PPARγ sumoylation-mediated lipid accumulation in lung cancer

Abstract

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 (PPARγ) is a nuclear hormone receptor regulating transcription of diverse gene sets involved in inflammation, metabolism, and suppressing tumor growth. Thiazolidinediones (TZDs), as selective PPARγ ligands, are insulin-sensitizing drugs widely prescribed for type 2 diabetic patients in the clinic. Here, we report that sumoylation of PPARγ couples lipid metabolism to tumor suppressive function of the receptor in lung cancer. We found that ligand activation of PPARγ dramatically induced de novo lipid synthesis as well as fatty acid beta (β)-oxidation in lung cancer both in vitro and in vivo. More importantly, it turns out that PPARγ regulation of lipid metabolism was dependent on sumoylation of PPARγ. Further biochemical analysis revealed that PPARγ-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 PPARγ sumoylation is not only critical for cellular lipid metabolism but also induces oxidative stress that contributes to tumor suppressive function of PPARγ. This study provides an important insight of future translational and clinical research into targeting PPARγ regulation of lipid metabolism in lung cancer patients accompanying type 2 diabetes.

BMP4 Upregulation Is Associated with Acquired Drug Resistance and Fatty Acid Metabolism in EGFR-Mutant Non-Small-Cell Lung Cancer Cells

“…Among these genes, Acyl-CoA synthetase long-chain family member 4 (ACSL4) was highly suppressed in PC9-Gef cells (Figure 5B; Table S4). Previous studies suggested that ACSL enzymatic activity plays a significant role in the maintenance of mutant lung cancer; furthermore, fatty acid oxidation mediated by ACSL enzymes is required for mutant lung tumorigenesis 32, 33. In this study, we found that knockdown of ACSL4 inhibits PC9-Gef colony formation (Figure S3).…”

Not So Slim Anymore—Evidence for the Role of SUMO in the Regulation of Lipid Metabolism

“…One such study showed that the tumor-suppressive function of PPARγ is associated with its regulation of lipid metabolism [110]. The activation of PPARγ dramatically induced de novo lipid synthesis as well as β-oxidation of fatty acids in lung cancer cells, both in vitro and in vivo [111]. Among the genes that were shown to be differentially expressed in a PPARγ-dependent manner in these cancer cells are genes involved in lipid synthesis, lipid uptake, triglyceride metabolism, and β-oxidation.…”

“…Among the genes that were shown to be differentially expressed in a PPARγ-dependent manner in these cancer cells are genes involved in lipid synthesis, lipid uptake, triglyceride metabolism, and β-oxidation. The SUMOylation of lysines 107 and 395 on PPARγ suppresses its lipid-dependent tumor-suppressive activity [111]. Another study linking SUMO activity with dysregulated-lipid metabolism in cancer shows that, in specific human-derived lung-cancer cells, Ubc9 upregulation mediates the conjugation of SUMO2 to the protein Fatty-Acid SyNthase (FASN)-a key enzyme for de novo synthesis of fatty acids [32].…”

Ginsenoside Rh2 reverses cyclophosphamide-induced immune deficiency by regulating fatty acid metabolism

“…Cancer cells exhibit a common feature of rapid proliferation, which requires large amounts of fatty acid (FA) accumulation in biologic membranes . During the process, cancer cells show a high rate of de novo lipogenesis accompanied by increased expression levels of lipogenic enzymes to restore metabolic homeostasis and the bioenergetics balance . In addition, the anticancer drug CY also leads to disorders of FA metabolism.…”

“…7 During the process, cancer cells show a high rate of de novo lipogenesis accompanied by increased expression levels of lipogenic enzymes to restore metabolic homeostasis and the bioenergetics balance. 9 In addition, the anticancer drug CY also leads to disorders of FA metabolism. Therefore, limiting FA availability might be an effective approach to inhibit the proliferation of cancer cells.…”