SAMD1 suppresses epithelial-mesenchymal transition (EMT) pathways in pancreatic ductal adenocarcinoma

Abstract

AbstractSAMD1 (SAM-domain containing protein 1), a CpG island-binding protein, plays a pivotal role in the repression of its target genes. Despite its significant correlation with outcomes in various tumor types, the role of SAMD1 in cancer has remained largely unexplored. In this study we focused on pancreatic ductal adenocarcinoma (PDAC) and revealed that SAMD1 acts as a repressor of genes associated with epithelial-mesenchymal transition (EMT). Upon deletion of SAMD1 in PDAC cells, we observed significantly increased migration rates. SAMD1 exerts its effects by binding to specific genomic targets, includingCDH2, encoding N-cadherin, which emerged as a driver of enhanced migration upon SAMD1 knockout. Furthermore, we discovered the FBXO11-containing E3 ubiquitin ligase complex as an interactor of SAMD1. FBXO11 ubiquitinates SAMD1 within its DNA-binding winged helix domain and inhibits SAMD1 chromatin binding genome-wide. HighFBXO11expression in PDAC is associated with poor prognosis and increased expression of EMT-related genes, underlining an antagonistic relationship between SAMD1 and FBXO11. In summary, our findings provide new insights into the regulation of EMT-related genes in PDAC, shedding light on the intricate role of SAMD1 and its interplay with FBXO11 in this cancer type.