Prognostic Implication of the m6A RNA Methylation Regulators in Rectal Cancer

Abstract

N6-methyladenosine (m6A) is a very common and abundant RNA modifications occurring in nearly all types of RNAs. Although the dysregulated expression of m6A regulators is implicated in cancer progression, our understanding of the prognostic value of the m6A regulators in rectal cancer is still quite limited. In this study, we analyzed the RNA expression levels of the 17 m6A regulator genes of 95 rectal cancer and 10 normal rectal samples from the The Cancer Genome Atlas Rectum Adenocarcinoma (TCGA-READ) dataset. Lasso regression analysis was conducted to build a prognostic model and calculate the risk score. The rectal cancer patients were then devided into the high-risk and low-risk groups according to the mean risk score. The prognostic value of the identified model was separately evaluated in the TCGA-READ and GSE87211 datasets. GSEA was conducted to analyze the functional difference of high-risk and low-risk rectal cancer patients. Our analysis revealed that rectal cancer patients with lower expression of YTHDC2 and METTL14 had a remarkable worse overall survival (P < 0.05). The prognostic value of the model was validated in GSE87211 datasets, with AUC = 0.612 for OS and AUC = 0.651 for RFS. Furthermore, the m6A modification-based risk score system is associated with activation of distinct signaling pathways, such as DNA repair, epithelial-mesenchymal transition, G2M checkpoint and the MYC pathway, that may contribute to the progression of rectal cancer. In conclusion, our findings demonstrated that the m6A RNA methylation regulators, specifically YTHDC2 and METTL14, were significantly down-regulated and might be potential prognostic biomarkers in rectal cancer.

The m6A RNA Modification Quantity and the Prognostic Effect of Reader YTHDC2 in Colorectal Cancer

“…This study initially explored the expression of YTHDC2 in CRC at the levels of RNA and protein, and the results was similar with previous TCGA-based studies. [20][21][22] In addition, low expression of YTHDC2 was reported in other types of cancers, such as lung adenocarcinoma, 17 non-small-cell lung cancer, 18 and head and neck squamous cell carcinoma, 19 which suggested that YTHDC2 probably functions as a tumor suppressor.…”

“…18 In the previous studies, YTHDC2 was identified to be a tumor suppressor in most types of cancer. 18 , 19 However, it is still controversial whether YTHDC2 promotes or suppresses CRC, 20 - 23 which needs to be explored further.…”

Functions, mechanisms, and therapeutic implications of METTL14 in human cancer

“…In addition, METTL14 downregulates XIST-dependent m 6 A-YTHDF2 pathways [ 84 ]. Significant downregulation of METTL14 and YTHDC2 may be a potential prognostic biomarker for rectal cancer [ 85 ]. Moreover, Dong et al revealed that in tumor-associated macrophages (TAMs) of CRC, knockout of METTL14 results in a decrease in m 6 A levels, an increase in EBI3, and dysfunction of antitumor T cells, which then promots the malignant progression of tumors [ 86 ].…”

The emerging roles of the interaction between m6A modification and c‐Myc in driving tumorigenesis and development

“…Epigenetic modifications have become the focus in the cancer research field. Among them, m6A modification has received great attention in cancer and has gained clinical significance (Chen, Wang, et al, 2021). m6A modification can affect the transcription, stability, and translation efficiency of c‐Myc through its regulators, namely writers, erasers, and readers, and thus plays a role in different types of tumors (Meyer & Jaffrey, 2014; Willbanks et al, 2021; Wood et al, 2021).…”