Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation.
Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation.
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DOI：
10.1016/j.cmet.2014.06.004
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发表时间：
2014-08-05
期刊：
影响因子：
29
通讯作者：
Wellen KE
中科院分区：
文献类型：
--
作者：
Lee JV;Carrer A;Shah S;Snyder NW;Wei S;Venneti S;Worth AJ;Yuan ZF;Lim HW;Liu S;Jackson E;Aiello NM;Haas NB;Rebbeck TR;Judkins A;Won KJ;Chodosh LA;Garcia BA;Stanger BZ;Feldman MD;Blair IA;Wellen KE
组蛋白乙酰化在基因调控、DNA复制和DNA损伤反应中发挥重要作用，但在肿瘤中经常被失调。我们假设肿瘤细胞组蛋白乙酰化水平部分取决于致癌代谢重编程介导的乙酰辅酶A可用性的变化。在这里，我们证明，乙酰辅酶A是动态调节的葡萄糖在癌细胞中的可用性和乙酰辅酶A的比例：辅酶A在细胞核内调节全球组蛋白乙酰化水平。在体内，致癌Kras或Akt的表达刺激组蛋白乙酰化变化，这先于肿瘤发展。此外，我们发现Akt对组蛋白乙酰化的影响是通过代谢酶ATP-柠檬酸裂解酶（ACLY）介导的，并且pAkt（Ser 473）水平与人类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。这些数据暗示乙酰辅酶A代谢是癌细胞中组蛋白乙酰化水平的关键决定因素。
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-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 (ACLY), 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.
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DOI：
10.1038/nrclinonc.2013.42
发表时间：
2013-05
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
通讯作者：
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影响因子：
64.8
作者：
Lu, Chao;Ward, Patrick S.;Kapoor, Gurpreet S.;Rohle, Dan;Turcan, Sevin;Abdel-Wahab, Omar;Edwards, Christopher R.;Khanin, Raya;Figueroa, Maria E.;Melnick, Ari;Wellen, Kathryn E.;O'Rourke, Donald M.;Berger, Shelley L.;Chan, Timothy A.;Levine, Ross L.;Mellinghoff, Ingo K.;Thompson, Craig B.
通讯作者：
Thompson, Craig B.
Warburg效应决定了丁酸酯介导的组蛋白乙酰化和细胞增殖的机制。
影响因子：
16
作者：
Donohoe, Dallas R.;Collins, Leonard B.;Wali, Aminah;Bigler, Rebecca;Sun, Wei;Bultman, Scott J.
通讯作者：
Bultman, Scott J.
影响因子：
64.5
作者：
Kaelin WG Jr;McKnight SL
通讯作者：
McKnight SL
影响因子：
4.8
作者：
Gunther, EJ;Belka, GK;Chodosh, LA
通讯作者：
Chodosh, LA