Coordinate regulation of stress signaling and epigenetic events by Acss2 and HIF-2 in cancer cells.
Coordinate regulation of stress signaling and epigenetic events by Acss2 and HIF-2 in cancer cells.
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DOI：
10.1371/journal.pone.0190241
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Garcia JA
中科院分区：
文献类型：
--
作者：
Chen R;Xu M;Nagati J;Garcia JA
癌细胞在恶劣的肿瘤微环境中生存，以缺氧和葡萄糖为特征，需要快速启动细胞保护措施。应激过程中代谢水平变化的代谢物是理想的信号线索，特别是用于应激反应信号转导的翻译后修饰。在缺氧或葡萄糖缺乏的癌细胞中，细胞内醋酸盐水平增加，醋酸盐是依赖于醋酸的乙酰辅酶a合成酶2 （Acss2）的底物，它也刺激Acss2从细胞质转移到细胞核。Acss2在细胞核内，而不是细胞质内，通过乙酰转移酶/辅激活因子Creb结合蛋白（Cbp）促进应激反应性缺氧诱导因子2α (HIF-2α)亚基的乙酰化，这一过程促进了稳定的Cbp/HIF-2α复合物的形成。除了促进从头转录外，Cbp和HIF-2α还共同调节局部组蛋白3表观遗传标记。在细胞培养和小鼠模型中，外源性乙酸增加了Acss2/HIF-2依赖性肿瘤的生长和转移。因此，哺乳动物体内的醋酸盐开关将营养摄入和应激信号与肿瘤生长和转移联系起来。
Survival of cancer cells in the harsh tumor microenvironment, characterized by oxygen and glucose deprivation, requires rapid initiation of cytoprotective measures. Metabolites whose levels change during stress are ideal signaling cues, particularly if used in post-translational modifications of stress-responsive signal transducers. In cancer cells exposed to oxygen or glucose deprivation, there is an increase in cellular levels of acetate, a substrate for acetate-dependent acetyl CoA synthetase 2 (Acss2) that also stimulates translocation of Acss2 from the cytosol to the nucleus. Nuclear, but not cytosolic, Acss2 promotes acetylation of the stress-responsive Hypoxia Inducible Factor 2α (HIF-2α) subunit by the acetyltransferase/coactivator Creb binding protein (Cbp), a process that facilitates stable Cbp/HIF-2α complex formation. In addition to promoting de novo transcription, Cbp and HIF-2α act in concert to regulate local histone 3 epigenetic marks. Exogenous acetate augments Acss2/HIF-2 dependent cancer growth and metastasis in cell culture and mouse models. Thus, an acetate switch in mammals links nutrient intake and stress signaling with tumor growth and metastasis.
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DOI：
10.1074/jbc.m901790200
发表时间：
2009-06-19
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Mole DR;Blancher C;Copley RR;Pollard PJ;Gleadle JM;Ragoussis J;Ratcliffe PJ
通讯作者：
Ratcliffe PJ
影响因子：
3.6
作者：
Chan CH;Garrity J;Crosby HA;Escalante-Semerena JC
通讯作者：
Escalante-Semerena JC
影响因子：
3.7
作者：
Chen R;Xu M;Nagati JS;Hogg RT;Das A;Gerard RD;Garcia JA
通讯作者：
Garcia JA
影响因子：
64.8
作者：
Mews P;Donahue G;Drake AM;Luczak V;Abel T;Berger SL
通讯作者：
Berger SL
影响因子：
3.2
作者：
Albaugh, Brittany N.;Arnold, Kevin M.;Denu, John M.
通讯作者：
Denu, John M.