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

Molecular Cancer

  ^{1    2    3    3    3    3    3    3    3    4    5    6    6    6    6    7    7} 

[1] 0000 0001 2360 039X, grid.12981.33, Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, 510080, Guangzhou, China;0000 0001 2360 039X, grid.12981.33, Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-Sen University, 510080, Guangzhou, China;0000 0004 1803 6191, grid.488530.2, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, 510060, Guangzhou, People’s Republic of China;0000 0004 1803 6191, grid.488530.2, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, 510060, Guangzhou, People’s Republic of China;0000 0000 9889 6335, grid.413106.1, State Key Laboratory of Molecular Oncology, Chinese Academy of Medical Science and Peking Union Medical College, 100021, Beijing, China;0000 0004 1803 6191, grid.488530.2, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, 510060, Guangzhou, People’s Republic of China;0000 0004 1762 1794, grid.412558.f, Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, 510060, Guangzhou, China;0000 0004 1803 6191, grid.488530.2, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, 510060, Guangzhou, People’s Republic of China;0000 0004 1803 6191, grid.488530.2, Department of Medical Oncology, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China;0000 0004 1803 6191, grid.488530.2, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, 510060, Guangzhou, People’s Republic of China;0000 0004 1803 6191, grid.488530.2, Department of Pathology, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China;

关键词: Colorectal cancer;    N-methyladenosine (mA);    METTL3;    SOX2;    IGF2BP2;   

DOI  :  10.1186/s12943-019-1038-7

来源: publisher

【 摘 要 】

BackgroundColorectal carcinoma (CRC) is one of the most common malignant tumors, and its main cause of death is tumor metastasis. RNA N6-methyladenosine (m6A) 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.MethodsWestern 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.ResultsUsing 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 subsequently recognized by the specific m6A “reader”, insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2), to prevent SOX2 mRNA degradation. Further, SOX2 expression positively correlated with METTL3 and IGF2BP2 in CRC tissues. The combined IHC panel, including “writer”, “reader”, and “target”, exhibited a better prognostic value for CRC patients than any of these components individually.ConclusionsOverall, our study revealed that METTL3, acting as an oncogene, maintained SOX2 expression through an m6A-IGF2BP2-dependent mechanism in CRC cells, and indicated a potential biomarker panel for prognostic prediction in CRC.

【 授权许可】

CC BY