Metabolic reprogramming is a hallmark of cancer. Herein we discover that the key glycolytic enzyme pyruvate kinase M2 isoform (PKM2), but not the related isoform PKM1, is methylated by co-activator-associated arginine methyltransferase 1 (CARM1). PKM2 methylation reversibly shifts the balance of metabolism from oxidative phosphorylation to aerobic glycolysis in breast cancer cells. Oxidative phosphorylation depends on mitochondrial calcium concentration, which becomes critical for cancer cell survival when PKM2 methylation is blocked. By interacting with and suppressing the expression of inositol-1,4,5-trisphosphate receptors (InsP₃Rs), methylated PKM2 inhibits the influx of calcium from the endoplasmic reticulum to mitochondria. Inhibiting PKM2 methylation with a competitive peptide delivered by nanoparticles perturbs the metabolic energy balance in cancer cells, leading to a decrease in cell proliferation, migration and metastasis. Collectively, the CARM1-PKM2 axis serves as a metabolic reprogramming mechanism in tumorigenesis, and inhibiting PKM2 methylation generates metabolic vulnerability to InsP₃R-dependent mitochondrial functions.

中文翻译：

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CARM1引起的PKM2甲基化激活有氧糖酵解，从而促进肿瘤发生。

代谢重编程是癌症的标志。在这里，我们发现关键的糖酵解酶丙酮酸激酶M2亚型（PKM2），而不是相关的亚型PKM1，被共激活因子相关的精氨酸甲基转移酶1（CARM1）甲基化。PKM2甲基化可逆地将乳腺癌细胞中新陈代谢的平衡从氧化磷酸化转变为有氧糖酵解。氧化磷酸化取决于线粒体钙浓度，当PKM2甲基化被阻断时，线粒体钙浓度对癌细胞的存活至关重要。通过与肌醇-1,4,5-_三三磷酸受体相互作用并抑制其表达（InsP ₃Rs），甲基化的PKM2抑制钙从内质网向线粒体的流入。用纳米颗粒递送的竞争性肽抑制PKM2甲基化会扰乱癌细胞中的代谢能平衡，从而导致细胞增殖，迁移和转移的减少。总的来说，CARM1-PKM2轴是肿瘤发生过程中的代谢重编程机制，抑制PKM2甲基化会产生对InsP ₃ R依赖的线粒体功能的代谢脆弱性。