Regulation of telomere homeostasis and genomic stability in cancer by N(6)-adenosine methylation (m(6)A)

The role of RNA methylation on N(6)-adenosine (m(6)A) in cancer has been acknowledged, but the underlying mechanisms remain obscure. Here, we identified homeobox containing 1 (HMBOX1) as an authentic target mRNA of m(6)A machinery, which is highly methylated in malignant cells compared to the normal counterparts and subject to expedited degradation upon the modification. m(6)A-mediated down-regulation of HMBOX1 causes telomere dysfunction and inactivation of p53 signaling, which leads to chromosome abnormalities and aggressive phenotypes. CRISPR-based, m(6)A-editing tools further prove that the methyl groups on HMBOX1 per se contribute to the generation of altered cancer genome. In multiple types of human cancers, expression of the RNA methyltransferase METTL3 is negatively correlated with the telomere length but favorably with fractions of altered cancer genome, whereas HMBOX1 mRNA levels show the opposite patterns. Our work suggests that the cancer-driving genomic alterations may potentially be fixed by rectifying particular epitranscriptomic program.