LncRNA CARMN m6A Demethylation by ALKBH5 Inhibits Mutant p53-Driven Tumor Progression through miR-5683/FGF2

Abstract

N-methyladenosine (m6A) is the abundant RNA modification in colorectal cancer. However, the biological significance of m6A methylation of LncRNA CARMN remains unknown in colorectal cancer, especially for mutant p53 Gain-of-function. Here, we found that CARMN reduced in the colorectal cancer patients with mutant p53, due to its rich m6A methylation, which promotes cancer proliferation, invasion, and metastasis in vitro and in vivo. Deeper investigation illustrates that ALKBH5 directly demethylated m6A level of CARMN at 477 sites, which maintains CARMN with a higher expression level. However, mutant p53 binds to the promoter of ALKBH5 to prevent its transcription, results in the high level m6A methylation of CARMN, subsequently read by YTHDF2/YTHDF3 and degraded. Meantime, overexpressing CARMN significantly suppressed colorectal cancer progression in vitro and in vivo. In addition, miR-5683 was identified as a direct downstream target of LncRNA CARMN, which plays anti-tumor effect through cooperating with CARMN to down-regulate FGF2 expression. Our study revealed the regulator and functional mechanism of CARMN in colorectal cancer with mutant p53, which may highlight a demethylation-based approach for the diagnosis and therapy of cancer.