METTL14 modulates glycolysis to inhibit colorectal tumorigenesis in p53‐wild‐type cells

Abstract

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 m6A‐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.

RNA methylation in inflammatory bowel disease

“…It has been identified both as a potential tumor suppressor, regulating mRNA modifications such as glycolysis genes related to cancer pathways, and as a factor that might promote CRC progression. 57 The dual functionality of METTL14 underscores the intricacies of its involvement in these distinct gastrointestinal conditions, 27,57,58 and further research is essential to unravel the precise mechanisms underlying its actions in IBD and CRC. Understanding the dual role of METTL14 provides valuable insights that can guide future investigations and therapeutic approaches for these complex diseases.…”

“…However, in the context of CRC, METTL14 exhibits a more complex role. It has been identified both as a potential tumor suppressor, regulating mRNA modifications such as glycolysis genes related to cancer pathways, and as a factor that might promote CRC progression 57 . The dual functionality of METTL14 underscores the intricacies of its involvement in these distinct gastrointestinal conditions, 27,57,58 and further research is essential to unravel the precise mechanisms underlying its actions in IBD and CRC.…”

Targeting RNA modifications with pharmacological agents: New frontiers in cancer therapy

“…The contrasting effects of METTL3 and METTL14 on CRC progression despite their complex formation and catalytic enhancement may be attributed to their preference for different targets, leading to diverse downstream pathways 8,71 . Moreover, the tumour‐suppressive role of METTL14 in p53‐wild‐type CRC cells, while not significantly affecting p53‐mutant or p53‐null CRC cells, highlights the influence of tumour heterogeneity on m6A regulators' roles 72 . The observed controversies can be attributed, at least partially, to this heterogeneity.…”

“… 8 , 71 Moreover, the tumour‐suppressive role of METTL14 in p53‐wild‐type CRC cells, while not significantly affecting p53‐mutant or p53‐null CRC cells, highlights the influence of tumour heterogeneity on m6A regulators' roles. 72 The observed controversies can be attributed, at least partially, to this heterogeneity. More examples of the complex roles of METTL3/METTL14 in diverse cancers are shown in Table 1 .…”

RNA modifications in cellular metabolism: implications for metabolism-targeted therapy and immunotherapy

“…In CRC, METTL14 repressed glycolysis via YTHDF2-dependent processing of pri-miR-6769b and pri-miR-499a, which attenuated SLC2A3 and PGAM1 expression, respectively. 231 In HCC, METTL14 stabilizes USP48 mRNA, which mediated deubiquitination at the K33 and K128 sites of SIRT6, thus hindered glycolytic reprogramming. 232 In RCC, METTL14 attenuated stability of BPTF mRNA, which constituted super-enhancers that activated downstream glycolysis-related genes like ENO2 and SRC.…”