TTC7B triggers the PI4KA-AKT1-RXRA-FTO axis and inhibits colon cancer cell proliferation by increasing RNA methylation.

Abstract

TTC7B is the PI4KA-binding protein. The upstream regulatory network associated with the expression of genes involved in RNA N6-adenine (m6A) methylation is not clear. Bioinformatics analysis revealed that the expression levels of TTC7B, PI4KA, and FTO are positively correlated with each other across human tissues. These genes are consistently downregulated in many cancers. We initially confirmed the correlation of the expression of these genes in colon cancer tissues from patients (n=105) and reported that TTC7B downregulation was significantly associated with poor prognosis. We subsequently performed a series of biological experiments and demonstrated that TTC7B upregulated RXRA expression probably through the PI4KA-mediated AKT1 pathway and that RXRA was a transcription factor for the FTO gene. TTC7B inhibited the proliferation of colon cancer cells by increasing the recruitment of RXRA to the FTO promoter, increasing FTO expression, and decreasing the total RNA m6A level. Ablation of FTO demethylase activity completely abolished the inhibitory effect of TTC7B on the proliferation of cancer cells in vitro and in vivo. In conclusion, our study demonstrated for the first time that TTC7B triggers the RXRA-FTO axis through PI4KA binding, which leads to a decrease in total RNA m6A modification and the inhibition of colon cancer progression.