ZEB1 Promotes Tumorigenesis And Metastasis In HCC Via Regulating PFKM

ZEB1 is a member of zinc finger and homeodomain family transcription factors,a growing number of studies have shown that ZEB1 is highly expressed in many malignancies,such as colorectal cancer,breast cancer,endometrial carcinoma,prostate cancer and gastric cancer.In recent years,we also have found that high expression of ZEB1 in 65.4%(72/110)hepatocellular carcinoma(HCC),and it was closely correlated with tumorigenesis,invasion,metastasis and frequent early recurrence of HCC.Aerobicglycolysis(Tumor cells are inclined to use glycolysis instead of oxidative phosphorylation for glucose metabolism even under sufficient oxygen supply conditions)is the most significant metabolic reprogramming in malignancy,and the regulation mechanism of glycolytic enzymes has become a hotspot in clinical and basic research of cancer.Up to now,it is still not clear whether glycolytic enzymes are regulated by ZEB1 and thus contribute to tumorigenesis and progression of HCC.To address this concern,we have carried out the following series of experiments.First,we knocked down ZEB1 in human HCC MHCC-97H cell,and found that expression level of the muscle isoform of phosphofructokinase(PFKM),the second rate-limiting enzyme in glycolysis,and glycolysis efficiency were robustly down regulated as detected by Western Blot,reverse transcription-polymerase chainreaction,glucose uptake and lactate production.Then,the decrease of PFKM expression level and glycolysis efficiency following kncokdown of ZEB1 were largely rescued by re-expression of ZEB1 or PFKM.In addition,the chromatin immunoprecipitation(ChIP)assay also demonstrated that ZEB1 can directly bound to the PFKM promoter region.Finally,the results of cell biological function experiments in vitro showed that ZEB1 promotes tumorigenesis and metastasis in HCC via regulating PFKM.In summary,our investigation on the molecular mechanism of ZEB1 promotes tumorigenesis and metastasis in HCC via regulating PFKM may provide new clues for the treatment of HCC.