PRSS23 promotes pancreatic cancer progression through regulating Hippo-YAP activity

Pancreatic ductal adenocarcinoma (PDAC) remains a highly aggressive malignancy characterized by a poor prognosis, highlighting the critical need to elucidate its underlying molecular mechanisms. In this study, we demonstrate the pivotal oncogenic role of PRSS23 in PDAC pathogenesis. Clinical analyses reveal that PRSS23 is frequently overexpressed in PDAC tumor tissues, and elevated expression levels are significantly associated with reduced patient survival. Functional experiments show that PRSS23 knockdown markedly suppresses PDAC cell proliferation in vitro and inhibits tumor growth and metastasis in vivo. Transcriptomic profiling identifies the Hippo signaling pathway as a key downstream effector of PRSS23. Specifically, depletion of PRSS23 leads to inactivation of YAP, the central transcriptional co-activator of the Hippo pathway. Molecular docking simulations suggest that PRSS23 facilitates the formation of a ternary complex involving the serine/threonine phosphatase PP2A and the Hippo kinase MST1. Subsequent experimental validation confirms that PRSS23 silencing disrupts the interaction between PP2A and MST1, resulting in increased MST1 phosphorylation. This enhancement of MST1 activity promotes the phosphorylation and cytoplasmic sequestration of YAP, thereby suppressing its oncogenic transcriptional functions. Collectively, our findings establish PRSS23 as a novel prognostic biomarker and a crucial regulatory node in PDAC progression. PRSS23 drives tumorigenesis and metastasis by stabilizing the PP2A-MST1 interaction, which impairs Hippo pathway signaling and leads to aberrant YAP activation. Targeting the PRSS23/PP2A/MST1 axis may therefore represent a promising therapeutic strategy for the treatment of PDAC.