MYC-Mediated USP39 Upregulation Stabilizes SRSF1 in Pancreatic Cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy primarily driven by oncogenic KRAS signaling. The splicing factor serine/arginine-rich splicing factor 1 (SRSF1) plays a key oncogenic role in PDAC through reciprocal cross-interactions with KRAS signaling. However, the mechanisms regulating SRSF1 protein stability remain poorly understood. In this study, we identify the deubiquitinase USP39 as a critical regulator of SRSF1 stability. It interacts with SRSF1 in an RNA-independent manner and suppresses its ubiquitination. USP39 is upregulated in PDAC and correlates with poor patient prognosis. Functional analyses demonstrate that USP39 promotes PDAC cell progression, in part through the stabilization of SRSF1. Mechanistically, MYC activates USP39 transcription through direct promoter binding. These findings define a MYC–USP39–SRSF1 regulatory axis that integrates transcriptional and posttranslational mechanisms in PDAC and suggest USP39 as a potential therapeutic target. Implications: USP39 functions as a central regulator that integrates transcriptional and posttranslational regulation in pancreatic cancer through the MYC–USP39–SRSF1 axis and represents a potential therapeutic target.