The p65 subunit of NF-κB and PARP1 assist Snail1 in activating fibronectin transcription

Abstract

SummarySnail1 is a transcriptional repressor of E-cadherin that triggers epithelial-mesenchymal transition (EMT). Here, we report assisted Snail1 interaction with the promoter of a typical mesenchymal gene, fibronectin (FN1), both in epithelial cells undergoing EMT and in fibroblasts. Together with Snail1, the p65 subunit of NF-kB and PARP1 bound to the FN1 promoter. We detected nuclear interaction of these proteins and demonstrated the requirement of all three for FN1 transcription. Moreover, other genes involved in cell movement mimic FN1 expression induced by Snail1 or TGF-b1 treatment and recruit p65NF-kB and Snail1 to their promoters. The molecular cooperation between Snail1 and NF-kB in transcription activation provides a new insight into how Snail1 can modulate a variety of cell programs.

Snail1-Expressing Fibroblasts in the Tumor Microenvironment Display Mechanical Properties That Support Metastasis

“…Therefore, Snail1 modulates the levels of these structural molecules in myofibroblasts at distinct levels: transcriptionally, acting as a coactivator of TGFb-induced ECM genes (23), and posttranscriptionally, inducing protein stabilization through this RhoA-dependent mechanism. The protein levels of LOX, the collagen crosslinking enzyme essential to generate stiffer ECMs (37), also increased in a Snail1-dependent manner.…”

“…However, molecular pathways modulated by Snail1 in fibroblasts are poorly defined, and no links between Snail1 activity and the generation of mechanical signals have been proposed. We have previously describe that a set of ECM genes can be transcriptionally upregulated by Snail1 (23) in cultured epithelial cells undergoing EMT and fibroblasts. Here, we demonstrate that expression of Snail1 in fibroblasts is required for the activation of RhoA and the acquisition of a myofibroblastic phenotype.…”

MCF-7 Cells Expressing Nuclear Associated Lysyl Oxidase-like 2 (LOXL2) Exhibit an Epithelial-to-Mesenchymal Transition (EMT) Phenotype and Are Highly Invasive in Vitro

“…In epithelial cells undergoing EMT, Snail1 also binds to the fibronectin (FN1) promoter together with p65 unit of NF-B and PARP1 to up-regulate its transcription (39). Expression of Snail1 is also tightly correlated with expression of vimentin (40 -42).…”

Differential Role of Snail1 and Snail2 Zinc Fingers in E-cadherin Repression and Epithelial to Mesenchymal Transition

“…20,29). Snail1 and Snail2 not only directly repress epithelial gene promoters, but also activate the expression of mesenchymal genes, like vimentin, fibronectin, and N-cadherin through indirect mechanisms not yet well understood (30). Nevertheless, and despite the high homology in their DNA binding and SNAG domains, Snail1 and Snail2 induce common and differential gene expression patterns when overexpressed in epithelial cells (31), pointing to distinct structural and/or functional characteristics between both factors.…”