The Mechanism Studies Of Glyceraldehyde-3-phosphate Dehydrogenase In The Liver Tumorigenesis And Adipocyte Differentiation

Up-regulated glyceraldehyde-3-phosphate dehydrogenase(GAPDH)is observed in multiple cancers with unclear mechanism.Using GAPDH transgenic mouse and a mouse model of DEN-induced hepatocellular carcinoma(HCC),we demonstrated that GAPDH overexpression led to an aggravated tumor development by activating cell proliferation and inflammation.In cultured hepatic cells,overexpression of full-length GAPDH or a catalytic domain deleted GAPDH(GAPDH?CD)similarly affected metabolism,up-regulated phosphoglycerate dehydrogenase(PHGDH)(the rate-limiting enzyme for serine synthesis),increased histone methylation levels and promoted proliferation.Consistently,inhibition of GAPDH by shRNA caused metabolism reprogramming,down-regulated PHGDH and histone methylation levels,and inhibited proliferation.The xenograft study suggested that HepG2 cells overexpressing either GAPDH or GAPDH?CD similarly promoted tumor development,while knockdown PHGDH in GAPDH overexpression cells significantly inhibited the tumor development.In the liver sections of HCC patients,65%patients showed increased GAPDH staining,which was positively correlated with PHGDH staining and H3K9me3 and H3K27me2 staining.Besides this,GAPDH and PHGDH were positively correlated at both transcriptional and protein levels of lung cancer patients.In conclusion,GAPDH increases histone methylation levels through up-regulating PHGDH,thus promotes the diversion from glycolysis to serine biosynthesis,which consequently accelerates HCC development.We further demonstrated that GAPDH and pGAPDHT151 were both upregulated in the livers of db/db mice compared to WT mice.Compared with WT mice,GAPDH transgenic mice showed aggregated NAFLD and white fat accumulation under high fat diet challenge.During adipocyte differentiation using 3T3-L1 cells,GAPDH expression was up-regulated in mature adipocyte compared with pre-adipocyte.While overexpression of GAPDH promoted adipocyte differentiation in 3T3-L1 cells,knockdown GAPDH inhibited adipocyte differentiation.Thus GAPDH may play critical roles in the development of obesity.In conclusion,GAPDH promotes both liver cancer and obesity development which makes it a potential therapeutic target for drug development.