FBXO11 Promotes Ubiquitination Of The Snail Family Of Transcription Factors In Cancer Progression And Epidermal Development

There are two different cell types——Epithelial and mesenchymal cells. They show different phenotype and function. But the two cell types possess plasticity and are interconvertible under certain circumstances. Epithelial cells can be reprogrammed into mesenchymal cells, a process known as epithelial–mesenchymal transition(EMT).Physiological EMT is strictly regulated. And it is important for the development and differentiation. But there are so many EMT-inducing signals, such as growth factors, cytokines. And they may cause unscheduled EMT. Aberrant activation of the embryonic EMT program contributes to pathologic conditions such as fibrosis and cancer. More than 90% of the epithelial malignant tumor metastasis was associated with EMT. In human cancer, such as lung cancer, liver cancer, colon cancer, breast cancer,EMT is an important process conducive to tumor invasion and dissemination. Thus,the research of EMT happened and regulation mechanism is important to develop targeted therapiesIntercellular adhesion impacts epithelial cell proliferation and motility in normal development and cancer. The Snail family of transcription factors are core inducers of epithelial-to-mesenchymal transition(EMT), and are under complex regulation that remains incompletely understood. Here we show that the F-box protein FBXO11 recognizes and promotes ubiquitin-mediated proteasomal degradation of multiple Snail family members including Scratch. Overexpression of FBXO11 in mesenchymal cells reduces Snail protein abundance and cell invasion. Conversely, depletion of endogenous FBXO11 in epithelial cancer cells causes Snail protein accumulation, EMT, and tumor invasion. FBXO11 is required for maintaining estrogen receptor expression in breast cancer cells. Expression of FBXO11 is downregulated by EMT-inducing signals. In human cancer, high levels of FBXO11 correlate with expression of epithelial markers and favorable prognosis. The results suggest FBXO11 sustains the epithelial state and suppresses cancer progression. Inactivation of FBXO11 in mice leads to neonatal lethality, epidermal thickening, and increased Snail protein levels in epidermis, validating FBXO11 is a physiological ubiquitin ligase of Snail. Moreover, in C. elegans, the FBXO11 mutant phenotype is attributed to the Snail factors as it is suppressed by inactivation/depletion of Snail homologs. Collectively, these findings suggest the FBXO11-Snail regulatory axis is evolutionarily conserved and critically governs carcinoma progression and mammalian epidermal development.