Deubiquitinase UCHL5 stabilizes ELK3 to potentiate cancer stemness and tumor progression in pancreatic adenocarcinoma (PAAD).

Aberrant ubiquitin-proteasome system (UPS) contributes to tumorigeneisis or drug resistance of Pancreatic Adenocarcinoma (PAAD). Previous studies have implicated the deubiquitinase UCHL5 was abnormally expressed in multiple malignancies. However, little was reported about the specific roles of UCHL5 in PAAD. We aimed to identify the biological roles of UCHL5 in PAAD and demonstrate its prognostic significance. Differential analysis revealed that UCHL5 expressed highly in tumors versus normal tissues, like TCGA-PAAD, GSE28735, GSE15471 and collected samples. Patients with high UCHL5 expressions had worse survival outcomes relative to those with low UCHL5 levels. Experimental assays showed that UCHL5 overexpression could significantly enhance cell proliferation, colony formation and self-renewal capacities. UCHL5 could also promote PAAD migration in vitro and in vivo. Mechanistically, UCHL5 could directly deubiquitinate and stabilize ELK3 proteins. UCHL5 relied on accumulated ELK3 proteins to drive cell growth, stem-like properties and migration abilities. In addition, enrichment analysis based on RNA-seq data implicated that ELK3 mainly correlated with Notch1 signaling and ELK3 could notably elevate ELK3 mRNA levels. UCHL5 could thus promote self-renewal abilities of PAAD and targeting ELK3 could inhibit the stemness features. In contrast, UCHL5 deficiency could suppress PAAD stemness features, and ectopic expression of ELK3 could rescue this effect. Last of all, we utilized the UCHL5 inhibitor, b-AP15, to treat PAAD cells and found that b-AP15 could inhibit the growth of PAAD cells in a dose-dependent manner. Collectively, our study uncovered the underlying mechanisms of UCHL5/ELK3/Notch1 axis in PAAD progression and stemness maintaince, shedding light on individualized treatment and risk stratification for PAAD patients.