{"title":"p53 induces circFRMD4A to suppress cancer development through glycolytic reprogramming and cuproptosis","authors":"Quan Liao, Jun Deng, Jing Tong, Yu Gan, Weiwei Hong, Hanzhi Dong, Mingming Cao, Chen Xiong, Yajie Chen, Bangxiang Xie, Fu-Ying Yang, Aikede Alifu, Guang-Biao Zhou, Shenglin Huang, Jianping Xiong, Qian Hao, Xiang Zhou","doi":"10.1016/j.molcel.2024.11.013","DOIUrl":null,"url":null,"abstract":"Cuproptosis is a type of copper-induced cell death that mainly impacts cells relying on mitochondrial metabolism. Although p53 regulates glycolytic metabolism, its role in cuproptosis remains unclear. Here, we report that the circular RNA, circFRMD4A, is crucial for p53-mediated metabolic reprogramming and cuproptosis. CircFRMD4A originates from the transcript of <em>FRMD4A</em>, which is transcriptionally activated by p53, and the formation of circFRMD4A is facilitated by the RNA-binding protein EWSR1. CircFRMD4A functions as a tumor suppressor and enhances the sensitivity of cancer cells to elesclomol-induced cuproptosis. Mechanistic analysis reveals that circFRMD4A interacts with and inactivates the pyruvate kinase PKM2, leading to a decrease in lactate production and a redirection of glycolytic flux toward the tricarboxylic acid cycle. Finally, p53 agonists and elesclomol coordinately suppress the growth of cancer in a xenograft mouse model. Altogether, our study uncovers that p53 promotes glycolytic reprogramming and cuproptosis via circFRMD4A and suggests a potential combination strategy against cancers with wild-type p53.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"5 1","pages":""},"PeriodicalIF":14.5000,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Cell","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.molcel.2024.11.013","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Cuproptosis is a type of copper-induced cell death that mainly impacts cells relying on mitochondrial metabolism. Although p53 regulates glycolytic metabolism, its role in cuproptosis remains unclear. Here, we report that the circular RNA, circFRMD4A, is crucial for p53-mediated metabolic reprogramming and cuproptosis. CircFRMD4A originates from the transcript of FRMD4A, which is transcriptionally activated by p53, and the formation of circFRMD4A is facilitated by the RNA-binding protein EWSR1. CircFRMD4A functions as a tumor suppressor and enhances the sensitivity of cancer cells to elesclomol-induced cuproptosis. Mechanistic analysis reveals that circFRMD4A interacts with and inactivates the pyruvate kinase PKM2, leading to a decrease in lactate production and a redirection of glycolytic flux toward the tricarboxylic acid cycle. Finally, p53 agonists and elesclomol coordinately suppress the growth of cancer in a xenograft mouse model. Altogether, our study uncovers that p53 promotes glycolytic reprogramming and cuproptosis via circFRMD4A and suggests a potential combination strategy against cancers with wild-type p53.
期刊介绍:
Molecular Cell is a companion to Cell, the leading journal of biology and the highest-impact journal in the world. Launched in December 1997 and published monthly. Molecular Cell is dedicated to publishing cutting-edge research in molecular biology, focusing on fundamental cellular processes. The journal encompasses a wide range of topics, including DNA replication, recombination, and repair; Chromatin biology and genome organization; Transcription; RNA processing and decay; Non-coding RNA function; Translation; Protein folding, modification, and quality control; Signal transduction pathways; Cell cycle and checkpoints; Cell death; Autophagy; Metabolism.