PPARγ sumoylation-mediated lipid accumulation in lung cancer.

Metabolic reprogramming as a crucial emerging hallmark of cancer is critical for tumor cells to maintain cellular bioenergetics, biosynthesis and reduction/oxidation (REDOX) balance. Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear hormone receptor regulating transcription of diverse gene sets involved in inflammation, metabolism, and suppressing tumor growth. Thiazolidinediones (TZDs), as selective PPAR gamma ligands, are insulin-sensitizing drugs widely prescribed for type 2 diabetic patients in the clinic. Here, we report that sumoylation of PPAR gamma couples lipid metabolism to tumor suppressive function of the receptor in lung cancer. We found that ligand activation of PPAR gamma dramatically induced de novo lipid synthesis as well as fatty acid beta (beta)-oxidation in lung cancer both in vitro and in vivo. More importantly, it turns out that PPAR gamma regulation of lipid metabolism was dependent on sumoylation of PPAR gamma. Further biochemical analysis revealed that PPAR gamma-mediated lipid synthesis depletes nicotinamide adenine dinucleotide phosphate (NADPH), consequently resulting in increased mitochondrial reactive oxygen species (ROS) level that subsequently disrupted REDOX balance in lung cancer. Therefore, liganded PPAR gamma sumoylation is not only critical for cellular lipid metabolism but also induces oxidative stress that contributes to tumor suppressive function of PPAR gamma. This study provides an important insight of future translational and clinical research into targeting PPAR gamma regulation of lipid metabolism in lung cancer patients accompanying type 2 diabetes.