Abstract
The set of events that convert adherent epithelial cells into migratory cells are collectively known as epithelial–mesenchymal transition (EMT). EMT is involved during development, for example, in triggering neural crest migration, and in pathogenesis such as metastasis. Here we discover FBXO32, an E3 ubiquitin ligase, to be critical for hallmark gene expression and phenotypic changes underlying EMT. Interestingly, FBXO32 directly ubiquitinates CtBP1, which is required for its stability and nuclear retention. This is essential for epigenetic remodeling and transcriptional induction of CtBP1 target genes, which create a suitable microenvironment for EMT progression. FBXO32 is also amplified in metastatic cancers and its depletion in a NSG mouse xenograft model inhibits tumor growth and metastasis. In addition, FBXO32 is essential for neuronal EMT during brain development. Together, these findings establish that FBXO32 acts as an upstream regulator of EMT by governing the gene expression program underlying this process during development and disease.
Highlights
The set of events that convert adherent epithelial cells into migratory cells are collectively known as epithelial–mesenchymal transition (EMT)
We show that FBXO32dependent K63-linked ubiquitination of C-terminal-binding protein1 (CtBP1) is required for its nuclear retention, which is essential for mediating transcriptional changes via epigenetic reprogramming of EMT target genes
FBXO32 is essential for epithelial–mesenchymal transition
Summary
The set of events that convert adherent epithelial cells into migratory cells are collectively known as epithelial–mesenchymal transition (EMT). Following the induction of epithelial to mesenchymal transition (EMT) program, cells undergo molecular and phenotypic remodeling that involves changes like cytoskeletal reorganization and loss of cell–cell junctions. This allows epithelial cells to escape from their original location by acquiring a migratory, mesenchymal identity[2]. Such a dramatic change in cell fate is essential for key processes during embryonic development, such as embryo implantation, embryonic layer formation, gastrulation and neural tube formation. Recent studies have suggested dispensability of the established key EMT transcription factors in driving metastasis and further vouched for a need of exploring more potent factors driving this process[17,18,19]
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