The acetate/ACSS2 switch regulates HIF-2 stress signaling in the tumor cell microenvironment.
The acetate/ACSS2 switch regulates HIF-2 stress signaling in the tumor cell microenvironment.
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DOI：
10.1371/journal.pone.0116515
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发表时间：
2015
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 JS;Hogg RT;Das A;Gerard RD;Garcia JA
缺氧诱导因子2(HIF-2)在低氧状态或低氧时的最佳应激信号需要特定的辅活化子/赖氨酸乙酰转移酶、CREB结合蛋白(CBP)和特定的脱乙酰酶Sirtuin 1(SIRT1)的耦合作用。我们最近报道，CBP对HIF-2的乙酰化还需要一个特定的乙酰辅酶A生成器，即乙酸酯依赖的乙酰辅酶A合成酶2(ACSS2)。在这项研究中，我们证明ACSS2/HIF-2信号不仅在缺氧时活跃，而且在缺糖时也是活跃的。醋酸盐水平在应激过程中升高，并与最大的低氧诱导因子-2α乙酰化和α/低氧诱导因子-2复合体的形成相一致。外源性醋酸酯可诱导缺氧诱导因子-2α乙酰化、α/缺氧诱导因子-2复合体形成和信号转导。ACSS2和HIF-2是在应激过程中最大限度的克隆形成、增殖、迁移和侵袭所必需的。醋酸盐还以ACSS2和HIF-2依赖的方式刺激小鼠侧翼肿瘤的生长和转移。因此，ACSS2/CBP/SIRT1/HIF-2信号将营养感知和应激信号与哺乳动物的癌症生长和进展联系起来。
Optimal stress signaling by Hypoxia Inducible Factor 2 (HIF-2) during low oxygen states or hypoxia requires coupled actions of a specific coactivator/lysine acetyltransferase, Creb binding protein (CBP), and a specific deacetylase, Sirtuin 1 (SIRT1). We recently reported that acetylation of HIF-2 by CBP also requires a specific acetyl CoA generator, acetate-dependent acetyl CoA synthetase 2 (ACSS2). In this study, we demonstrate that ACSS2/HIF-2 signaling is active not only during hypoxia, but also during glucose deprivation. Acetate levels increase during stress and coincide with maximal HIF-2α acetylation and CBP/HIF-2α complex formation. Exogenous acetate induces HIF-2α acetylation, CBP/HIF-2α complex formation, and HIF-2 signaling. ACSS2 and HIF-2 are required for maximal colony formation, proliferation, migration, and invasion during stress. Acetate also stimulates flank tumor growth and metastasis in mice in an ACSS2 and HIF-2 dependent manner. Thus, ACSS2/CBP/SIRT1/HIF-2 signaling links nutrient sensing and stress signaling with cancer growth and progression in mammals.
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影响因子：
3.8
作者：
Knowles HJ;Schaefer KL;Dirksen U;Athanasou NA
通讯作者：
Athanasou NA
影响因子：
9.7
作者：
Vordermark, D;Kraft, P;Flentje, M
通讯作者：
Flentje, M
影响因子：
64.8
作者：
Metallo, Christian M.;Gameiro, Paulo A.;Bell, Eric L.;Mattaini, Katherine R.;Yang, Juanjuan;Hiller, Karsten;Jewell, Christopher M.;Johnson, Zachary R.;Irvine, Darrell J.;Guarente, Leonard;Kelleher, Joanne K.;Vander Heiden, Matthew G.;Iliopoulos, Othon;Stephanopoulos, Gregory
通讯作者：
Stephanopoulos, Gregory
DOI：
10.1124/jpet.105.087536
发表时间：
2005-10-01
影响因子：
3.5
作者：
Mathew, R;Arun, P;Namboodiri, MAA
通讯作者：
Namboodiri, MAA
影响因子：
4.7
作者：
Salnikow, Konstantin;Aprelikova, Olga;Niederhuber, John
通讯作者：
Niederhuber, John