Abstract
BACKGROUND: Although transcriptomic studies have stratified pancreatic ductal adenocarcinoma (PDAC) into clinically relevant subtypes, classical or basal-like, further research is needed to identify the transcriptional regulators of each subtype. Previous studies identified HNF4α as a key regulator of the classical subtype, but the distinct contributions of its isoforms (P1 and P2), which display dichotomous functions in normal development and gastrointestinal malignancies, remain unexplored. OBJECTIVE: The objective of this study is to investigate the role of HNF4α P1 and P2 isoforms in regulating growth and differentiation. DESIGN: We performed functional, transcriptomic, and epigenetic analysis after exogenous expression in HNF4α-negative models or CRISPRi-mediated knockdown of endogenous isoforms. RESULTS: We characterized the variable expression of P1 isoforms in HNF4α-positive tumors. We demonstrate that P1 isoforms are less compatible with growth than P2 isoforms. Despite sharing a common DNA binding domain, we show that P1 isoforms are stronger transcriptional regulators. CONCLUSIONS: Our study characterizes the functional roles of HNF4α P1 and P2 isoforms in PDAC and highlights the necessity of considering different isoforms when studying molecular regulators.