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N6-methyladenosine methyltransferase METTL3 promotes colorectal cancer cell proliferation through enhancing MYC expression.

ABSTRACT: N6-methyladenosine (m6A) modification is the most common chemical modification in eukaryotic mRNA, which plays a crucial role in regulating mRNA stability, splicing, and translation. METTL3 (methyltransferase like 3), a major RNA N6-adenosine methyltransferase, has been reported to participate in the progression of many cancers. However, its function in colorectal cancer (CRC) remains largely unknown. In this study, we revealed that METTL3 played an oncogenic role in CRC. We found that METTL3 was significantly upregulated in CRC, using quantitative real-time PCR, western blotting, and immunohistochemical staining, and upregulation of METTL3 was associated with clinicopathological features. Functionally, knockdown of METTL3 suppressed CRC cell proliferation in vitro and in vivo. In contrast, overexpression of METTL3 promoted the growth of CRC cells both in vitro and in vivo. Mechanistically, METTL3 exerted its function through enhancing MYC expression, at least partially in an m6A-IGF2BP1-dependent manner. In conclusion, we found that METTL3 was frequently upregulated in human CRC and promoted CRC progression though enhancing MYC expression. This provided new insights into the molecular mechanisms underlying the development of colorectal cancer.

SUBMITTER: Xiang S

PROVIDER: S-EPMC7270026 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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N6-methyladenosine methyltransferase METTL3 promotes colorectal cancer cell proliferation through enhancing MYC expression.

Xiang Song S Liang Xiaolong X Yin Shuo S Liu Jian J Xiang Zheng Z

American journal of translational research 20200515 5

N6-methyladenosine (m6A) modification is the most common chemical modification in eukaryotic mRNA, which plays a crucial role in regulating mRNA stability, splicing, and translation. METTL3 (methyltransferase like 3), a major RNA N6-adenosine methyltransferase, has been reported to participate in the progression of many cancers. However, its function in colorectal cancer (CRC) remains largely unknown. In this study, we revealed that METTL3 played an oncogenic role in CRC. We found that METTL3 wa ...[more]

PMID: 32509177

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Project description:Gastric cancer (GC) is the fifth most common cancer and the third deadliest cancer in the world, and the occurrence and development of GC are influenced by epigenetics. Methyltransferase-like 3 (METTL3) is a prominent RNA n6-adenosine methyltransferase (m6A) that plays an important role in tumor growth by controlling the work of RNA. This study aimed to reveal the biological function and molecular mechanism of METTL3 in GC. The expression level of METTL3 in GC tissues and cells was detected by qPCR, Western blot and immunohistochemistry, and the expression level and prognosis of METTL3 were predicted in public databases. CCK-8, colony formation, transwell and wound healing assays were used to study the effect of METTL3 on GC cell proliferation and migration. In addition, the enrichment effect of METTL3 on DEK mRNA was detected by the RIP experiment, the m6A modification effect of METTL3 on DEK was verified by the MeRIP experiment and the mRNA half-life of DEK when METTL3 was overexpressed was detected. The dot blot assay detects m6A modification at the mRNA level. The effect of METTL3 on cell migration ability in vivo was examined by tail vein injection of luciferase-labeled cells. The experimental results showed that METTL3 was highly expressed in GC tissues and cells, and the high expression of METTL3 was associated with a poor prognosis. In addition, the m6A modification level of mRNA was higher in GC tissues and GC cell lines. Overexpression of METTL3 in MGC80-3 cells and AGS promoted cell proliferation and migration, while the knockdown of METTL3 inhibited cell proliferation and migration. The results of in vitro rescue experiments showed that the knockdown of DEK reversed the promoting effects of METTL3 on cell proliferation and migration. In vivo experiments showed that the knockdown of DEK reversed the increase in lung metastases caused by the overexpression of METTL3 in mice. Mechanistically, the results of the RIP experiment showed that METTL3 could enrich DEK mRNA, and the results of the MePIP and RNA half-life experiments indicated that METTL3 binds to the 3'UTR of DEK, participates in the m6A modification of DEK and promotes the stability of DEK mRNA. Ultimately, we concluded that METTL3 promotes GC cell proliferation and migration by stabilizing DEK mRNA expression. Therefore, METTL3 is a potential biomarker for GC prognosis and a therapeutic target.

Dataset Information

N6-methyladenosine methyltransferase METTL3 promotes colorectal cancer cell proliferation through enhancing MYC expression.

Publications

N6-methyladenosine methyltransferase METTL3 promotes colorectal cancer cell proliferation through enhancing MYC expression.

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