GSE127960
ß-catenin/Tcf7l2 dependent transcriptional regulation of GLUT1 gene expression by Zic family proteins in colon cancer
The Zinc finger of the cerebellum (ZIC) proteins have been implicated to function in normal tissue development. Mutations or deletions of ZIC genes have been found to be associated with neural-related abnormalities. Recent studies point out the critical functions of Zic proteins in cancers and the potential tumor suppressive functions in colon cancer development and progression. To elucidate the functional roles of Zic proteins in colorectal cancer, we employed CRISPR/Cas9 genome editing to knock out the Zic5 gene and analyze the chromatin localization pattern and transcriptional regulation of target gene expression. Zic5 regulates glucose metabolism through the regulation of expression of the GLUT1/SLC2A1 gene. Zic5 knockout is accompanied by an increased glycolytic state, tolerance to a low glucose condition, and derepression of metabolic genes especially GLUT1 gene expression. Reciprocally, the loss of Zic2 partially restored the glucose uptake by decreasing GLUT1 gene expression, pointing out the balance between the different Zic family proteins. Mechanistically, Zic5 is recruited by the ß-catenin/TCF7l2 complex to the promoters of the target genes. Loss of ß-catenin or TCF7l2 significantly diminishes the chromatin binding of Zic5 globally. Our studies suggest that the Wnt/ß-catenin signaling pathway has a strong influence on the function of Zic proteins and glucose metabolism in colorectal cancers through GLUT1, thus interfering Wnt/ß-catenin - Zic5 axis regulated aerobic glycolysis represents a potentially effective strategy to selectively target colon cancer cells. Overall design: To characterize the functions of glucose metabolism regulated by Zic family proteins using Zic5 knockout human cancer cell lines