Nur77 Transcriptional Activated-long Noncoding RNA WFDC21P Suppresses Hepatocellular Carcinoma Via Modulating Glycolysis

Hepatocellular carcinoma(HCC)is one of the leading mortality causes worldwide.Mounting evidences show that long noncoding RNAs(lncRNAs)play functional roles in tumorigenesis and progression of HCC.Orphan nuclear receptor Nur77 plays diversely roles in HCC progression.However,the regulation of lncRNAs by Nur77 in HCC is still poorly understood.In this study,lncRNAs related to Nur77 were firstly screened by lncRNAs microarray.The long noncoding RNA-WFDC21P was found to be regulated by Nur77 and have a significant correlation with Nur77 both in HCC cells and clinical HCC samples.Luciferase reporter assays and chromatin immunoprecipitation assays indicted that Nur77 directly bound to the NBREs on the promoter region of WFDC21P to stimulate its transcription.To illustrate the biological functions,WFDC21P was ectopic expressed or knocked down in HCC cells.It could be demonstated that overexpression of WFDC21P efficiently inhibited the HCC cells proliferation and tumor growth in nude mice.In contrast,depletion of WFDC21P facilitated HCC cells proliferation,increased xenograft tumor growth.In clinical samples,WFDC21P expression level was much higher in the para-carcinoma tissues than that in HCC tissues.Further experiments demonstrated that WFDC21P attenuated glucose uptake and lactate production,thereby leading to suppressed glycolytic capacity in HCC cells.Mechanistically,WFDC21P could interact with two glycolytic rate-limiting enzymes,platelet-type phosphofructokinase(PFKP)and pyruvate kinase M2(PKM2).These interactions not only abrogated the tetramer formation and activity of PFKP,but also suppressed the nuclear translocation and transcriptional regulation ability of PKM2,consequently resulted profoundly decreased glycoolysis.The inhibitory effect of WFDC21P on HCC was thus largely dependent on its regulatins of PFKP and PKM2,as verified both in vitro and in vivo.In sum,this study not only elucidates the transcriptional regulation of WFDC21P by Nur77,but also demonstrates the regulatory mechanism of WFDC21P on glycolysis by interacting with and regulating PFKP and PKM2.These results therefore suggest that WFDC21P could be a promising tumor suppressor in HCC.