METTL3 facilitates tumor progression via an m6A-IGF2BP2-dependent mechanism in colorectal carcinoma

作者：Ting Li, Pei-Shan Hu, Zhixiang Zuo, Jin-Fei Lin, Xingyang Li, Qi-Nian Wu, Zhan‐Hong Chen, Zhao-Lei Zeng, Feng Wang, Jian Zheng, Demeng Chen, Bo Li, Tiebang Kang, Dan Xie, Dongxin Lin, Huai‐Qiang Ju, Rui‐Hua Xu · 发表于：Molecular Cancer · 年份：2019 · DOI：10.1186/s12943-019-1038-7 · 被引用次数：892 · 研究领域：RNA modifications and cancer、Cancer-related gene regulation、Cancer, Hypoxia, and Metabolism

Abstract Background Colorectal carcinoma (CRC) is one of the most common malignant tumors, and its main cause of death is tumor metastasis. RNA N 6 -methyladenosine (m 6 A) is an emerging regulatory mechanism for gene expression and methyltransferase-like 3 (METTL3) participates in tumor progression in several cancer types. However, its role in CRC remains unexplored. Methods Western blot, quantitative real-time PCR (RT-qPCR) and immunohistochemical (IHC) were used to detect METTL3 expression in cell lines and patient tissues. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and transcriptomic RNA sequencing (RNA-seq) were used to screen the target genes of METTL3. The biological functions of METTL3 were investigated in vitro and in vivo. RNA pull-down and RNA immunoprecipitation assays were conducted to explore the specific binding of target genes. RNA stability assay was used to detect the half-lives of the downstream genes of METTL3. Results Using TCGA database, higher METTL3 expression was found in CRC metastatic tissues and was associated with a poor prognosis. MeRIP-seq revealed that SRY (sex determining region Y)-box 2 (SOX2) was the downstream gene of METTL3. METTL3 knockdown in CRC cells drastically inhibited cell self-renewal, stem cell frequency and migration in vitro and suppressed CRC tumorigenesis and metastasis in both cell-based models and PDX models. Mechanistically, methylated SOX2 transcripts, specifically the coding sequence (CDS) regions, were su...