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Cancer metastasis remains a significant challenge and the leading cause of cancer-associated deaths. It is postulated that during metastasis cells undergo epithelial-to-mesenchymal transition (EMT), a process characterized by loss of cell–cell contacts and increased migratory and invasive potential. ZEB1 is one the most prominent transcriptional repressors of genes associated with EMT. We identified caspase-8-associated protein 2 (CASP8AP2 or FLASH) as a novel posttranscriptional regulator of ZEB1. Here we demonstrate that FLASH protects ZEB1 from proteasomal degradation brought by the action of the ubiquitin ligases SIAH1 and F-box protein FBXO45. As a result, loss of FLASH rapidly destabilized ZEB1 and reversed EMT cellular characteristics. Importantly, loss of FLASH blocked transforming growth factor-β-induced EMT and enhanced sensitivity to chemotherapy. Thus, we propose that FLASH–ZEB1 interplay may be a protective mechanism against ZEB1 degradation in cells undergoing EMT and may be an efficacious target for therapies aimed to block EMT progression.

FLASH protects ZEB1 from degradation and supports cancer cells' epithelial-to-mesenchymal transition