Abstract
Objectives: The purpose of this study was to investigate the role of 13 m5C-related regulators in colon adenocarcinoma (COAD) and determine their prognostic value. Methods: Gene expression and clinicopathological data were obtained from The Cancer Genome Atlas (TCGA) datasets. The expression of m5C-related regulators was analyzed with clinicopathological characteristics and alterations within m5C-related regulators. Subsequently, different subtypes of patients with COAD were identified. Then, the prognostic value of m5C-related regulators in COAD was confirmed via univariate Cox regression and least absolute shrinkage and selection operator (LASSO) Cox regression analyses. The prognostic value of risk scores was evaluated using the Kaplan-Meier method, receiver operating characteristic (ROC) curve. The correlation between the two m5C-related regulators, risk score, and clinicopathological characteristics were explored. Additionally, Gene Set Enrichment Analysis (GSEA), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and Gene Ontology (GO) analysis were performed for biological functional analysis. Finally, the expression level of two m5C-related regulators in clinical samples and cell lines was detected by quantitative reverse transcription-polymerase chain reaction and through the Human Protein Atlas database. Results: m5C-related regulators were found to be differentially expressed in COAD with different clinicopathological features. We observed a high alteration frequency in these genes, which were significantly correlated with their mRNA expression levels. Two clusters with different prognostic features were identified. Based on two independent prognostic m5C-related regulators (NSUN6 and ALYREF), a risk signature with good predictive significance was constructed. Univariate and multivariate Cox regression analyses suggested that the risk score was an independent prognostic factor. Furthermore, this risk signature could serve as a prognostic indicator for overall survival in subgroups of patients with different clinical characteristics. Biological processes and pathways associated with cancer, immune response, and RNA processing were identified. Conclusion: We revealed the genetic signatures and prognostic values of m5C-related regulators in COAD. Together, this has improved our understanding of m5C RNA modification and provided novel insights to identify predictive biomarkers and develop molecular targeted therapy for COAD.
Highlights
Changes in gene expression are closely associated with the development of disease, and epigenetic processes are heritable changes in gene expression that do not alter the nucleotide sequence (Wu and Morris, 2001)
The expression of ALKBH1 (p = 0.036), ALYREF (p < 0.001), NOP2 (p < 0.001), NSUN2 (p < 0.001), NSUN4 (p < 0.001), NSUN5 (p < 0.001), NSUN6 (p < 0.001), NSUN7 (p = 0.006), and YBX1(p < 0.001) were significantly upregulated in tumor tissues compared with the adjacent mucosa
We found that the expression of TET family genes (TET1, TET2, TET3) were highly related to each other and had little correlation with ALKBH1
Summary
Changes in gene expression are closely associated with the development of disease, and epigenetic processes are heritable changes in gene expression that do not alter the nucleotide sequence (Wu and Morris, 2001). Increasing evidence suggests that RNA modifications play critical roles in tumorigenesis and the progression of different cancers (Barbieri and Kouzarides, 2020; Begik et al, 2020). M5C RNA modification is found in a variety of RNAs, including messenger RNAs, transfer RNAs, ribosomal RNAs. Increasing evidence suggests that RNA modifications play critical roles in tumorigenesis and the progression of different cancers (Barbieri and Kouzarides, 2020; Begik et al, 2020). M5C RNA modification plays a critical role in the translation, transport, and stability of mRNAs, and is closely associated with the biogenesis and function of other RNA species (Xue et al, 2020; Hussain, 2021). As a dynamic and reversible process, m5C RNA modification is primarily regulated by “writers” (adenosine methyltransferases) and “erasers” (demethylases), and achieves different functions by interacting with “readers” (m5C-binding proteins). The “readers”, such as ALYREF and YBX1, recognize and bind to methylated RNAs to realize different functions (Nombela et al, 2021; Xie et al, 2020)
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