RNA N6-methyladenosine reader IGF2BP3 regulates cell cycle and angiogenesis in colon cancer

Background N6-Methyladenosine (m6A) modification has been implicated in multiple processes for colon cancer development. IGF2BP3 was a newly reported m6A reader, whereas its role in colon cancer remains unclear. Methods The expression of m6A associated enzymes and total m6A level were measured by We...

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Published in:Journal of experimental & clinical cancer research 2020-09, Vol.39 (1), p.1-203, Article 203
Main Authors: Yang, Zhou, Wang, Tingfeng, Wu, Dejun, Min, Zhijun, Tan, Jingyun, Yu, Bo
Format: Article
Language:English
Subjects:
Analysis
Angiogenesis
Cell cycle
Colon cancer
Colorectal cancer
DNA replication
Enzymes
IGF2BP3
Medical prognosis
Metastasis
Methylation
Methyltransferases
N6-Methyladenosine
Polyclonal antibodies
Proteins
RNA
Software packages
Survival analysis
Vascular endothelial growth factor
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Summary:Background N6-Methyladenosine (m6A) modification has been implicated in multiple processes for colon cancer development. IGF2BP3 was a newly reported m6A reader, whereas its role in colon cancer remains unclear. Methods The expression of m6A associated enzymes and total m6A level were measured by Western Blotting analysis and m6A RNA Methylation Quantification Kit respectively. Cell cycle was analyzed by flowcytometry. The interaction of IGF2BP3 and related targets was analyzed by RNA immunoprecipitation (RIP) and m6A RNA immunoprecipitation (MeRIP) assays. Results We investigated all m6A regulated enzymes in colon cancer and found only the overexpression of IGF2BP3 was associated with cancer progression and survival based on The Cancer Genome Atlas (TCGA) databases. Additionally, we also demonstrated IGF2BP3 was associated with DNA replication in the cell cycle. Knockdown of IGF2BP3 significantly repressed percentage of S phase of cell cycle as well as cell proliferation. Further research demonstrated IGF2BP3 bound to the mRNA of Cyclin D1 (CCND1, checkpoint of G1/S phase of cell cycle) and reduced its mRNA stability via reading m6A modification in the CDS region. Overexpression of Cyclin D1 in IGF2BP3 down-regulated cells completely rescued the inhibited percentage of S phase in cell cycle as well as cell proliferation. Additionally, we also demonstrated a similar role of IGF2BP3 at VEGF. IGF2BP3 bound to the mRNA of VEGF and reads m6A modification, thus regulated both expression and stability of VEGF mRNA. Knockdown of IGF2BP3 repressed angiogenesis in colon cancer via regulating VEGF. Conclusion Knockdown of IGF2BP3 repressed DNA replication in the S phase of cell cycle and angiogenesis via reading m6A modification of CCND1 and VEGF respectively. IGF2BP3 was a possible prognosis marker and potential therapeutic target of colon cancer. Keywords: IGF2BP3, N6-Methyladenosine, Angiogenesis, Cell cycle, DNA replication
ISSN:1756-9966
0392-9078
1756-9966
DOI:10.1186/s13046-020-01714-8