Acetyl-CoA promotes glioblastoma cell adhesion and migration through Ca(2+)-NFAT signaling.
Acetyl-CoA promotes glioblastoma cell adhesion and migration through Ca(2+)-NFAT signaling.
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DOI：
10.1101/gad.311027.117
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发表时间：
2018-04-01
影响因子：
10.5
通讯作者：
Wellen KE
中科院分区：
文献类型：
--
作者：
Lee JV;Berry CT;Kim K;Sen P;Kim T;Carrer A;Trefely S;Zhao S;Fernandez S;Barney LE;Schwartz AD;Peyton SR;Snyder NW;Berger SL;Freedman BD;Wellen KE
在这里，李等人。研究了乙酰辅酶A产生影响基因表达的分子机制以及乙酰辅酶A如何促进恶性表型。他们的研究结果表明，乙酰辅酶 A 可以以位点特异性方式增强 H3K27ac，并且细胞粘附基因的表达是由乙酰辅酶 A 部分通过 Ca2+-NFAT 信号传导的激活来驱动的。代谢物乙酰辅酶 A (乙酰-CoA) 是赖氨酸乙酰化所需的乙酰基供体，从而将代谢、信号传导和表观遗传学联系起来。营养物质的可用性会改变癌细胞中乙酰辅酶A的水平，与整体组蛋白乙酰化和基因表达的变化相关。然而，人们对乙酰辅酶A产生影响基因表达的具体分子机制及其在促进恶性表型中的功能作用知之甚少。在这里，使用组蛋白 H3 Lys27 乙酰化 (H3K27ac) ChIP-seq（染色质免疫沉淀 [ChIP] 与新一代测序相结合）并标准化为外源参考基因组 (ChIP-Rx)，我们发现乙酰辅酶 A 丰度的变化会触发 H3K27ac 的位点特异性调节，与基因表达相关，而不是统一相关。 在所有基因上调节这个标记。参与整合素信号传导和细胞粘附的基因在胶质母细胞瘤细胞中被鉴定为乙酰辅酶A反应性的，并且我们证明ATP柠檬酸裂解酶（ACLY）依赖性乙酰辅酶A的产生促进细胞迁移和粘附到细胞外基质。从机制上讲，转录因子 NFAT1（活化 T 细胞核因子 1）被发现可介导乙酰辅酶 A 依赖性基因调节和细胞粘附。这是通过调节 Ca2+ 信号而发生的，当乙酰辅酶 A 丰富时触发 NFAT1 核转位。因此，本研究的结果证实，乙酰辅酶 A 在特定位点影响 H3K27ac，与基因表达相关，并且细胞粘附基因的表达是由乙酰辅酶 A 部分通过激活 Ca2+-NFAT 信号传导来驱动的。
Here, Lee et al. investigated the molecular mechanisms by which acetyl-CoA production impacts gene expression and how acetyl-CoA promotes malignant phenotypes. Their findings show that acetyl-CoA can enhance H3K27ac in a locus-specific manner and that expression of cell adhesion genes is driven by acetyl-CoA in part through activation of Ca2+–NFAT signaling. The metabolite acetyl-coenzyme A (acetyl-CoA) is the required acetyl donor for lysine acetylation and thereby links metabolism, signaling, and epigenetics. Nutrient availability alters acetyl-CoA levels in cancer cells, correlating with changes in global histone acetylation and gene expression. However, the specific molecular mechanisms through which acetyl-CoA production impacts gene expression and its functional roles in promoting malignant phenotypes are poorly understood. Here, using histone H3 Lys27 acetylation (H3K27ac) ChIP-seq (chromatin immunoprecipitation [ChIP] coupled with next-generation sequencing) with normalization to an exogenous reference genome (ChIP-Rx), we found that changes in acetyl-CoA abundance trigger site-specific regulation of H3K27ac, correlating with gene expression as opposed to uniformly modulating this mark at all genes. Genes involved in integrin signaling and cell adhesion were identified as acetyl-CoA-responsive in glioblastoma cells, and we demonstrate that ATP citrate lyase (ACLY)-dependent acetyl-CoA production promotes cell migration and adhesion to the extracellular matrix. Mechanistically, the transcription factor NFAT1 (nuclear factor of activated T cells 1) was found to mediate acetyl-CoA-dependent gene regulation and cell adhesion. This occurs through modulation of Ca2+ signals, triggering NFAT1 nuclear translocation when acetyl-CoA is abundant. The findings of this study thus establish that acetyl-CoA impacts H3K27ac at specific loci, correlating with gene expression, and that expression of cell adhesion genes are driven by acetyl-CoA in part through activation of Ca2+–NFAT signaling.
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影响因子：
29
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
通讯作者：
Wellen KE
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
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：
Ho PC;Bihuniak JD;Macintyre AN;Staron M;Liu X;Amezquita R;Tsui YC;Cui G;Micevic G;Perales JC;Kleinstein SH;Abel ED;Insogna KL;Feske S;Locasale JW;Bosenberg MW;Rathmell JC;Kaech SM
通讯作者：
Kaech SM
影响因子：
5.8
作者：
Li, Heng
通讯作者：
Li, Heng