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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:The forkhead transcription factor FOXK2 plays a critical role in suppressing tumorigenesis and mediating cytotoxic drug action in breast cancer. However, the mechanism by which the biological function of FOXK2 is regulated remains poorly understood. Here, we investigated the role of SUMOylation in modulating FOXK2-mediated drug sensitivity. We identified SUMOylation consensus motifs within the FOXK2 sequence and constructed two SUMOylation-defective double mutants by converting lysine 527 and 633 to arginines and glutamic acid 529 and 635 to alanines, respectively. We found that both the FOXK2 SUMOylation-deficient (K527/633 R) and (E529/635 A) mutants were ineffective in mediating the cytotoxic function of paclitaxel when compared to the wild-type (WT) FOXK2. When overexpressed, unlike the wild-type (WT) FOXK2, the K527/633 R mutant had little effect on the sensitivity of MCF-7 and MDA-MB-231 cells to paclitaxel, as examined by cell viability and clonogenic assays. Our results also showed that MCF-7 cells overexpressing the K527/633 R mutant form of FOXK2 or the empty expression vector have lower protein and mRNA levels of its tumour suppressive transcriptional target FOXO3 compared to the wild-type FOXK2. Consistently, ChIP assays revealed that unlike wild-type FOXK2, the SUMOylation-defective (K527/633 R) mutant is unable to bind to the FOXO3 promoter, despite expressing comparable levels of protein and having the same subcellular localization as the wild-type FOXK2 in MCF-7 cells. Interestingly, expression of neither the wild-type nor the K527/633 R mutant FOXK2 had any effect on the proliferation and paclitaxel sensitivity of the MCF-7 TaxR paclitaxel-resistant cells. In agreement, both the wild-type and the (K527/633 R) mutant FOXK2 failed to bind to the endogenous FOXO3 promoter in these cells. Collectively, our results suggest that SUMOylation positively regulates FOXK2 transcriptional activity and has a role in mediating the cytotoxic response to paclitaxel through the tumour suppressor FOXO3.

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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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