Sun, Lei

Abstract Zinc finger E-box binding homeobox 1 (ZEB1) is a transcription factor regulating epithelial to mesenchymal transition (EMT). To date, regulation of ZEB1 by key signaling pathways including RAS/RAF/MEK/ERK remains unclear, and few studies have focused on molecular associations or functional alterations of ZEB1 by post-translational modification. Here, we report an interaction of ZEB1 with the deubiquitinase USP10 that is regulated by MEK-ERK signaling. USP10 removes the K27 linkage ubiquitination chain on ZEB1 that enhances K48 polyubiquitination and promotes ZEB1 proteasomal degradation. However, constitutive activation of ERK can phosphorylate USP10 at Ser236 to impair its interaction with ZEB1 and, thereby, stabilize ZEB1 protein shown to promote colorectal cancer metastasis in mice. Conversely, inhibition of MEK-ERK blocks USP10 phosphorylation to enhance the USP10-ZEB1 interaction which can suppress ZEB1-mediated tumor cell migration and metastasis in vivo. Together, these data demonstrate a novel function of USP10 in the regulation of ZEB1 ubiquitination and protein stability that can inhibit ZEB1-mediated tumor metastasis.