Methyl CpG binding protein 2 promotes colorectal cancer metastasis by regulating N⁶-methyladenosine methylation through methyltransferase-like 14

RNA N-6-methyladenosine (m(6)A) is an emerging regulatory mechanism for tumor progression in several types of cancer. However, the underlying regulation mechanisms of m(6)A methylation in colorectal cancer (CRC) remain unknown. Although the oncogenic function of methyl CpG binding protein 2 (MeCP2) has been reported, it is still unclear whether MeCP2 could alter RNA m(6)A methylation state. Here, we systematically identified MeCP2 as a prometastasis gene to regulate m(6)A methylation in CRC. Interestingly, MeCP2 could bind to methyltransferase-like 14 (METTL14) to coregulate tumor suppressor Kruppel-like factor 4 (KLF4) expression through changing m(6)A methylation modification. Furthermore, insulin-like growth factor 2 mRNA-binding protein 2 recognized the unique modified m(6)A methylation sites to enhance KLF4 mRNA stability. Taken together, these findings highlight the novel function of MeCP2 for regulating m(6)A methylation and reveal the underlying molecular mechanism for the interaction between MeCP2 and METTL14, which offers a better understanding of CRC progression and metastasis.