Kazuhiro FUKUMURA

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies and is characterized by pronounced phenotypic plasticity, metabolic adaptation, and therapeutic resistance within a dense and desmoplastic tumor microenvironment. Although transcriptional deregulation has been extensively investigated, post-transcriptional regulation, particularly the control of mRNA stability, has emerged as a critical and previously underexplored contributor to PDAC progression. RNA-binding proteins (RBPs), together with cis-regulatory RNA elements and epitranscriptomic modifications such as N6-methyladenosine (m6A), form interconnected regulatory networks that dynamically modulate mRNA turnover and thereby shape protein output in response to microenvironmental stress. By selectively stabilizing transcripts encoding epithelial–mesenchymal transition (EMT) regulators, metabolic enzymes, and stress-response factors, these networks promote reversible, non-genetic adaptation without requiring permanent genetic alterations. This regulatory flexibility supports invasion, therapeutic tolerance, and intratumoral heterogeneity under hypovascular and nutrient-limited conditions. Recent advances further suggest that targeting mRNA stability through small molecules and RNA-directed strategies may provide new therapeutic opportunities in PDAC. In this review, we summarize current insights into post-transcriptional mechanisms regulating mRNA stability in PDAC, highlight key knowledge gaps, and discuss their potential translational implications.

Human pre-mRNA splicing requires the removal of introns with highly variable lengths, from tens to over a million nucleotides. Therefore, mechanisms of intron recognition and splicing are likely not universal. Recently, we reported that splicing in a subset of human short introns with truncated polypyrimidine tracts depends on RBM17 (SPF45), instead of the canonical splicing factor U2 auxiliary factor (U2AF) heterodimer. Here, we demonstrate that SAP30BP, a factor previously implicated in transcriptional control, is an essential splicing cofactor for RBM17. In vitro binding and nuclear magnetic resonance analyses demonstrate that a U2AF-homology motif (UHM) in RBM17 binds directly to a newly identified UHM-ligand motif in SAP30BP. We show that this RBM17-SAP30BP interaction is required to specifically recruit RBM17 to phosphorylated SF3B1 (SF3b155), a U2 small nuclear ribonucleoprotein (U2 snRNP) component in active spliceosomes. We propose a mechanism for splicing in a subset of short introns, in which SAP30BP guides RBM17 in the assembly of active spliceosomes.