The FOXC1/FBP1 signaling axispromotes tumorigenicity by enhancing the Warburg effect in colorectal cancer.

Background:?Aberrant expression of Forkhead Box transcription factors plays vital roles in the oncogenesis and metastasis of many types of cancer. The purpose of this study is to elucidate the function of Forkhead Box C1(FOXC1) in colorectal cancer (CRC)malignancy maintenance.?Methods:?FOXC1 expression in CRC specimens was analyzed in the TCGA database and validated by immunohistochemistry using a tissue microarray (TMA). The effect of FOXC1 expression on cancer proliferation and glycolysis was assessed in cells by altering the expression of FOXC1?in vitro?and?in vivo. Mechanistic investigation was carried out by using cell and molecular biology approaches.?Results:?FOXC1 was found to be overexpressed in CRC specimens compared with that in the adjacent benign tissues. Univariate survival analyses of the TCGA and validated cohorts showed that high expression of FOXC1 was significantly correlated with shortened patient survival (P< 0.05). Attenuation of FOXC1 expression inhibited proliferation， clone formation and decreased glucose consumption and lactate production. By contrast， overexpression of FOXC1 had the opposite effect. Furthermore， increased FOXC1 expression downregulated the expression of a key glycolytic enzyme，fructose-1， 6-Bisphosphatase 1 (FBP1). Mechanistically， FOXC1 bound directly to the promoter regions of the FBP1 gene and negatively regulated its transcriptional activity. Aberrant FBP1 expression contributes to CRC tumorigenicity， and decreased FBP1 coupled with increased FOXC1 provided better prognostic information than FOXC1 did alone.?Conclusions:?The FOXC1/FBP1 axis induces cell proliferation， reprograms the metabolic process in CRC and provides potential prognostic predictors and therapeutic targets for patients with CRC