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// Ai N.H. Phan 1, 2 , Vu T.A. Vo 1, 2 , Tuyen N.M. Hua 1, 2 , Min-Kyu Kim 1, 2 , Se-Young Jo 3 , Jong-Whan Choi 1 , Hyun-Won Kim 1 , Jaekyoung Son 3 , Young-Ah Suh 3 and Yangsik Jeong 1, 2 1 Department of Biochemistry, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do, Republic of Korea 2 Department of Global Medical Science, Institute of Lifestyle Medicine, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do, Republic of Korea 3 Asan Institute for Life Sciences, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Songpa-gu, Republic of Korea Correspondence to: Yangsik Jeong, email: yjeong@yonsei.ac.kr Keywords: PPARγ, sumoylation, lipid metabolism, lung cancer Received: April 18, 2017 Accepted: June 19, 2017 Published: July 31, 2017 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.

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.