Targeting glutaryl-CoA dehydrogenase-driven acetyl coenzyme A acetyltransferase 2 crotonylation dysregulates cholesterol metabolism in pancreatic cancer cells.

Cancer cells rely on the metabolic reprogramming of amino acids to regulate the production of specific metabolites in the tumor microenvironment and support tumor growth. We demonstrated that the upregulation of glutaryl-CoA dehydrogenase (GCDH), a key gene encoding a metabolic enzyme involved in the conversion of lysine and tryptophan to crotonyl-CoA, was correlated with worse prognosis in patients with pancreatic ductal adenocarcinoma (PDAC), as GCDH depletion inhibits PDAC growth. Mechanistically, GCDH promotes cholesterol biosynthesis by enhancing the CREB Binding Protein (CBP)-mediated crotonylation (Kcr) modification of acetyl coenzyme A acetyltransferase 2(ACAT2). Importantly, ACAT2-Kcr induces the dissociation of the Insig1-SCAP complex, thereby facilitating the transport and activation of the SCAP-SREBP2 complex during its translocation from the endoplasmic reticulum (ER) to the Golgi apparatus. Conversely, ACAT2 decrotonylation triggers ER stress and promotes the apoptosis of PDAC cells. This study reveals the roles of GCDH in controlling cholesterol metabolism and PDAC progression and suggests that GCDH is a new target for therapeutic intervention in patients with PDAC.