LncRNA CARMN m6A demethylation by ALKBH5 inhibits mutant p53‐driven tumour progression through miR‐5683/FGF2

• Published in: Clinical and translational medicine 2024-07, Vol.14 (7), p.e1777-n/a
• Main Authors: Liu, Nannan, Jiang, Xinxiu, Zhang, Ge, Long, Shuaiyu, Li, Jiehan, Jiang, Meimei, Jia, Guiyun, Sun, Renyuan, Zhang, Lingling, Zhang, Yingjie
• Format: Article
• Language: English
• Subjects: Adenosine - analogs & derivatives; Adenosine - genetics; Adenosine - metabolism; AlkB Homolog 5, RNA Demethylase - genetics; AlkB Homolog 5, RNA Demethylase - metabolism; ALKBH5; Animals; Atherosclerosis; CARMN; Cell Line, Tumor; Colorectal cancer; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Demethylation; Disease Progression; FGF2; Gene amplification; Gene Expression Regulation, Neoplastic; Genomes; Humans; Infrared imaging systems; Mice; Mice, Nude; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miR‐5683; mutant TP53; Mutation; Neuroblastoma; Proteins; Rectum; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Smooth muscle; Software; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 2001-1326; 2001-1326
• DOI: 10.1002/ctm2.1777

N‐methyladenosine (m6A) represents a prevalent RNA modification observed in colorectal cancer. Despite its abundance, the biological implications of m6A methylation on the lncRNA CARMN remain elusive in colorectal cancer, especially for mutant p53 gain‐of‐function. Here, we elucidate that CARMN exhibits diminished expression levels in colorectal cancer patients with mutant p53, attributed to its rich m6A methylation, which promotes cancer proliferation, invasion and metastasis in vitro and in vivo. Further investigation illustrates that ALKBH5 acts as a direct demethylase of CARMN, targeting 477 methylation sites, thereby preserving CARMN expression. However, the interaction of mutant p53 with the ALKBH5 promoter impedes its transcription, enhancing m6A methylation levels on CARMN. Subsequently, YTHDF2/YTHDF3 recognise and degrade m6A‐modified CARMN. Concurrently, overexpressing CARMN significantly suppressed colorectal cancer progression in vitro and in vivo. Additionally, miR‐5683 was identified as a direct downstream target of lncRNA CARMN, exerting an antitumour effect by cooperatively downregulating FGF2 expression. Our findings revealed the regulator and functional mechanism of CARMN in colorectal cancer with mutant p53, potentially offering insights into demethylation‐based strategies for cancer diagnosis and therapy. The m6A methylation of CARMN that is prime for mutant p53 gain‐of‐function‐induced malignant progression of colorectal cancer, identifying a promising approach for cancer therapy. CARMN was downregulated by mutant p53 through ALKBH5. Mutant p53 transcriptionally decreased the expression of ALKBH5 by binding to its promoter. CARMN collaborates with miR‐5683 to downregulate FGF2 and induce autophagy. CARMN suppressed colon cancer growth in vivo and could be used as a potential tumour inhibitor.