ESRP1-regulated DNMT3B isoform switching determines the malignant potential of pancreatic cancer

Epithelial splicing regulatory protein 1 (ESRP1) is a key regulator of epithelial-mesenchymal transition (EMT) and cancer progression, including in pancreatic ductal adenocarcinoma (PDAC). We show that ESRP1-mediated isoform switching of DNA methyltransferase 3B (DNMT3B) correlates with the metastatic potential of pancreatic cancer cells. The expression of DNMT3B splicing variants was closely linked to ESRP1 level. Ectopic expression of mesenchymal DNMT3B isoforms 3 and 7, lacking part of the methyltransferase catalytic domain, significantly enhanced lung metastasis and tumor growth, while epithelial DNMT3B isoforms 1 and 2, with an intact catalytic domain, suppressed these effects in mouse models. Differential expression of DNMT3B isoforms also correlated with overall survival in PDAC patients. Deletion of exons 21-22, differentially spliced region between epithelial and mesenchymal isoforms, increased cell proliferation and migration, similar to mesenchymal DNMT3B. RNA sequencing revealed that mesenchymal DNMT3B isoforms 3 and 7 were associated with aggressive tumor phenotypes. Among differentially expressed target genes of DNMT3B isoforms, Fibulin 1 (FBLN1), a key regulator of the tumor microenvironment, regulates cancer cell migration and EMT. Taken together, our results highlight the central role of ESRP1-mediated DNMT3B isoform switching in pancreatic cancer progression and metastasis and suggest that DNMT3B isoforms may serve as potential biomarkers for this disease.