title: Phosphorylation of PPARγ at Ser84 promotes glycolysis and cell proliferation in hepatocellular carcinoma by targeting PFKFB4.
abstract: Peroxisome proliferator-activating receptor γ (PPARγ), a transcription factor, is involved in many important biological processes, including cell terminal differentiation, survival and apoptosis. However, the role of PPARγ, which regulates tumour promoter and oncogene expression, is not well understood in hepatocellular carcinoma (HCC). In the present study, based on evidence from clinical samples that phosphorylation of PPARγ at Ser84 is up-regulated in human liver tumours, we confirmed that phosphorylation of PPARγ was also significantly increased in an HCC mouse model and was increased by Mitogen-activated protein kinase (MEK)/ Extracellular-signal-regulated kinases (ERK) kinase. Next, we performed an RNA microarray analysis, and our data indicated that dephosphorylation of PPARγ at Ser84 affects the expression of glycolysis-related genes and pro-proliferation genes, which supposedly promote proliferation of HCC cells. Using a chromatin immunoprecipitation (ChIP) assay, we demonstrated that the observed PPARγ-mediated induction of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4) expression was directly modulated by the transcriptional activity of its promoter. Furthermore, using knockdown of PFKFB4, we elucidated that the stimulation of PPARγ phosphorylation on glycolysis and proliferation in HCC is dependent on PFKFB4. Together, these findings extend our understanding of how liver tumour cells reprogram their glycolytic pathways by post-translational modification of specific transcription factors and lay a foundation for the screening of new targets for the treatment of HCC.
authors: State Key Laboratory of Pharmaceutical Biotechnology and Model Animal Research Center (MARC), Nanjing University, Nanjing 210023, China.
authors: Yuxin
authors: Y
authors: Shu
authors: State Key Laboratory of Pharmaceutical Biotechnology and Model Animal Research Center (MARC), Nanjing University, Nanjing 210023, China.
authors: Yan
authors: Y
authors: Lu
authors: State Key Laboratory of Pharmaceutical Biotechnology and Model Animal Research Center (MARC), Nanjing University, Nanjing 210023, China.
authors: Xiaojuan
authors: X
authors: Pang
authors: State Key Laboratory of Pharmaceutical Biotechnology and Model Animal Research Center (MARC), Nanjing University, Nanjing 210023, China.
authors: Wei
authors: W
authors: Zheng
authors: State Key Laboratory of Pharmaceutical Biotechnology and Model Animal Research Center (MARC), Nanjing University, Nanjing 210023, China.
authors: Yahong
authors: Y
authors: Huang
authors: State Key Laboratory of Pharmaceutical Biotechnology and Model Animal Research Center (MARC), Nanjing University, Nanjing 210023, China.
authors: Jiahong
authors: J
authors: Li
authors: The State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing 100871, China.|Institute of System Biomedicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
authors: Jianguo
authors: J
authors: Ji
authors: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors: Can
authors: C
authors: Zhang
authors: State Key Laboratory of Pharmaceutical Biotechnology and Model Animal Research Center (MARC), Nanjing University, Nanjing 210023, China.
authors: Pingping
authors: P
authors: Shen
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009368:Neoplasm Transplantation; D047495:PPAR gamma / Q000378:metabolism*; D025481:Phosphofructokinase-2 / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D012694:Serine / Q000378:metabolism*
chemical_list: C506672:PFKFB4 protein, human; D047495:PPAR gamma; D012694:Serine; D025481:Phosphofructokinase-2
keywords: PFKFB4; PPARγ; glycolysis; hepatocellular carcinoma; phosphorylation