SNAIL and miR-34a feed-forward regulation of ZNF281/ZBP99 promotes epithelial-mesenchymal transition

Hahn, Stefanie; Jackstadt, René; Siemens, Helge; Hünten, Sabine; Hermeking, Heiko

doi:10.1038/emboj.2013.236

Cited by 152 publications

(148 citation statements)

References 75 publications

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“…Among other direct miR-34a targets that induce cancer cell invasion are c-KIT (51), AXL (52), and c-MET (53). We recently showed that the zinc finger 281 protein (ZNF281) is also an important miR-34 target with respect to EMT (54). We demonstrated that the expression of ZNF281 is controlled by miR-34 and SNAIL in a coherent feed-forward loop, where SNAIL and ZNF281 induce each other, whereas miR-34 can directly repress both of them.…”

Section: Methodsmentioning

confidence: 99%

IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis

Rokavec¹,

Öner²,

Li³

et al. 2014

J. Clin. Invest.

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Members of the miR-34 family are induced by the tumor suppressor p53 and are known to inhibit epithelialto-mesenchymal transition (EMT) and therefore presumably suppress the early phases of metastasis. Here, we determined that exposure of human colorectal cancer (CRC) cells to the cytokine IL-6 activates the oncogenic STAT3 transcription factor, which directly represses the MIR34A gene via a conserved STAT3-binding site in the first intron. Repression of MIR34A was required for IL-6-induced EMT and invasion. Furthermore, we identified the IL-6 receptor (IL-6R), which mediates IL-6-dependent STAT3 activation, as a conserved, direct miR-34a target. The resulting IL-6R/STAT3/miR-34a feedback loop was present in primary colorectal tumors as well as CRC, breast, and prostate cancer cell lines and associated with a mesenchymal phenotype. An active IL-6R/ STAT3/miR-34a loop was necessary for EMT, invasion, and metastasis of CRC cell lines and was associated with nodal and distant metastasis in CRC patient samples. p53 activation in CRC cells interfered with IL-6-induced invasion and migration via miR-34a-dependent downregulation of IL6R expression. In Mir34a-deficient mice, colitis-associated intestinal tumors displayed upregulation of p-STAT3, IL-6R, and SNAIL and progressed to invasive carcinomas, which was not observed in WT animals. Collectively, our data indicate that p53-dependent expression of miR-34a suppresses tumor progression by inhibiting a IL-6R/STAT3/miR-34a feedback loop.

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Section: Methodsmentioning

confidence: 99%

IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis

Rokavec¹,

Öner²,

Li³

et al. 2014

J. Clin. Invest.

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650

470

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“…In summary, our study revealed a direct activator role for Drosophila Snail, a function that is seemingly conserved from flies to humans (Sakai et al 2006;Stemmer et al 2008;Reece-Hoyes et al 2009;Hu et al 2010;Tao et al 2011;Wels et al 2011;Hahn et al 2013) and places the Snail family of proteins in the category of dually acting TFs.…”

Section: A New View Of How Snail Regulates Diverse Developmental Procmentioning

confidence: 99%

“…Although the studies in HepG2 cells and in quail show that full activation by Snail requires a partner factor, vertebrate Snail proteins can also activate on their own in vitro (Huang et al 2009;Tao et al 2011;Wels et al 2011;Hahn et al 2013). Potential synergistic effects have not been analyzed in these studies.…”

Section: Motif Prediction Identifies a New Motif Essential For Snail mentioning

confidence: 99%

“…An activator role for Snail has been shown by genetic studies and reporter assays in Caenorhabditis elegans, mice, and quail-showing that Snail family members can activate B0507.1 (ReeceHoyes et al 2009), MMP15 (Tao et al 2011), and Snail2 (Sakai et al 2006)-and by in vitro studies of the p15 INK4b (Hu et al 2010) and ZNF281 genes (Hahn et al 2013). Furthermore, Snail can increase Wnt target gene expression in human cell lines independent of direct DNA binding but via physical interaction with b-catenin (Stemmer et al 2008).…”

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confidence: 99%

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A conserved role for Snail as a potentiator of active transcription

et al. 2014

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The transcription factors of the Snail family are key regulators of epithelial–mesenchymal transitions, cell morphogenesis, and tumor metastasis. Since its discovery in Drosophila ∼25 years ago, Snail has been extensively studied for its role as a transcriptional repressor. Here we demonstrate that Drosophila Snail can positively modulate transcriptional activation. By combining information on in vivo occupancy with expression profiling of hand-selected, staged snail mutant embryos, we identified 106 genes that are potentially directly regulated by Snail during mesoderm development. In addition to the expected Snail-repressed genes, almost 50% of Snail targets showed an unanticipated activation. The majority of “Snail-activated” genes have enhancer elements cobound by Twist and are expressed in the mesoderm at the stages of Snail occupancy. Snail can potentiate Twist-mediated enhancer activation in vitro and is essential for enhancer activity in vivo. Using a machine learning approach, we show that differentially enriched motifs are sufficient to predict Snail's regulatory response. In silico mutagenesis revealed a likely causative motif, which we demonstrate is essential for enhancer activation. Taken together, these data indicate that Snail can potentiate enhancer activation by collaborating with different activators, providing a new mechanism by which Snail regulates development.

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“…The EMT process functions necessarily in the embryonic development by differentiating into different tissues, facilitating the morphological formation of various organs and regenerating tissues after injury. The induction of EMT can be triggered by many factors ranging from cytokines including TGF-β, and types of transcription factors such as Twist [56][57][58], Snail [59][60][61], Slug [62,63] and KLF8 [64][65][66], to various signaling pathways encompassing the ones we have discussed above, and certain exogenous drug agents will be discussed below.…”

Section: The Notch Pathwaymentioning

confidence: 99%

Pancreatic Cancer Stem Cells

Zhu

Zhang

SpringerReference

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Studies are emerging in support of the cancer stem cells (CSCs) theory which considers that a tiny subset of cancer cells is exclusively responsible for the initiation and malignant behavior of a cancer. This cell population, also termed CSCs, possesses the capacity both to self-renew, producing progeny that have the identical tumorigenic potential, and to differentiate into the bulk of cancer cells, helping serve the formation of the tumor entities, which, altogether, build the hierarchically organized structure of a cancer. In this review, we try to articulate the complicated signaling pathways regulating the retention of the characteristics of pancreatic CSCs, and in the wake of which, we seek to offer insights into the CSCs-relevant targeted therapeutics which are, in the meantime, confronted with bigger challenges than ever.

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SNAIL and miR-34a feed-forward regulation of ZNF281/ZBP99 promotes epithelial-mesenchymal transition

Cited by 152 publications

References 75 publications

IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis

IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis

A conserved role for Snail as a potentiator of active transcription

Pancreatic Cancer Stem Cells

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