The enhanced genomic 6\u2009mA metabolism contributes to the proliferation and migration of TSCC cells

Lei Xi,Ying Xu,Xiyang Liu,Fangming Zhang,Zhenxi Zhang,Ying Yang,Jinghui Li,Quan Du

doi:10.1038/s41368-022-00161-9

Abstract

In contrast to the well-established genomic 5-methylcytosine (5mC), the existence of N6-methyladenine (6 mA) in eukaryotic genomes was discovered only recently. Initial studies found that it was actively regulated in cancer cells, suggesting its involvement in the process of carcinogenesis. However, the contribution of 6 mA in tongue squamous cell carcinoma (TSCC) still remains uncharacterized. In this study, a pan-cancer type analysis was first performed, which revealed enhanced 6 mA metabolism in diverse cancer types. The study was then focused on the regulation of 6 mA metabolism, as well as its effects on TSCC cells. To these aspects, genome 6 mA level was found greatly increased in TSCC tissues and cultured cells. By knocking down 6 mA methylases N6AMT1 and METTL4, the level of genomic 6 mA was decreased in TSCC cells. This led to suppressed colony formation and cell migration. By contrast, knockdown of 6 mA demethylase ALKBH1 resulted in an increased 6 mA level, enhanced colony formation, and cell migration. Further study suggested that regulation of the NF-κB pathway might contribute to the enhanced migration of TSCC cells. Therefore, in the case of TSCC, we have shown that genomic 6 mA modification is involved in the proliferation and migration of cancer cells.

Highlights

In eukaryotic genomes, there are two forms of DNA methylation that have been characterized so far, namely 5-methylcytosine (5mC) and N6-methyladenine (6 mA)
(3) When 6 mA levels of the in vitro cultured cancer cells were examined, a great increase of 646fold was revealed relative to the cancer tissues; while the increase was only 3.72-fold for 5mC levels
The enhanced 6 mA metabolism in diverse cancer types As an essential epigenetic process, genomic DNA metabolism consists of DNA methylation and demethylation

Summary

Introduction

There are two forms of DNA methylation that have been characterized so far, namely 5-methylcytosine (5mC) and N6-methyladenine (6 mA). In contrast to the wellestablished 5mC methylation, exist of 6 mA methylation was only recently revealed in eukaryotic genomes including Drosophila, Caenorhabditis elegans, Chlamydomonas, plants, and mammals.[1,2,3,4,5,6,7,8] As an aspect of the 6 mA study, its metabolic processes including methylation and demethylation were investigated This led to the characterization of two 6 mA methylases (N6AMT1, METTL4) and one demethylase (ALKBH1).[5,8,9] METTL4 was a recently identified 6 mA metabolic enzyme, which was independently characterized by Kweon[9] and our group.[10]. These suggest the active roles of this novel epigenetic modification in the process of carcinogenesis

Methods

Results

Conclusion