m6A methyltransferase METTL3 maintains colon cancer tumorigenicity by suppressing SOCS2 to promote cell proliferation

Autor: Xian Ming Chen, Nicholas W. Mathy, Tao Yu, Rongrong Liang, Ting Chen, Ji-Hao Xu, Ai-Yu Gong, Kuangyi Tian, Qi-Kui Chen
Rok vydání: 2020
Předmět:
Male
0301 basic medicine
Cancer Research
Adenosine
leucine-rich repeat-containing G protein-coupled receptor 5
Carcinogenesis
RNA Stability
Cell
Datasets as Topic
Suppressor of Cytokine Signaling Proteins
medicine.disease_cause
Receptors
G-Protein-Coupled
Gene Knockout Techniques
0302 clinical medicine
Colon surgery
SOCS2
Colectomy
Regulation of gene expression
Chemistry
Articles
methyltransferase like 3
General Medicine
Transfection
Middle Aged
Cell cycle
Gene Expression Regulation
Neoplastic
medicine.anatomical_structure
Oncology
Gene Knockdown Techniques
030220 oncology & carcinogenesis
Colonic Neoplasms
Female
Colon
colorectal cancer
Methylation
Tubercidin
m6A modification
03 medical and health sciences
Cell Line
Tumor
Spheroids
Cellular
medicine
Humans
RNA
Messenger
Aged
Cell Proliferation
Neoplasm Staging
Cancer
Methyltransferases
medicine.disease
tumorigenesis
030104 developmental biology
suppressor of cytokine signaling 2
Cancer research
Zdroj: Oncology Reports
ISSN: 1791-2431
1021-335X
DOI: 10.3892/or.2020.7665
Popis: N6-methyladenosine (m6A) RNA modification maintained by N6-methyltransferases and demethylases is involved in multiple biological functions. Methyltransferase like 3 (METTL3) is a major N6-methyltransferase. However, the role of METTL3 and its installed m6A modification in colorectal tumorigenesis remains to be fully elucidated. METTL3 is highly expressed as indicated in colorectal cancer samples in the TCGA and Oncomine databases, implying its potential role in colon tumorigenesis. SW480 cell line with stable METTL3 knockout (METTL3-KO) was generated using CRISPR/Cas9 and were confirmed by the loss of METTL3 expression and suppression of m6A modification. The proliferation of METTL3-KO cells was significantly inhibited compared with that of control cells. METTL3-KO decreased the decay rate of suppressor of cytokine signaling 2 (SOCS2) RNA, resulting in elevated SOCS2 protein expression. m6A-RNA immunoprecipitation-qPCR (MeRIP-qPCR) revealed that SOCS2 mRNA was targeted by METTL3 for m6A modification. Similar to METTL3-KO SW480 cells, SW480 cells treated with 3-deazaadenosine, an RNA methylation inhibitor, exhibited elevated SOCS2 protein expression. Increased levels of SOCS2 in METTL3-KO SW480 cells were associated with decreased expression of leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), contributing to the inhibition of cell proliferation. The underlying associations among METTL3, SOCS2, and LGR5 were further confirmed in SW480 cells transfected with si-METTL3 and in tumor samples from patients with colorectal cancer. Taken together, our data demonstrate that an increased level of METTL3 may maintain the tumorigenicity of colon cancer cells by suppressing SOCS2.
Databáze: OpenAIRE
Externí odkaz: