZEB2 [18] [19] [20]. In the result, we found reduction in the ZEB1 mRNA level in shSALL4-expressing cells (Fig. 2A), while the others were not significantly changed (Fig. 2B and Fig. S4). "
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