METTL3 Promotes the Progression of Gastric Cancer via Targeting the MYC Pathway

Abstract

Methyltransferase-like 3 (METTL3), a major component of the N6-methyladenosine (m6A) methyltransferase complex, has been suggested to function as an oncogene in several cancers. However, its biological mechanism and the involved pathways in gastric cancer (GC) remain unknown. Here, we reported that frequent upregulation of METTL3 was responsible for the aberrant m6A levels in gastric carcinoma. On the other hand, a high level of METTL3 was significantly associated with several clinicopathological features and poor survival in patients with GC. The knockdown of METTL3 effectively inhibited cell proliferation and migration and invasion capacity. Moreover, overexpression of METTL3 considerably augmented its oncogenic function. Integrated RNA-seq and m6A-seq analysis first indicated that several component molecules (e.g., MCM5, MCM6, etc.) of MYC target genes were mediated by METTL3 via altered m6A modification. Our work uncovers the oncogenic roles of METTL3 in GC and suggests a critical mechanism of GC progression.

Development and Validation of an m6A RNA Methylation Regulator-Based Signature for Prognostic Prediction in Cervical Squamous Cell Carcinoma

“…Proteins that selectively bind m6A can be defined as m6A "readers" (HNRNPC, YTHDF1, YTHDF2, YTHDC2, and YTHDC1) that exert regulatory functions by selective recognition of methylated RNA (4). Emerging evidence has revealed the cancer promoter or suppressor role of m6A regulators in the development of various malignancies (5)(6)(7), whereas the correlation between prognosis of CESC and m6A RNA methylation regulators is still unclear.…”

Analysis of N6-methyladenosine (m6A) methyltransferase reveals METTL14 and ZC3H13 as tumor suppressor genes in breast cancer

“…METTL3 was up-regulated in acute myeloid leukemia cells, enhanced translation of c-MYC, BCL2 and PTEN mRNAs, blocks cell differentiation and apoptosis and promotes leukemia progression [36,37]. METTL3 was also over-expressed in pancreatic cancer, bladder cancer, glioma and gastric cancer, and promotes proliferation, invasion and drug resistance of cancer cells [38][39][40][41]. By contrast, METTL14 was down-regulated in colorectal cancer and hepatocellular carcinoma, and could inhibit cancer cells growth and metastasis by regulating m6A-dependent primary microRNA processing [12,42].…”

The prognostic value of METTL3 in cancer patients: a meta-analysis

“…METTL3 was considered to be a methyltransferase, part of the methyltransferase complex, and was responsible for the m6A modi cation [27,53].METTL3 was involved in many signal pathways such as PI3K / Akt [31,[54][55][56][57][58], MAPK [22] ,Wnt /beta-Catenin [47,59,60] and p38 / ERK [61]pathways,which were all associated with tumor deterioration. In addition, METTL3 could in uence the development of tumor by regulating some transcription factors or important oncogenes.Studies had found that METTL3 could positively regulate the expression of oncogene EZH2 [24,25,62].It promoted the expression of MYC as well as increased stability of protein by regulating the m6A methylation of MYC mRNA to lead to carcinogenesis in PCA and gastric cancer, promote the occurrence of OSCC tumor and affect the growth and invasion of BCA cells [40,[63][64][65][66].When METTL3 was silenced, it inhibited the activity of the Wnt pathway by reducing the m6A methylation level of LEF1 mRNA and reducing protein expression [59,67].…”

“…The studies were screened according to the following procedure [19,[39][40][41][42][43][44][45][46][47][48] (Fig. 1).At rst We retrieved a total of 349 articles from the online database.After preliminary screening and duplicate checking, 253 articles were retained.Through reading the title and abstract of the articles, the articles were further screened.Studies of 207 related to METTL3 expression and cancer prognosis were excluded according to exclusion criteria.…”