Reduced m6A modification predicts malignant phenotypes and augmented Wnt/PI3K‐Akt signaling in gastric cancer

Abstract

Background As the most abundant epigenetic modification on mRNAs and long non‐coding RNAs, N6‐methyladenosine (m6A) modification extensively exists in mammalian cells. Controlled by writers (methyltransferases), readers (signal transducers), and erasers (demethylases), m6A influences mRNA structure, maturation, and stability, thus negatively regulating protein expression in a post‐translational manner. Nevertheless, current understanding of m6A's roles in tumorigenesis, especially in gastric cancer (GC) remains to be unveiled. In this study, we assessed m6A's clinicopathological relevance to GC and explored the underlying mechanisms. Methods By referring to a proteomics‐based GC cohort we previously generated and the TCGA‐GC cohort, we merged expressions of canonical m6A writers (METTL3/METTL14), readers (YTHDF1/YTHDF2/YTHDF3), and erasers (ALKBH5/FTO), respectively, as W, R, and E signatures to represent m6A modification. We stratified patients according to these signatures to decipher m6A's associations with crucial mutations, prognosis, and clinical indexes. m6A's biological functions in GC were predicted by gene set enrichment analysis (GSEA) and validated by in vitro experiments. Results We discovered that W and R were potential tumor suppressive signatures, while E was a potential oncogenic signature in GC. According to W/R/E stratifications, patients with low m6A‐indications were accompanied with higher mutations of specific genes ( CDH1 , AR , GLI3 , SETBP1 , RHOA , MUC6 , and TP53 ) and also demonstrated adverse clinical outcomes. GSEA suggested that reduced m6A was correlated with oncogenic signaling and phenotypes. Through in vitro experiments, we proved that m6A suppression (represented by METTL14 knockdown) promoted GC cell proliferation and invasiveness through activating Wnt and PI3K‐Akt signaling, while m6A elevation (represented by FTO knockdown) reversed these phenotypical and molecular changes. m6A may also be involved in interferon signaling and immune responses of GC. Conclusions Our work demonstrated that low‐m6A signatures predicted adverse clinicopathological features of GC, while the reduction of RNA m6A methylation activated oncogenic Wnt/PI3K‐Akt signaling and promoted malignant phenotypes of GC cells.

Diagnostic, progressive and prognostic performance of m6A methylation RNA regulators in lung adenocarcinoma

“…Besides, it was note-worthy that YTHDF2 was merely reported to be involved with TP53 in peripheral T-cell lymphoma and gastric cancer yet [66,67]. YTHDF1 was functionally interactional with TP53 in gastric cancer [67]. To the best of our knowledge, it was not clear yet that TP53 mutant impacted the expression of WTAP, RBM15, and KIAA1429, in which more evidences were required to elucidate their mechanistic correlation.…”

“…Thus, we inferred that those regulators were likely only effective in some types of LUAD, while the specific reasons required following elucidation. Besides, it was note-worthy that YTHDF2 was merely reported to be involved with TP53 in peripheral T-cell lymphoma and gastric cancer yet [66,67]. YTHDF1 was functionally interactional with TP53 in gastric cancer [67].…”

High expression of WTAP leads to poor prognosis of gastric cancer by influencing tumour‐associated T lymphocyte infiltration

“…The role of WTAP in GC is currently rarely reported and controversial. Zhang C et al found that low m6A levels can lead to the proliferation of GC cells, resulting in GC progression . Wang et al studied the related effects of m6A methylation on the prognosis of GC and found that m6A methylation can lead to the progression of GC and can lead to poor prognosis of GC patients .…”

Multiple Functions and Mechanisms Underlying the Role of METTL3 in Human Cancers

“…Dysregulation of METTL3 in various cancers can also influence cancer cell EMT (23,49,50), apoptosis (36,47), and stem cell self-renewal (38,39), which have been identified to be important in cancer progression. In addition, METTL3-mediated m 6 A modification can directly regulate the transcription and translation of oncogenes and tumor suppressors coupled to the most of the important pathways involved in cancer cell progression, such as the PI3K/AKT (36,44,47,57,60,62), wnt/βcatenin (46), and P38/ERK (26) pathways. METTL3 can also regulate cancer-related gene expression via m 6 A modification (30,42,66,67).…”

“…Knockdown of METTL3 results in a reduction in m 6 A and subsequently promotes cancer cell proliferation and invasion by activating PI3K-AKT signaling. Several studies noted that knockdown of METTL3 inhibited PI3K expression and reduced the levels of the phosphorylated form of AKT, ribosomal protein S6 kinase B1 (p70S6K, an AKT downstream effector), β-catenin, and cyclin D1 (36,44,47,57). METTL3 knockdown significantly suppressed cell proliferation, and METTL3 acted as an oncogene in acute myeloid leukemia cells by suppressing Myc expression via a reduction in the m 6 A level in Myc mRNA (44,58).…”