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

SUBMITTER: Phan ANH

PROVIDER: S-EPMC5669906 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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PPARγ sumoylation-mediated lipid accumulation in lung cancer.

Phan Ai N H ANH Vo Vu T A VTA Hua Tuyen N M TNM Kim Min-Kyu MK Jo Se-Young SY Choi Jong-Whan JW Kim Hyun-Won HW Son Jaekyoung J Suh Young-Ah YA Jeong Yangsik Y

Oncotarget 20170731 47

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 di ...[more]

PMID: 29137280

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Project description:BackgroundLigamentum flavum (LF) hypertrophy is the main cause of lumbar spinal canal stenosis (LSCS). Previous studies have shown that LF hypertrophy tissue exhibits abnormal lipid accumulation, but the regulatory mechanism remains unclear. The objective of this study was to explore the function and potential mechanism of ACSM5 in LF lipid accumulation.MethodsTo assess the ACSM5 expression levels, lipid accumulation and triglyceride (TG) level in LF hypertrophy and normal tissue, we utilized RT-qPCR, western blot, oil red O staining, and TG assay kit. The pearson correlation coefficient assay was used to analyze the correlation between ACSM5 levels and lipid accumulation or TG levels in LF hypertrophy tissue. The role of ACSM5 in free fatty acids (FFA)-induced lipid accumulation in LF cells was assessed in vitro, and the role of ACSM5 in LF hypertrophy in mice was verified in vivo. To investigate the underlying mechanisms of ACSM5 regulating lipid accumulation in LF, we conducted the mRNA sequencing, bioinformatics analysis, and rescue experiments.ResultsIn this study, we found that ACSM5, which was significantly down-regulated in LF tissues, correlated with lipid accumulation. In vitro cell experiments demonstrated that overexpression of ACSM5 significantly inhibited FFA-induced lipid accumulation and fibrosis in LF cells. In vivo animal experiments further confirmed that overexpression of ACSM5 inhibited LF thickening, lipid accumulation, and fibrosis. Mechanistically, ACSM5 inhibited lipid accumulation of LF cells by inhibiting FABP4-mediated PPARγ signaling pathway, thereby improving hypertrophy and fibrosis of LF.Conclusionsour findings elucidated the important role of ACSM5 in the regulation of LF lipid accumulation and provide insight into potential therapeutic interventions for the treatment of LF hypertrophy. This study further suggested that therapeutic strategies targeting lipid deposition may be an effective potential approach to treat LF hypertrophy-induced LSCS.

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PPAR? sumoylation-mediated lipid accumulation in lung cancer.

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PPARγ sumoylation-mediated lipid accumulation in lung cancer.

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