PKM2 methylation by CARM1 activates aerobic glycolysis to promote tumorigenesis.
PKM2 methylation by CARM1 activates aerobic glycolysis to promote tumorigenesis.
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DOI：
10.1038/ncb3630
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发表时间：
2017-11
影响因子：
21.3
通讯作者：
Xu W
中科院分区：
文献类型：
--
作者：
Liu F;Ma F;Wang Y;Hao L;Zeng H;Jia C;Wang Y;Liu P;Ong IM;Li B;Chen G;Jiang J;Gong S;Li L;Xu W
新陈代谢重新编程是癌症的一个标志。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，是由共激活物相关的精氨酸甲基转移酶1(CARM1)甲基化的。在乳腺癌细胞中，PKM2甲基化可逆地将代谢平衡从氧化磷酸化转变为有氧糖酵解。氧化磷酸化依赖于线粒体钙浓度，当PKM2甲基化被阻断时，线粒体钙浓度对癌细胞的生存至关重要。甲基化的PKM2通过与肌醇1，4，5-三磷酸受体(IP3Rs)相互作用并抑制其表达，抑制内质网(ER)向线粒体的钙内流。通过纳米颗粒传递的竞争性多肽抑制PKM2甲基化，扰乱癌细胞的代谢能量平衡，导致细胞增殖、迁移和转移减少。总体而言，CARM1-PKM2轴在肿瘤发生中作为代谢重编程机制，抑制PKM2甲基化产生依赖IP3R的线粒体功能的代谢脆弱性。
Metabolic reprogramming is a hallmark of cancer. Herein we discovered 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 mitochondria 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 (IP3Rs), methylated PKM2 inhibits the influx of calcium from endoplasmic reticulum (ER) to mitochondria. Inhibiting PKM2 methylation with a competitive peptide delivered by nanoparticle perturbs metabolic energy balance in cancer cells, leading to decrease of 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 IP3R-dependent mitochondrial functions.
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DOI：
10.1126/science.1211485
发表时间：
2011-12-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Anastasiou D;Poulogiannis G;Asara JM;Boxer MB;Jiang JK;Shen M;Bellinger G;Sasaki AT;Locasale JW;Auld DS;Thomas CJ;Vander Heiden MG;Cantley LC
通讯作者：
Cantley LC
影响因子：
2.6
作者：
Cheng H;Qin Y;Fan H;Su P;Zhang X;Zhang H;Zhou G
通讯作者：
Zhou G
影响因子：
64.5
作者：
Cárdenas C;Miller RA;Smith I;Bui T;Molgó J;Müller M;Vais H;Cheung KH;Yang J;Parker I;Thompson CB;Birnbaum MJ;Hallows KR;Foskett JK
通讯作者：
Foskett JK
影响因子：
14.9
作者：
Haug K;Salek RM;Conesa P;Hastings J;de Matos P;Rijnbeek M;Mahendraker T;Williams M;Neumann S;Rocca-Serra P;Maguire E;González-Beltrán A;Sansone SA;Griffin JL;Steinbeck C
通讯作者：
Steinbeck C
影响因子：
10.5
作者：
Guo, Jessie Yanxiang;Chen, Hsin-Yi;White, Eileen
通讯作者：
White, Eileen