SEC14L2 contributes to tumor progression by enhancing USP5-driven RBM3 deubiquitination in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) persists as a highly lethal malignancy with a dire prognosis and scarce therapeutic advancements, highlighting an urgent demand for innovative prognostic markers and molecular targets. Herein, we identify Section 14-like lipid binding 2 (SEC14L2) as a pivotal oncogene in PDAC pathogenesis. Elevated SEC14L2 expression is established as a potent and consistent prognostic indicator, strongly associated with adverse clinical outcomes across multiple independent patient cohorts. Functional analyses confirm that SEC14L2 drives malignant progression by enhancing proliferation and inhibiting apoptosis in PDAC cells. Mechanistically, we elucidate that SEC14L2 orchestrates the recruitment of ubiquitin-specific-processing protease 5 (USP5) to RNA-binding motif protein 3 (RBM3). This interaction facilitates USP5-mediated deubiquitination of RBM3 at lysine 84, specifically cleaving K48-linked polyubiquitin chains, which consequently stabilizes the RBM3 protein. The accumulated RBM3 then augments the mRNA stability of doublecortin-like kinase 1 (DCLK1), a recognized mediator of tumorigenesis. Furthermore, we uncover that the transcription factor SP1 acts as a key upstream regulator, directly governing the transcriptional activation of SEC14L2 and fostering its frequent upregulation in PDAC. Our findings delineate a novel SP1/SEC14L2/USP5/RBM3/DCLK1 signaling axis that critically propels PDAC progression, thereby nominating SEC14L2 as a compelling therapeutic target for this devastating disease.