2. Academic Validation
  3. METTL3 facilitates tumor progression via an m6A-IGF2BP2-dependent mechanism in colorectal carcinoma

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

  • Mol Cancer. 2019 Jun 24;18(1):112. doi: 10.1186/s12943-019-1038-7.
Ting Li 1 2,  Pei-Shan Hu 1,  Zhixiang Zuo 1,  Jin-Fei Lin 1 2,  Xingyang Li 1,  Qi-Nian Wu 1 3,  Zhan-Hong Chen 1 4,  Zhao-Lei Zeng 1,  Feng Wang 1 2,  Jian Zheng 1,  Demeng Chen 5,  Bo Li 6,  Tie-Bang Kang 1,  Dan Xie 1 3,  Dongxin Lin 1 7,  Huai-Qiang Ju 8,  Rui-Hua Xu 9 10
Affiliations

Affiliations

  • 1 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, People's Republic of China.
  • 2 Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
  • 3 Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
  • 4 Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510060, China.
  • 5 Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
  • 6 Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China.
  • 7 State Key Laboratory of Molecular Oncology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100021, China.
  • 8 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, People's Republic of China. juhq@sysucc.org.cn.
  • 9 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, People's Republic of China. xurh@sysucc.org.cn.
  • 10 Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China. xurh@sysucc.org.cn.
PMID: 31230592 DOI: 10.1186/s12943-019-1038-7
Abstract

Background: Colorectal 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.

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 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.

Conclusions: Overall, 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.

Keywords

Colorectal cancer; IGF2BP2; METTL3; N6-methyladenosine (m6A); SOX2.

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