METTL3/YTHDF2 m6A axis promotes the malignant progression of bladder cancer by epigenetically suppressing RRAS

Abstract

The present study aimed to explore the potential roles of the methyltransferase-like 3 (METTL3)-mediated methylation of RAS related (RRAS) mRNA in the tumorigenesis and development of bladder cancer (BCa). For this purpose, the relative expression levels of METTL3 in BCa specimens and cell lines were measured using reverse transcription-quantitative PCR (RT-qPCR) and western blot analysis. The association between the METTL3 expression level and the clinical characteristics of patients with BCa was analyzed using The Cancer Genome Atlas (TCGA) and Gene Expression Profiling Interactive Analysis databases. Cellular experiments were performed to confirm the effects of METTL3 on the proliferative, migratory and invasive capacities of BCa cells. RT-qPCR, western blot analysis, methylated RNA immunoprecipitation (MeRIP)-qPCR and dual-luciferase report assays were utilized to verify the METTL3/RRAS/YTH N 6 -methyladenosine (m6A) RNA binding protein 2 (YTHDF2) regulatory axis in BCa. The results revealed that METTL3 expression was markedly increased in BCa specimens and cell lines, and was associated with poor clinical characteristics of patients with BCa. In vitro and in vivo assays demonstrated that the silencing of METTL3 markedly suppressed the proliferative, migratory and invasive capacities of BCa cells. MeRIP-PCR and dual-luciferase report assays indicated that METTL3 could bind to the m6A sites of RRAS mRNA and suppress the transcriptional activity of RRAS. YTHDF2 could recognize the m6A sites of RRAS and mediate RRAS degradation. On the whole, the findings of the present study reveal the pivotal role of METTL3-catalyzed m6A modification in BCa tumorigenesis and development. The change could facilitate BCa tumor growth and metastasis by suppressing RRAS expression in an m6A YTHDF2-dependent manner. Targeting the METTL3/RRAS/YTHDF2 regulatory axis may thus prove to be a promising strategy for the diagnosis and therapy of BCa.

METTL3 promotes osteoblast ribosome biogenesis and alleviates periodontitis

“…Recent evidence showed that METTL3 promotes cholangiocarcinoma progression by YTHDF2-mediated IFIT2 mRNA degradation [ 49 ]. METTL3 facilitates bladder cancer growth and metastasis by suppressing RRAS expression in a YTHDF2‑dependent manner [ 50 ]. To illuminate if YTHDF2 recognized the mRNA of Dkk3 and Sostdc1 and modulated the mRNA decay, RIP-PCR and RNA stability assay were performed.…”

Repurposable Drugs for Immunotherapy and Strategies to Find Candidate Drugs

“…Attempts to develop cancer therapies on the basis of gene expression data have been made for various types of carcinomas. For example, studies based on gene expression data have been conducted in endometrial cancer [ 103 ], lung adenocarcinoma [ 104 ], and bladder cancer [ 105 ]. Regarding breast cancer, as we have introduced here, the search for repurposing drugs on the basis of gene expression data is underway.…”

Cancer metastasis under the magnifying glass of epigenetics and epitranscriptomics

“…About YTHDF2, the METTL3/YTHDF2 m 6 A axis promotes tumorigenesis in bladder cancer by mediating degradation of RRAS [ 235 ], SETD7, and KLF4 [ 236 ]. Also, METTL3 depletion suppressed metastasis [ 236 ].…”