Abstract
Snail (SNAI1), a central transcription factor driving epithelial-mesenchymal transition (EMT), is pivotal in cancer metastasis and tissue remodeling. Owing to its labile nature, Snail activity is tightly controlled by post-translational modifications that dictate its stability. Here this review summarizes how the ubiquitin-proteasome system orchestrates Snail degradation through coordinated phosphorylation and ubiquitination, mediated by diverse E3 ligases and regulated by kinases, acetyltransferases and deubiquitinases. These mechanisms dynamically adjust Snail levels in both the cytoplasm and nucleus, thereby modulating EMT outcomes. In parallel, emerging studies reveal that chaperone-mediated autophagy (CMA) provides an additional layer of regulation. Through recognition of KFERQ-like motifs, CMA selectively directs cytoplasmic Snail to lysosomes for LAMP2A-dependent degradation, functioning as a quality control system. Impairment of CMA leads to nuclear accumulation of Snail, enhancing its EMT-inducing and prometastatic potential. Together, the ubiquitin-proteasome system and CMA represent complementary, context-dependent axes that maintain Snail homeostasis. Their disruption facilitates EMT activation and metastatic progression. By integrating recent findings, this review highlights the dual degradative control of Snail and its implications for cancer biology, providing a conceptual framework for therapeutic approaches aimed at restoring degradative balance and limiting metastasis.