title: FLASH protects ZEB1 from degradation and supports cancer cells' epithelial-to-mesenchymal transition.
abstract: 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.
authors.affiliation: Department of Medicine, Feist-Weiller Cancer Center, LSU Health, Shreveport, LA, USA.
authors.forename: C F
authors.initials: CF
authors.lastname: Abshire
authors.affiliation: Department of Medicine, Feist-Weiller Cancer Center, LSU Health, Shreveport, LA, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Carroll
authors.affiliation: Department of Medicine, Feist-Weiller Cancer Center, LSU Health, Shreveport, LA, USA.
authors.forename: A-M
authors.initials: AM
authors.lastname: Dragoi