Abstract
The epithelial-to-mesenchymal transition (EMT) is a cellular reprogramming process converting epithelial cells into mesenchymal cell morphology. Snail is a critical regulator of EMT by both suppressing epithelial gene expression and promoting mesenchymal gene expression. Expression and activity of Snail are tightly controlled at transcriptional and post-translational levels. It has previously been reported that Snail undergoes phosphorylation and ubiquitin-dependent proteasome degradation. Here, we report nuclear phosphatase SCP4/CTDSPL2 acts as a novel Snail phosphatase. SCP4 physically interacts with and directly dephosphorylates Snail. SCP4-mediated dephosphorylation of Snail suppresses the ubiquitin-dependent proteasome degradation of Snail and consequently enhances TGFβ-induced EMT. The knockdown of SCP4 in MCF10A mammary epithelial cells leads to attenuated cell migration. Collectively, our finding demonstrates that SCP4 plays a critical role in EMT through Snail dephosphorylation and stabilization.
Highlights
The epithelial –mesenchymal transition (EMT) is the process whereby epithelial cells lose cell polarity and cell –cell contacts, and undergo drastic morphological changes, acquiring highly migratory and invasive properties [1 –5]
We reported that SCP4 acts as a novel nuclear phosphatase for Snail
We found that SCP4 could stabilize Snail in EMT-relevant MCF10A cells
Summary
The epithelial –mesenchymal transition (EMT) is the process whereby epithelial cells lose cell polarity and cell –cell contacts, and undergo drastic morphological changes, acquiring highly migratory and invasive properties [1 –5]. It is thought to be critical for many developmental events such as gastrulation and neural crest migration. EMT is found to provide tumour cells with the ability to migrate and invade adjacent tissues, which accounts for approximately 90% of human cancer deaths [7,8]. One of the hallmarks of EMT is functional loss of E-cadherin, a metastatic suppressor during tumour progression [9]. Downregulation of E-cadherin is an essential step towards the invasive phase of carcinoma, and in many metastatic cancers, which is largely due to transcriptional repression [10]
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