METTL3 May Drive m6A-dependent Glycolysis in Colorectal Cancer

Colorectal cancer (CRC) is one of the most fatal diseases that can affect both men and women. According to the CDC, it is the second deadliest cancer in the US and the third deadliest in the world. Early detection is key to survival, so it’s important to get screened regularly, but it’s also important to understand how the disease forms and progresses on a molecular level.

Epigenetic regulation plays a large part in a variety of diseases, especially in colorectal cancer. Usually, DNA methylation is the most prominent and influential epigenetic mark, but it turns out that m6A also has a hand in disease development.

N6-methyladenosine (m6A) is the most common RNA modification found in eukaryotes. It plays a large role in regulating mRNA translation and stability, and it’s already a known biomarker in Gastric Cancer.

Researchers from the Shanghai Jiao Tong University set out to determine the effect that m6a modification has on glycolysis and how it relates to CRC development. The team, led by Dr. Chaoqin Shen, examined three different groups of tissue samples from patients who had undergone surgery for CRC between 2012 and 2019. The first tissue group (Cohort 1) was made up of fresh tissues and paraffin-embedded tissues. Cohort 2 consisted of only paraffin-embedded tissues, and Cohort 3 consisted of only fresh tissues.
To begin, they performed a PCR on the samples from Cohort 1, focusing on two molecules: METTL3—an RNA methyltransferase, and fluorodeoxyglucose (FDG)—a tracer molecule used in PET scans to detect cancerous tissue.

global m6A abundance in CRC patients with high vs. low FDG uptake in Cohort 1

m6A dot blot assay showing global m6A abundance in CRC patients with FDG high uptake or FDG low uptake in Cohort 1.

They found a significant correlation between METTL3 expression and FDG uptake, which they confirmed by using RNA-seq analysis to compare the gene expression profiles of METTL3 and CRC cells. Specifically, they discovered 2848 downregulated genes and 3046 upregulated genes after the knockout of METTL3, which resulted in a reduction of important members of the glycolysis pathway in CRC cells.

The team then used the EpiQuik m6 A RNA Methylation Quantification Kit to identify the increased m6a levels in the mRNA of the CRC cells after the knockout of METTL3. They discovered a significant decrease in m6a levels of the METTL3 knockout cells when compared to the wild type, as demonstrated in the image below:

Levels of m6A in mRNA of HCT116 WT and METTL3- knockout cells

The global m6A levels in mRNA of HCT116 WT and METTL3- knockout cells were measured by the EpiQuik™ m6 A RNA Methylation Quantification Kit.

The next step was to determine if METTL3 acted as an oncogene for CRC development. The team focused on two other key functional components in the glycolytic pathway: Hexokinase 2 (HK2), which helps to facilitate the first step of glycolysis, and Glucose transporter 1 (GLUT1), which transports glucose in colon cells.

They measured m6A levels of HK2 and GLUT1 by MeRIP-qPCR and found that the gene expression had vastly increased in the presence of METTL3. This result suggests that METTL3 activates and stabilizes these two genes by m6A methylation, driving glycolysis in CRC tissues, leading to disease progression.

Correlation between METTL3 expression and HK2 & GLUT1 in CRC tissues

Correlation between METTL3 expression and HK2 IHC scores (left) and GLUT1 IHC scores (right) in CRC tissues of Cohort 2.

The role of m6a methylation in CRC development is still not well known. This study offers valuable insight into how METTL3, an RNA methyltransferase, can potentially highjack a cell’s existing metabolic function, allowing for cancer progression. Further research is needed to hopefully target these pathways in order to develop potential treatments and therapies for CRC.

Source
Shen, C. et al. (2020) m6A-dependent glycolysis enhances colorectal cancer progression., Mol Cancer 19, 72.

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