NSUN6 as a Key RNA Methylation Regulator in Colon Cancer

Abstract

Background RNA methylation plays an important role in epigenetic modifications, which involves in the regulation of RNA processing, stability and translation. While the cross-talking and the mechanism of multi-type RNA methylation in colon cancer needs further investigation. Here we report the comprehensive analysis of the RNA methylation regulators for N6-methyladenosine, N1-metylasdenosine and 5-methylcytosine in the tumorigenesis and progression of colon cancer. Methods The mRNA expression and genetic mutation of 40 RNA modification regulators in patients with colon cancer were obtained from TCGA and GEO database. Consensus clustering is applied to classify the patients based on the regulator expression. The patients with different survival rates are examined for their gene mutations, biological pathways, and immune properties. The regulators with the highest vimp score are identified to be important for survival using the improved random forest analysis method. Biopsy samples from 108 patients are used to validate the key regulators using tissue microarray and specific antibodies. Finally, the mechanism underlying the methylation regulators is further examined by GSVA and correlation analysis. Results The patients are clearly clustered into two groups with different survivals. The patients with the worse survival are correlated with dysregulated KRAS signaling, hypoxia and immune responses. They are also prone to increased stromal scores and myeloid-derived suppressor cells. Markedly, m5C methyltransferase NSUN6 is identified as the most significant regulator for prognosis. The upregulated expression of NSUN6 is further proved in 108 patients by immunohistochemistry and tissue array, suggesting its association with better prognosis and lower tumor staging. Bioinformatic analysis indicates that NSUN6 enhances the expression of E3 ubiquitin ligase FBXW7, activates ubiquitin-proteolysis and suppresses oncogene expression. Conclusions Patients with colon cancer are clearly clustered into different survivals by RNA methylation regulators, and the worse prognosis is relevant to dysregulated KRAS signaling, hypoxia and immune response. NSUN6 is found to prolong the survival and strongly correlated with FBXW7 that reduces the oncogene expression and activates the ubiquitin-proteolysis.