Identification of a novel signature based on RNA methylation-associated anoikis-related genes for predicting prognosis and characterizing immune landscape in colorectal cancer.

Background: RNA methylation is a potential target for cancer therapy, while anoikis, a form of programmed cell death, is linked to cancer metastasis. However, the prognostic and immune significance of RNA methylation- and anoikis-related genes in colorectal cancer (CRC) remains unknown.

Methods: Transcriptomic and clinicopathological data for CRC were obtained from TCGA and the GEO databases. A novel signature was constructed based on RNA methylation- and anoikis-related genes using univariate and multivariate Cox regression as well as LASSO Cox regression methods. CRC patients were stratified into low- and high-risk groups based on this signature. Differences in prognosis, immune infiltration, and drug sensitivity between two groups were analyzed. Finally, immunohistochemistry, western blot, and RT-qPCR were employed to validate the expression of the key gene SERPINE1 in CRC tissues and cells, as well as the effect of FTO on its expression.

Results: We identified 79 differentially expressed RNA methylation-associated anoikis-related genes (RMRARGs) in both cancerous and normal tissues. A signature composed of 9 key genes (BID, FASN, PLK1, CDKN3, MYC, EPHA2, SERPINE1, CD36, PDK4) was established. Kaplan-Meier analysis revealed a poorer prognosis in the high-risk group. Compared to the other three published models, this signature demonstrated superior predictive performance based on the ROC curve analysis. Functional analyses highlighted differences in drug sensitivities and signaling pathways between risk groups. Furthermore, immune analysis results showed that risk score was associated with some immune cells and immune checkpoints. Immunohistochemistry showed high SERPINE1 expression in CRC tissues, with FTO expression positively correlated with SERPINE1. Furthermore, RT-qPCR and western blot indicated FTO knockdown markedly downregulated SERPINE1 levels.

Conclusion: Our findings underscore the prognostic value of this signature in CRC patients and its utility in assessing immune status. Additionally, the m6A demethylase FTO regulates the expression of the anoikis-related gene SERPINE1.