Augmentation of the RNA m6A reader signature is associated with poor survival by enhancing cell proliferation and EMT across cancer types

Abstract

N6-Methyladenosine (m6A) RNA modification plays a critical role in the posttranscriptional regulation of gene expression. Alterations in cellular m6A levels and m6A-related genes have been reported in many cancers, but whether they play oncogenic or tumor-suppressive roles is inconsistent across cancer types. We investigated common features of alterations in m6A modification and m6A-related genes during carcinogenesis by analyzing transcriptome data of 11 solid tumors from The Cancer Genome Atlas database and our in-house gastric cancer cohort. We calculated m6A writer (W), eraser (E), and reader (R) signatures based on corresponding gene expression. Alterations in the W and E signatures varied according to the cancer type, with a strong positive correlation between the W and E signatures in all types. When the patients were divided according to m6A levels estimated by the ratio of the W and E signatures, the prognostic effect of m6A was inconsistent according to the cancer type. The R and especially the R2 signatures (based on the expression of IGF2BPs) were upregulated in all cancers. Patients with a high R2 signature exhibited poor prognosis across types, which was attributed to enrichment of cell cycle- and epithelial–mesenchymal transition-related pathways. Our study demonstrates common features of m6A alterations across cancer types and suggests that targeting m6A R proteins is a promising strategy for cancer treatment.

FTO Inhibits Epithelial Ovarian Cancer Progression by Destabilising SNAI1 mRNA through IGF2BP2

“…Many cancers exhibit alterations in the expression of m6A-related genes and cellular m6A levels. However, the oncogenic or tumour-suppressor roles of m6A are inconsistent across cancer types [ 8 ], and the role of m6A in EOC remains unclear.…”

Modification patterns and metabolic characteristics of m6A regulators in digestive tract tumors

“…M6A clusters with increased expression of IGF2BPs showed the worst outcomes in STAD and ESCA. Indeed, previous studies have showed that the reader and especially the IGF2BPs were upregulated in cancers, patients with a high IGF2BPs signature exhibited poor prognosis across cancer types [ [29] , [30] , [31] ]. However, the clusters in COAD and READ characterized by nearly all m6A regulators with reduced expression showed the best results in the survival analysis.…”

Mechanisms and clinical landscape of N6-methyladenosine (m6A) RNA modification in gastrointestinal tract cancers

“…ROC analysis revealed an area under the curve of 0.929, outperforming commonly used biomarkers such as carcinoembryonic antigen and carbohydrate antigen 199. This indicated that the m6A levels in peripheral blood RNA have high accuracy in diagnosing gastric cancer [ 169 , 170 ]. In pancreatic cancer, m6A levels showed promise as a predictive and prognostic marker.…”