USP20 mediates bladder cancer progression via altering the activity of Hippo-YAP axis through directly stabilizing YAP1 protein

Abstract Yes-associated protein 1 (YAP1) mediated hippo pathway has attracted several research importance in various types of malignancies. The hampered Hippo-YAP1 axis in bladder cancer (BC) was identified as a major driver of BC progression and oncogenesis. The activity of Hippo pathway is controlled via regulation of phosphorylation cascade of MST1/2-LATS1/2-YAP1, while other modification as ubiquitination of hippo pathway protein also mediated the activity of Hippo pathway through the co-regulation of E3 ligases and deubiquitinases. In this study, we identified USP20 as a Hippo/YAP1 pathway activity related deubiquitinase through combined analysis of siRNA screening and deubiquitinase over-expression. Further analysis identified that USP20 directed regulated the YAP1 expression and target gene of YAP1, connective tissue growth factor (CTGF) as well as cysteine-rich angiogenic inducer 61 (CYR61). Tissue microarray assay confirmed that USP20 was elevated in tumor tissue and correlated with YAP1 expression. Mechanism study identified that USP20 directly interacted with YAP1 protein and promoted the stability of YAP1 protein through hampering the K48-linked poly-ubiquitination. Our findings in this study revealed that USP20 as a novel deubiquitinase in regulating the Hippo-YAP1 pathway in BC.