FOXA2 suppresses PKM2 transcription and affects the Wnt/beta-catenin activity to block aerobic glycolysis in thyroid carcinoma

Aerobic glycolysis is critical for the energy metabolism of cancer cells. This study focuses on the regulation of forkhead box A2 (FOXA2) on pyruvate kinase M2 (PKM2) and their effects on the glycolytic activity and malignant phenotype of thyroid carcinoma (THCA) cells. By analysing four Gene Expression Omnibus datasets and querying bioinformatics systems, we obtained FOXA2 as a poorly expressed transcription factor in THCA. Later, we validated decreased mRNA and protein levels of FOXA2 in THCA cells by quantitative polymerase chain reaction and western blot assays. FOXA2 upregulation in THCA cells suppressed the glucose uptake and lactate production, and it reduced the extracellular acidification rate, but increased the oxygen consumption rate of cells. Meanwhile, the FOXA2 overexpression blocked the proliferation and mobility, and the tumourigenic activity of cancer cells. The chromatin immunoprecipitation and luciferase assays showed that FOXA2 bound to PKM2 promoter and suppressed the transcription of PKM2, which was highly expressed in THCA cells. Further upregulation of PKM2 elevated the beta-catenin, c-Myc and cyclin D1 levels and restored the glycolytic activity as well as the malignant properties of cancer cells. Collectively, this work reveals that FOXA2 suppresses aerobic glycolysis and progression of THCA by blocking PKM2 transcription and inactivating the Wnt/beta-catenin pathway.

Automated summary

Aerobic glycolysis is critical for cancer cell metabolism. This study found that the transcription factor FOXA2 is poorly expressed in thyroid carcinoma (THCA) cells. Upregulation of FOXA2 suppressed glucose uptake, lactate production, and acidification rate, while increasing oxygen consumption rate in THCA cells. FOXA2 overexpression also blocked proliferation, mobility, and tumorigenic activity of cancer cells. Furthermore, FOXA2 was found to bind to the PKM2 promoter and suppress its transcription, which was highly expressed in THCA cells. Upregulation of PKM2 restored glycolytic activity and malignant properties of cancer cells by activating the Wnt/beta-catenin pathway.