METTL16‐mediated N6‐methyladenosine modification of Soga1 enables proper chromosome segregation and chromosomal stability in colorectal cancer

Abstract N6‐methyladenosine (m6A) is the most prevalent internal modification in mammalian messenger RNAs and is associated with numerous biological processes. However, its role in chromosomal instability remains to be established. Here, we report that an RNA m6A methyltransferase, METTL16, plays an indispensable role in the progression of chromosome segregation and is required to preserve chromosome stability in colorectal cancer (CRC) cells. Depletion or inhibition of the methyltransferase activity of METTL16 results in abnormal kinetochore‐microtubule attachment during mitosis, leading to delayed mitosis, lagging chromosomes, chromosome mis‐segregation and chromosomal instability. Mechanistically, METTL16 exerts its oncogenic effects by enhancing the expression of suppressor of glucose by autophagy 1 ( Soga1 ) in an m6A‐dependent manner. CDK1 phosphorylates Soga1, thereby triggering its direct interaction with the polo box domain of PLK1. This interaction facilitates PLK1 activation and promotes mitotic progression. Therefore, targeting the METTL16‐Soga1 pathway may provide a potential treatment strategy against CRC because of its essential role in maintaining chromosomal stability.