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.

中文翻译：

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p53 诱导 circFRMD4A 通过糖酵解重编程和 cuproptosis 抑制癌症发展


铜矿病是一种铜诱导的细胞死亡，主要影响依赖于线粒体代谢的细胞。尽管 p53 调节糖酵解代谢，但其在 cupropsis 中的作用仍不清楚。在这里，我们报道了环状 RNA circFRMD4A 对 p53 介导的代谢重编程和 cuproptosis 至关重要。CircFRMD4A 来源于 FRMD4A 的转录本，该转录本由 p53 转录激活，并且 RNA 结合蛋白 EWSR1 促进 circFRMD4A 的形成。CircFRMD4A 起肿瘤抑制因子的作用，增强癌细胞对电氯醇诱导的 cuproptosis 的敏感性。机制分析表明，circFRMD4A 与丙酮酸激酶 PKM2 相互作用并使其失活，导致乳酸产生减少，糖酵解通量重新定向到三羧酸循环。最后，p53 激动剂和 elesclomol 在异种移植小鼠模型中协调抑制癌症的生长。总而言之，我们的研究发现 p53 通过 circFRMD4A 促进糖酵解重编程和糖酵解重编程，并提出了一种针对野生型 p53 癌症的潜在联合策略。