N⁶ -methyladenosine Steers RNA Metabolism and Regulation in Cancer

As one of the most studied ribonucleic acid (RNA) modifications in eukaryotes, N⁶ -methyladenosine (m⁶ A) has been shown to play a predominant role in controlling gene expression and influence physiological and pathological processes such as oncogenesis and tumor progression. Writer and eraser proteins, acting opposite to deposit and remove m⁶ A epigenetic marks, respectively, shape the cellular m⁶ A landscape, while reader proteins preferentially recognize m⁶ A modifications and mediate fate decision of the methylated RNAs, including RNA synthesis, splicing, exportation, translation, and stability. Therefore, RNA metabolism in cells is greatly influenced by these three classes of m⁶ A regulators. Aberrant expression of m⁶ A regulators has been widely reported in various types of cancer, leading to cancer initiation, progression, and drug resistance. The close links between m⁶ A and cancer shed light on the potential use of m⁶ A methylation and its regulators as prognostic biomarkers and drug targets for cancer therapy. Given the notable effects of m⁶ A in reversing chemoresistance and enhancing immune therapy, it is a promising target for combined therapy. Herein, we summarize the recent discoveries on m⁶ A and its regulators, emphasizing their influences on RNA metabolism, their dysregulation and impacts in diverse malignancies, and discuss the clinical implications of m⁶ A modification in cancer.