Abstract
BackgroundEpigenetic alterations are involved in various aspects of colorectal carcinogenesis. N6-methyladenosine (m6A) modifications of RNAs are emerging as a new layer of epigenetic regulation. As the most abundant chemical modification of eukaryotic mRNA, m6A is essential for the regulation of mRNA stability, splicing, and translation. Alterations of m6A regulatory genes play important roles in the pathogenesis of a variety of human diseases. However, whether this mRNA modification participates in the glucose metabolism of colorectal cancer (CRC) remains uncharacterized.MethodsTranscriptome-sequencing and liquid chromatography-tandem mass spectrometry (LC-MS) were performed to evaluate the correlation between m6A modifications and glucose metabolism in CRC. Mass spectrometric metabolomics analysis, in vitro and in vivo experiments were conducted to investigate the effects of METTL3 on CRC glycolysis and tumorigenesis. RNA MeRIP-sequencing, immunoprecipitation and RNA stability assay were used to explore the molecular mechanism of METTL3 in CRC.ResultsA strong correlation between METTL3 and 18F-FDG uptake was observed in CRC patients from Xuzhou Central Hospital. METTL3 induced-CRC tumorigenesis depends on cell glycolysis in multiple CRC models. Mechanistically, METTL3 directly interacted with the 5′/3’UTR regions of HK2, and the 3’UTR region of SLC2A1 (GLUT1), then further stabilized these two genes and activated the glycolysis pathway. M6A-mediated HK2 and SLC2A1 (GLUT1) stabilization relied on the m6A reader IGF2BP2 or IGF2BP2/3, respectively.ConclusionsMETTL3 is a functional and clinical oncogene in CRC. METTL3 stabilizes HK2 and SLC2A1 (GLUT1) expression in CRC through an m6A-IGF2BP2/3- dependent mechanism. Targeting METTL3 and its pathway offer alternative rational therapeutic targets in CRC patients with high glucose metabolism.
Highlights
Epigenetic alterations are involved in various aspects of colorectal carcinogenesis
Methyltransferase-like 3 (METTL3) is closely correlated with glycolysis in colorectal cancer To explore the correlation between m6A modifications with glycolysis metabolism in colorectal cancer (CRC), real-time PCR analysis was performed to compare the regulated-m6A gene expression profiles in 47 CRC patients who had been imaged for 18F-FDG [18F]-Fluoro2-deoxyglucose positron emission tomography (PET) (Cohort 1)
Further analysis revealed that a significant correlation between FDG uptake and METTL3 immunohistochemical staining existed in CRC patients of Cohort 1 (Fig. 1d-e)
Summary
Epigenetic alterations are involved in various aspects of colorectal carcinogenesis. N6methyladenosine (m6A) modifications of RNAs are emerging as a new layer of epigenetic regulation. Alterations of m6A regulatory genes play important roles in the pathogenesis of a variety of human diseases. Whether this mRNA modification participates in the glucose metabolism of colorectal cancer (CRC) remains uncharacterized. Despite that the substantial diagnostic and therapeutic strategies have been improved, the survival time of CRC patients have been increased in recent years, the mortality rate of colorectal cancer remains high [2]. Recent studies found that inhibition of EGFR signaling resulted in dramatically lung cancer reduction by reversing of Warburg effect and reactivation of oxidative phosphorylation [7], which highlights the perspective role for the therapeutic target of glycolysis. The molecular basis for glycolysis and its role in cancer growth remain unclear
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