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2016 ; 5
(8
): e254
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FLASH protects ZEB1 from degradation and supports cancer cells
epithelial-to-mesenchymal transition
#MMPMID27526108
Abshire CF
; Carroll JL
; Dragoi AM
Oncogenesis
2016[Aug]; 5
(8
): e254
PMID27526108
show ga
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-?-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.