Abstract
BackgroundN6-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.MethodsThe 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.ResultsWe 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.ConclusionKnockdown 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.
Highlights
N6-Methyladenosine (m6A) modification has been implicated in multiple processes for colon cancer development
Our research comprehensively investigated m6A modification in colon cancer and subsequently focused on the m6A modification read by IGF2BP3
The expression of IGF2BP3 was related to survival and progression of colon cancer We further investigated the association of m6A associated enzymes with survival and progression
Summary
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. Whereas the methylation modification of RNA is m6A (N6-methyladenosine, 6methyl adenine) and uridine modification (U -tail), in which N6-methyladenine (m6A) is the most common [1]. The methylation modification of DNA and histones primarily play role at the transcriptional level. In the process of m6A, three types of molecules are involved: Writers, Erasers and Readers. The modification of m6A is regulated by 3 classes of enzymes: Writers (METTL3, METTL14, WTAP, etc.), Erasers (FTO, ALKBH5, etc.) and some m6A modified binding protein as Readers (YTHDF1 / 2 / 3, etc.) [2, 3]. The m6A Readers interpret RNA methylation modification information and participate in the translation and degradation of downstream RNA [4]
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