m6A modification regulates cell proliferation via reprogramming the balance between glycolysis and pentose phosphate pathway

Abstract

Abstract N6-methyladenosine (m6A) stands as the predominant modification in eukaryotic mRNA and is involved in various biological functions. Aberrant m6A has been implicated in abnormal cellular phenotypes, including defects in stem cell differentiation and tumorigenesis. However, the precise effects of m6A on cell proliferation and the underlining mechanism of metabolic gene regulation remain incompletely understood. Here, we established a cellular environment with low-m6A levels and observed a severe impairment of cell proliferation. Mechanistic studies revealed that the depletion of m6A on TIGAR mRNA led to increased expression, subsequently inhibiting glycolysis while promoting the pentose phosphate pathway (PPP). A genome-wide CRISPR-Cas9 screen identified numerous genes involved in cell proliferation that are sensitive to m6A modification, with G6PD emerging as a key regulator. Integration of gene expression and survival data from cancer patients suggested that patients with elevated G6PD expression may exhibit enhanced responsiveness to tumor growth inhibition through m6A suppression. Our findings elucidate the critical role of m6A in cell proliferation, highlighting the therapeutic potential of targeting m6A-mediated metabolic pathways in cancer.