Lee Joyce V, Carrer Alessandro, Shah Supriya, Snyder Nathaniel W, Wei Shuanzeng, Venneti Sriram, Worth Andrew J, Yuan Zuo-Fei, Lim Hee-Woong, Liu Shichong, Jackson Ellen, Aiello Nicole M, Haas Naomi B, Rebbeck Timothy R, Judkins Alexander, Won Kyoung-Jae, Chodosh Lewis A, Garcia Benjamin A, Stanger Ben Z, Feldman Michael D, Blair Ian A, Wellen Kathryn E
Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.
Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.
Cell Metab. 2014 Aug 5;20(2):306-319. doi: 10.1016/j.cmet.2014.06.004. Epub 2014 Jul 3.
Histone acetylation plays important roles in gene regulation, DNA replication, and the response to DNA damage, and it is frequently deregulated in tumors. We postulated that tumor cell histone acetylation levels are determined in part by changes in acetyl coenzyme A (acetyl-CoA) availability mediated by oncogenic metabolic reprogramming. Here, we demonstrate that acetyl-CoA is dynamically regulated by glucose availability in cancer cells and that the ratio of acetyl-CoA:coenzyme A within the nucleus modulates global histone acetylation levels. In vivo, expression of oncogenic Kras or Akt stimulates histone acetylation changes that precede tumor development. Furthermore, we show that Akt's effects on histone acetylation are mediated through the metabolic enzyme ATP-citrate lyase and that pAkt(Ser473) levels correlate significantly with histone acetylation marks in human gliomas and prostate tumors. The data implicate acetyl-CoA metabolism as a key determinant of histone acetylation levels in cancer cells.
组蛋白乙酰化在基因调控、DNA复制以及对DNA损伤的反应中发挥着重要作用，并且在肿瘤中常常失调。我们推测肿瘤细胞的组蛋白乙酰化水平部分由致癌代谢重编程介导的乙酰辅酶A（acetyl-CoA）可用性变化所决定。在此，我们证明癌细胞中乙酰辅酶A受葡萄糖可用性动态调控，并且细胞核内乙酰辅酶A与辅酶A的比例调节整体组蛋白乙酰化水平。在体内，致癌性Kras或Akt的表达会刺激肿瘤发生之前的组蛋白乙酰化变化。此外，我们表明Akt对组蛋白乙酰化的作用是通过代谢酶ATP-柠檬酸裂解酶介导的，并且pAkt(Ser473)水平与人神经胶质瘤和前列腺肿瘤中的组蛋白乙酰化标记显著相关。这些数据表明乙酰辅酶A代谢是癌细胞中组蛋白乙酰化水平的关键决定因素。
