Human cancer cells compensate the genes unfavorable for translation by N(6)-methyladenosine modification and enhance their translation efficiency

BACKGROUND: N(6)-methyladenosine (m(6)A) is the methylation of RNA adenosines that participates in multiple biological processes, such as facilitating translation of host genes via the reader protein YTHDF1. The core writer protein of m(6)A in humans is METTL3. METHODS: We utilized YTHDF1 target genes and normal or si-METTL3 NGS (next-generation sequencing) data from HeLa cells generated by a previous work and collected known human oncogenes from a website. We evaluated the translation capability of these m(6)A genes or oncogenes by comparing their mRNA lengths and codon usage bias. Additionally, we calculated the translation efficiency of all genes expressed in the normal or si-METTL3 HeLa cells using NGS data. RESULTS: The m(6)A genes are enriched in oncogenes compared to the non-m(6)A genes. We observed significantly longer mRNA lengths for the m(6)A genes, especially for the oncogenes. We also observed stronger codon usage bias for the m(6)A genes than for the non-m(6)A genes. We provided evidence that the longer mRNA lengths and stronger codon bias were unfavorable for translation. However, this disadvantage was compensated by m(6)A modification because the m(6)A genes but not the non-m(6)A genes showed higher translation efficiencies in normal cells than in si-METTL3 cells. CONCLUSIONS: HeLa cells compensate for genes unfavorable for translation by m(6)A modification and enhance their translation efficiency. This compensation could originally have been designed for oncogenes, since we observed enrichment of m(6)A genes in the oncogenes. If oncogenes modified by m(6)A obtain higher translation efficiencies and eventually facilitate cancer cell proliferation, then this strategy may be used by cancers for rapid cell growth.