title: Glyceraldehyde-3-phosphate dehydrogenase promotes liver tumorigenesis by modulating phosphoglycerate dehydrogenase.
abstract: Up-regulated glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is observed in multiple cancers with unclear mechanism. Using GAPDH transgenic mouse and a mouse model of diethylnitrosamine-induced hepatocellular carcinoma (HCC), here we show that GAPDH overexpression aggravated tumor development by activating cell proliferation and inflammation. In cultured hepatic cells, overexpression of GAPDH or a catalytic domain-deleted GAPDH (GAPDHΔCD) affected metabolism, up-regulated phosphoglycerate dehydrogenase (PHGDH), increased histone methylation levels, and promoted proliferation. Consistently, inhibition of GAPDH by short hairpin RNA reprogrammed metabolism down-regulated PHGDH and histone methylation, and inhibited proliferation. The xenograft study suggested that HepG2 cells overexpressing GAPDH or GAPDHΔCDsimilarly promoted tumor development, whereas knockdown PHGDH in GAPDH overexpressing cells significantly inhibited tumor development. In liver sections of HCC patients, increased GAPDH staining was found to be positively correlated with PHGDH and histone methylation staining.
  
  
  
  GAPDH increases histone methylation levels by up-regulating PHGDH, promoting diversion from glycolysis to serine biosynthesis, and consequently accelerating HCC development. (Hepatology 2017;66:631-645).
authors.affiliation: Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei, P. R. China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Liu
authors.affiliation: Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei, P. R. China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China.
authors.forename: Ming
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China.
authors.forename: Yangkai
authors.initials: Y
authors.lastname: Li
authors.affiliation: Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei, P. R. China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei, P. R. China.
authors.forename: Weili
authors.initials: W
authors.lastname: Xue
authors.affiliation: Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China.
authors.forename: Ninghe
authors.initials: N
authors.lastname: Ding
authors.affiliation: Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei, P. R. China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei, P. R. China.
authors.forename: Jianshuang
authors.initials: J
authors.lastname: Li
authors.affiliation: School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Miao
authors.affiliation: Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China.
authors.forename: Xinran
authors.initials: X
authors.lastname: Liu
authors.affiliation: Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei, P. R. China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China.
authors.forename: Kun
authors.initials: K
authors.lastname: Huang
mesh_terms: D000818:Animals; D001707:Biopsy, Needle; D015153:Blotting, Western; D063646:Carcinogenesis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics; D004195:Disease Models, Animal; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000235:genetics*; D007150:Immunohistochemistry; D016014:Linear Models; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental; D050543:Phosphoglycerate Dehydrogenase / Q000235:genetics*; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D018709:Statistics, Nonparametric; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D050543:Phosphoglycerate Dehydrogenase; C546243:GAPDH2 protein, mouse; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)