Journal Article

METTL3/YTHDF2 m6A axis accelerates colorectal carcinogenesis through epigenetically suppressing YPEL5

Tang, Weiwei, Chen, Yongxiong, Xu, Yidan, Wang, Gueyhorng, Zhou, Dan, Chen, Fangfang, Wang, Yanting, Han, Yinshu, Xu, Binbin, Xu, Yajie, Fu, Shanshan

2021

Overview

N6‐methyladenosine (m6A) has emerged as the most prevalent post‐transcriptional modification on mRNA that contributes prominently to tumorigenesis. However, the specific function of m6A methyltransferase methyltransferase‐like 3 (METTL3) in colorectal cancer (CRC) remains elusive. Herein, we explored the biological function of METTL3 in CRC progression. Clinically, METTL3 was frequently upregulated in CRC tissues, cell lines, and plasma samples and its high expression predicted poor prognosis of CRC patients. Functionally, knockdown of METTL3 significantly repressed CRC cell proliferation and migration in vitro, while its overexpression accelerated CRC tumor formation and metastasis both in vitro and in vivo. Mechanistically, METTL3 epigenetically repressed YPEL5 in an m6A‐YTHDF2‐dependent manner by targeting the m6A site in the coding sequence region of the YPEL5 transcript. Moreover, overexpression of YPEL5 significantly reduced CCNB1 and PCNA expression. Collectively, we identified the pivotal role of METTL3‐catalyzed m6A modification in CRC tumorigenesis, wherein it facilitates CRC tumor growth and metastasis through suppressing YPEL5 expression in an m6A‐YTHDF2‐dependent manner, suggesting a promising strategy for the diagnosis and therapy of CRC. Here, we demonstrate that methyltransferase‐like 3 (METTL3)‐catalyzed N6‐methyladenosine (m6A) modification facilitates tumor growth and metastasis in colorectal cancer (CRC). METTL3 can reduce YPEL5 expression in an m6A‐YTHDF2‐dependent manner. Our findings highlight a novel m6A regulatory mechanism, with ‘writer’ METTL3, ‘reader’ YTHDF2, and ‘target’ YPEL5 being promising diagnostic or therapeutic targets in CRC.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Adenosine - metabolism / Antibodies / Carcinogenesis / Cell cycle / Cell Cycle Proteins - genetics / Cell Line, Tumor / Cell migration / Cell proliferation / Colorectal cancer / Colorectal Neoplasms - metabolism / Colorectal Neoplasms - pathology / Epigenesis, Genetic / Fluorides / Gene expression / Humans / Immunoglobulins / Laboratory animals / m6A modification / Medical prognosis / Metastases / Metastasis / Methyltransferase / Methyltransferases / Methyltransferases - metabolism / N6-methyladenosine / Prognosis / prognostic biomarker / Proliferating cell nuclear antigen / Proteins / RNA / RNA modification / RNA-Binding Proteins - metabolism / Transcription / Tumorigenesis