The TET3/GATA6 Axis Drives Lipid Metabolism and Therapeutic Vulnerabilities in Pancreatic Ductal Adenocarcinoma.

ABSTRACT: Metabolic reprogramming is a hallmark of cancer, with dysregulated lipid metabolism contributing to tumor progression and therapy resistance. This study identifies the DNA demethylase TET3 as a key regulator of lipogenic metabolism in pancreatic ductal adenocarcinoma (PDAC). TET3 expression is elevated in the lipogenic PDAC subtype and correlates with poor patient prognosis. Genetic ablation of TET3 disrupts lipid homeostasis, alters the saturated-to-monounsaturated fatty acid ratio, and reduces proliferative capacity. Mechanistically, TET3 represses GATA6 expression through recruitment of histone deacetylases (HDACs) to its promoter, leading to H3K27 deacetylation, independent of its catalytic activity. Loss of TET3 derepresses GATA6, which in turn suppresses lipogenic enzymes, such as st

SUBMITTER: Liu S 

PROVIDER: S-EPMC12499388 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature