PPP1R26 drives hepatocellular carcinoma progression by controlling glycolysis and epithelial-mesenchymal transition

Abstract

Background: Hepatocellular carcinoma (HCC) is usually diagnosed at an advanced stage due to rapid progression. Glycolysis supports anabolic growth and metastasis to promote HCC progression. However, the molecular mechanisms linking glycolysis and metastasis in HCC are not completely defined. Methods: The expression of PPP1R26 in human HCC tissues was evaluated by immunohistochemistry, and the clinical significance of PPP1R26 in the progression and prognosis of the HCC patients were analyzed. The PPP1R26-binding proteins were determined by mass spectrometry analysis. The function of PPP1R26 in glycolysis, EMT and tumorigenesis were evaluated in HCC cells. Glucose uptake and tumor growth were evaluated using PET imaging in mouse xenografts in vivo. Protein binding was confirmed by co-immunoprecipitation and immunofluorescence co-localization. Protein-RNA binding was determined by RNA-immunoprecipitation (RIP) experiment. The binding of protein on the promoter was evaluated by chromatin immunoprecipitation assay (ChIP). Results: PPP1R26 is upregulated in human HCC tissues and its upregulation is significantly associated with metastasis and the poor survival of the patients. PPP1R26 activates glycolysis in HCC cells and in mouse xenografts in vivo. PPP1R26 drives glycolysis by binding to PTBP1 to facilitate the mRNA splicing of PKM2. Simultaneously, overexpressed PPP1R26 induces the nuclear accumulation of PKM2 to inhibit the expression of E-cadherin further to drive EMT. Mechanistically, PPP1R26 binds with Ser37-phosphorylated PKM2 and TGIF2 in the nucleus and blocks the binding of TGIF2 with CDH1 promoter to inhibit the transcription of CDH1. Conclusion: PPP1R26 promotes glycolysis by enhancing PKM2 splicing and simultaneously activates EMT by forming a PPP1R26-PKM2-TGIF2 complex to drive HCC progression. Therefore, targeting PPP1R26 attenuates HCC progression and provides a potential therapeutic strategy for the HCC patients with upregulation of PPP1R26.