Regulation of divergent epithelial-to-mesenchymal transition responses via the CDK4/6-USP51 pathway through ZEB1 protein stabilization

Epithelial-to-mesenchymal transition (EMT) is a cellular process important for numerous developmental processes, wound healing and cancer progression. In the context of heterogenous nature of cancer, EMT occurs at the forefront of tumor invasion, although the precise molecular mechanisms governing its spatial dynamics remain unclear. This study aimed to explore the diverse responses to EMT in monolayer cell cultures of MCF10A epithelial cell with induction of Zinc-finger E-box binding homeobox 1 (ZEB1), an EMT-inducing transcription factor. ZEB1-induced MCF10A cells exhibited EMT in space- and cell density-dependent manner. The expression of ZEB1 was modulated by the ubiquitin-proteasome pathway. We found that CDK4/6 and USP51 enhanced ZEB1 protein stability via deubiquitination. Moreover, suppressing USP51 and CDK4/6 activity attenuated cell migration, a characteristic of the mesenchymal phenotype, in ZEB1-induced MCF10A cells. Finally, we demonstrated that CDK4/6 kinase activity is important for cell migration as well as stabilizing ZEB1 in the mesenchymal breast cancer cell line MDA-MB-231. These insights could pave the way for developing more targeted and effective therapies targeting at ZEB1 and EMT in advanced cancers.