UBR5 regulates the progression of colorectal cancer cells through Snail-induced epithelial–mesenchymal transition

TL;DR

This study shows that UBR5 controls colorectal cancer progression by regulating Snail, a key driver of cancer cell spread.

Contribution

The paper identifies UBR5 as a novel E3 ubiquitin ligase that targets Snail for degradation in colorectal cancer.

Findings

UBR5 binds and degrades Snail, reducing tumor invasion in colorectal cancer cells.

Low UBR5 levels in human tumors correlate with worse prognosis.

UBR5's E3 ligase activity is essential for Snail degradation and epithelial state maintenance.

Abstract

Snail is a core inducer of epithelial-to-mesenchymal transition. Here, we show that UBR5 promotes ubiquitin-mediated degradation of Snail and regulates the progression of colorectal cancer cells through its E3 ubiquitin ligase function. UBR5 specifically binds to Snail in vitro, but not Slug, and its degradation depends on snail phosphorylation. Depletion of endogenous UBR5 causes Snail protein accumulation, epithelial-to-mesenchymal transition, and tumor invasion in colorectal cancer cells. Conversely, the overexpression of UBR5 reduces Snail protein abundance and cellular invasiveness. The activity-deficient mutant UBR5 C2768S disrupts its binding and degradation to Snail, thereby losing the ability to regulate epithelial-to-mesenchymal transition in colorectal cancer cells. UBR5 is lowly expressed in human colorectal cancer versus normal tissues, and high UBR5 levels correlate with favorable prognosis, suggesting that UBR5 sustains the epithelial state and inhibits cancer progression. These findings establish the UBR5-Snail axis as a mechanism of post-translational regulation of epithelial-to-mesenchymal transition and colorectal cancer metastasis.

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