Abstract
IntroductionThe methylation at position N6 of adenine is called N6-methyladenosine (m6A). This transcriptional RNA modification exerts a very active and important role in RNA metabolism and in other biological processes. However, the activities of m6A associated with malignant liver hepatocellular carcinoma (LIHC) are unknown and are worthy of study.Materials and MethodsUsing the data of University of California, Santa Cruz (UCSC), the expression of M6A methylation regulators in pan-cancer was evaluated as a screening approach to identify the association of M6A gene expression and 18 cancer types, with a specific focus on LIHC. LIHC datasets of The Cancer Genome Atlas (TCGA) were used to explore the expression of M6A methylation regulators and their clinical significance. Gene Ontology (GO) analysis and Gene Set Enrichment Analysis (GSEA) were used to explore the underlying mechanism based on the evaluation of aberrant expression of m6A methylation regulators.ResultsThe expression alterations of m6A-related genes varied across cancer types. In LIHC, we found that in univariate Cox regression analysis, up-regulated m6A modification regulators were associated with worse prognosis, except for ZC3H13. Kaplan–Meier survival curve analysis indicated that higher expression of methyltransferase-like protein 3 (METTL3) and YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) genes related to the worse survival rate defined by disease-related survival (DSS), overall survival (OS), progression-free interval (PFI), and disease-free interval (DFI). Up-regulated m6A methylation regulator group (cluster2) obtained by consensus clustering was associated with poor prognosis. A six-gene prognostic signature established using the least absolute shrinkage and selection operator (LASSO) Cox regression algorithm performed better in the early (I + II; T1 + T2) stages than in the late (III + IV; T3 + T4) stages of LIHC. Using the gene signature, we constructed a risk score and found that it was an independent predictive factor for prognosis. Using GSEA, we identified processes involved in DNA damage repair and several biological processes associated with malignant tumors that were closely related to the high-risk group.ConclusionIn summary, our study identified several genes associated with m6A in LIHC, especially METTL3 and YTHDF1, and confirmed that a risk signature comprised of m6A-related genes was able to forecast prognosis.
Highlights
The methylation at position N6 of adenine is called N6-methyladenosine (m6A)
The risk score results were an independent prognostic factor of liver hepatocellular carcinoma (LIHC). We found that those evaluating the combination of m6A-related genes were based on 13 major M6A genes, including methyltransferase-like protein 3 (METTL3), METTL14, Wilms Tumor 1-associated protein (WTAP), KIAA1429, RBM15, ZC3H13, YTHDC1, YTHDC2, YTHDF1, YTHDF2, HNRNPC, fat mass and obesity-associated protein (FTO), and alkB homolog 5 (ALKBH5)
In our investigation of the correlation of m6Arelated genes, we found that there is a significant relationship between the 20 M6A genes, and in particular, IGF2BP3 and HNRNPA2B1, RBM15B, and YTHDF2
Summary
The methylation at position N6 of adenine is called N6-methyladenosine (m6A). This transcriptional RNA modification exerts a very active and important role in RNA metabolism and in other biological processes. M6A methyltransferases ( called “writers”) responsible for this type of RNA modification include KIAA1429, zinc finger CCCH domain-containing protein 13 (ZC3H13), methyltransferase-like protein 3 (METTL3), METTL14, METTL16, RNA-binding motif protein (RBM15), and Wilms Tumor 1-associated protein (WTAP) (Akichika et al, 2019). M6A-binding proteins ( called “readers”) include YTHDC1-2, insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs), heterogeneous nuclear ribonucleoproteins (HNRNPs), and the YTH N6-methyladenosine RNA binding proteins 1 to 3 (YTHDF1–3) (Wang et al, 2014; Liao et al, 2018)
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