p53基因突变在结肠癌中的频率约为40-50%。目前正开发各种治疗方法以针对表达突变p53的肿瘤。然而，针对表达野生型p53的结肠癌的潜在治疗靶点很少。在本研究中，我们展示了METTL14仅在表达p53野生型（p53-WT）的结肠癌细胞中受到野生型p53的转录激活并抑制肿瘤生长。METTL14的缺失会促进METTL14肠上皮细胞特异性敲除的小鼠模型中的AOM/DSS和AOM诱导的结肠癌生长。此外，METTL14通过有选择地促进m6A-YTHDF2依赖pri-miR-6769b/pri-miR-499a的处理，抑制p53-WT结肠癌的有氧酵解作用，从而通过抑制SLC2A3和PGAM1的表达来限制。生物合成成熟的miR-6769b-3p和miR-499a-3p分别降低SLC2A3和PGAM1的水平，并抑制恶性表型。临床上，METTL14仅作为p53-WT结肠癌患者总体生存的有益预后因素。这些结果揭示了METTL14在肿瘤中的失活的新机制，并且最重要的是，揭示了METTL14的激活是p53依赖性癌症生长抑制的关键机制，可用于治疗p53-WT结肠癌。©2023作者。根据CC BY 4.0许可证发表。

The frequency of p53 mutations in colorectal cancer (CRC) is approximately 40-50%. A variety of therapies are being developed to target tumors expressing mutant p53. However, potential therapeutic targets for CRC expressing wild-type p53 are rare. In this study, we show that METTL14 is transcriptionally activated by wild-type p53 and suppresses tumor growth only in p53-wild-type (p53-WT) CRC cells. METTL14 deletion promotes both AOM/DSS and AOM-induced CRC growth in mouse models with the intestinal epithelial cell-specific knockout of METTL14. Additionally, METTL14 restrains aerobic glycolysis in p53-WT CRC, by repressing SLC2A3 and PGAM1 expression via selectively promoting m6 A-YTHDF2-dependent pri-miR-6769b/pri-miR-499a processing. Biosynthetic mature miR-6769b-3p and miR-499a-3p decrease SLC2A3 and PGAM1 levels, respectively, and suppress malignant phenotypes. Clinically, METTL14 only acts as a beneficial prognosis factor for the overall survival of p53-WT CRC patients. These results uncover a new mechanism for METTL14 inactivation in tumors and, most importantly, reveal that the activation of METTL14 is a critical mechanism for p53-dependent cancer growth inhibition, which could be targeted for therapy in p53-WT CRC.© 2023 The Authors. Published under the terms of the CC BY 4.0 license.