HDAC5 Loss Enhances Phospholipid-Derived Arachidonic Acid Generation and Confers Sensitivity to cPLA2 Inhibition in Pancreatic Cancer

HDAC5 is a class IIa histone deacetylase member that is down-regulated in multiple solid tumors, including pancreatic cancer, and loss of HDAC5 is associated with unfavorable prognosis. In this study, assessment of The Cancer Genome Atlas pancreatic adenocarcinoma dataset revealed that expression of HDAC5 correlates negatively with arachidonic acid (AA) metabolism, which has been implicated in inflammatory responses and cancer progression. Nontargeted metabolomics analysis revealed that HDAC5 knockdown resulted in a significant increase in AA and its downstream metabolites, such as eicosanoids and prostaglan-dins. HDAC5 negatively regulated the expression of the gene encoding calcium-dependent phospholipase A2 (cPLA2), the key enzyme in the production of AA from phospholipids. Mecha-nistically, HDAC5 repressed cPLA2 expression via deacetylation of GATA1. HDAC5 knockdown in cancer cells enhanced sen - sitivity to genetic or pharmacologic inhibition of cPLA2 in vitro and in vivo. Fatty acid supplementation in the diet reversed the sensitivity of HDAC5-deficient tumors to cPLA2 inhibition. These data indicate that HDAC5 loss in pancreatic cancer results in the hyperacetylation of GATA1, enabling the upregu-lation of cPLA2, which contributes to overproduction of AA. Dietary management plus cPLA2-targeted therapy could serve as a viable strategy for treating HDAC5-deficient pancreatic cancer patients. Significance: The HDAC5-GATA1-cPLA2-AA signaling axis regulates sensitivity to fat restriction plus cPLA2 inhibition in pancreatic ductal adenocarcinoma, proposing dietary manage-ment as a feasible strategy for treating a subset of patients with pancreatic cancer.

Automated summary

HDAC5 loss is associated with unfavorable prognosis in pancreatic cancer by regulating the expression of cPLA2 and arachidonic acid (AA). Deacetylation of GATA1 by HDAC5 represses cPLA2 expression. Dietary management along with cPLA2-targeted therapy can be an effective strategy for treating HDAC5-deficient pancreatic cancer.