OTUD4 regulates pancreatic cancer progression via Hippo/YAP axis.

The over-activation of Hippo/YAP axis was often observed in pancreatic adenocarcinoma (PAAD), while the detailed mechanism is not totally understood. Recent studies demonstrated that the ubiquitin modification, which controlled the protein stability of YAP, played important roles in Hippo signaling and PAAD progression. In order to understand the underlying link between YAP protein stability and Hippo activity in PAAD progression, we carried out GSEA bioinformatic analysis coupled with siRNA screening and identified OTUD4 as an important effector for Hippo signaling in PAAD. OTUD4, which was highly expressed in PAAD tissue, correlated with Hippo target gene expression in PAAD tissues. Depletion of OTUD4 significantly reduced the activity of Hippo/YAP axis and hampered PAAD progression. Mechanism studies revealed that OTUD4 could interact with YAP and promote YAP K48-linked poly-ubiquitination and degradation in PAAD. In conclusion, our study identified an interesting regulation mechanism between OTUD4 and Hippo signaling in PAAD, while targeting OTUD4 could be a plausible strategy for PAAD therapy. Abbreviation: OTUD4, OTU Domain-Containing Protein 4; YAP, Yes-Associated Protein; TEAD, Transcriptional Enhanced Associate Domain transcriptional factor; TCGA, The Cancer Genome Atlas; ATCC, American Type Culture Collection; DMEM, Dulbecco's Modified Eagle Medium; DUB, Deubiquitinase; GSEA, Gene Set Enrichment Analysis; NES, Normalized Enrichment Score; ECL, Enhanced Chemiluminescence; PVDF, Polyvinylidene Fluoride; PMSF, Phenyl Methane Sulfonyl Fluoride; PFA, Paraformaldehyde; Co-IP, Coimmunoprecipitation; IHC, Immunohistochemistry; CHX, Cycloheximide; IF, Immunofluorescence; GEO, Gene Expression Omnibus.