SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation.
SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation.
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DOI：
10.1038/nature11043
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发表时间：
2012-07-05
期刊：
影响因子：
64.8
通讯作者：
Chua, Katrin F.
中科院分区：
文献类型：
--
作者：
Barber, Matthew F.;Michishita-Kioi, Eriko;Xi, Yuanxin;Tasselli, Luisa;Kioi, Mitomu;Moqtaderi, Zarmik;Tennen, Ruth I.;Paredes, Silvana;Young, Nicolas L.;Chen, Kaifu;Struhl, Kevin;Garcia, Benjamin A.;Gozani, Or;Li, Wei;Chua, Katrin F.
Sirtuin 蛋白调节影响基因组稳定性、代谢和衰老的多种细胞途径。 SIRT7 是一种哺乳动物去乙酰化酶，其生化活性、分子靶点和生理功能尚不清楚。在这里，我们证明 SIRT7 是一种 NAD+ 依赖性 H3K18Ac（组蛋白 H3 的乙酰化赖氨酸 18）脱乙酰酶，可稳定癌细胞的转化状态。全基因组结合研究表明，SIRT7 与一组特定基因靶标的启动子结合，使 H3K18Ac 去乙酰化并促进转录抑制。 SIRT7 靶基因的范围部分是由其与癌症相关的 ETS 转录因子 ELK4 的相互作用定义的，并且包含许多与肿瘤抑制相关的基因。值得注意的是，H3K18Ac 的选择性低乙酰化与致癌转化有关，并且在患者中与侵袭性肿瘤表型和不良预后相关。我们发现 SIRT7 对 H3K18Ac 的脱乙酰作用对于维持人类癌细胞的基本特征是必要的，包括锚定独立生长和逃避接触抑制。此外，SIRT7 对于与病毒癌蛋白 E1A 的细胞转化相关的 H3K18Ac 整体低乙酰化是必需的。最后，SIRT7 缺失显着降低了小鼠体内人类癌细胞异种移植物的致瘤性。我们的工作共同确定了 SIRT7 作为一种高度选择性的 H3K18Ac 脱乙酰酶，并证明了 SIRT7 在染色质调节、细胞转化程序和体内肿瘤形成中的关键作用。
Sirtuin proteins regulate diverse cellular pathways that influence genomic stability, metabolism, and ageing. SIRT7 is a mammalian sirtuin whose biochemical activity, molecular targets, and physiologic functions have been unclear. Here we show that SIRT7 is an NAD+-dependent H3K18Ac (acetylated lysine 18 of histone H3) deacetylase that stabilizes the transformed state of cancer cells. Genome-wide binding studies reveal that SIRT7 binds to promoters of a specific set of gene targets, where it deacetylates H3K18Ac and promotes transcriptional repression. The spectrum of SIRT7 target genes is defined in part by its interaction with the cancer-associated ETS transcription factor ELK4, and comprises numerous genes with links to tumour suppression. Notably, selective hypoacetylation of H3K18Ac has been linked to oncogenic transformation, and in patients is associated with aggressive tumour phenotypes and poor prognosis. We find that deacetylation of H3K18Ac by SIRT7 is necessary for maintaining essential features of human cancer cells, including anchorage-independent growth and escape from contact inhibition. Moreover, SIRT7 is necessary for a global hypoacetylation of H3K18Ac associated with cellular transformation by the viral oncoprotein E1A. Finally, SIRT7 depletion markedly reduces the tumourigenicity of human cancer cell xenografts in mice. Together, our work establishes SIRT7 as a highly selective H3K18Ac deacetylase and demonstrates a pivotal role for SIRT7 in chromatin regulation, cellular transformation programs, and tumour formation in vivo.
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邮票：用于探索DNA结合基序相似性的网络工具。
影响因子：
14.9
作者：
Mahony, Shaun;Benos, Panayiotis V
通讯作者：
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影响因子：
7.8
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1146/annurev.pathol.4.110807.092250
发表时间：
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期刊：
Annual review of pathology
影响因子：
--
作者：
Haigis MC;Sinclair DA
通讯作者：
Sinclair DA
影响因子：
64.8
作者：
Ebert, Benjamin L.;Pretz, Jennifer;Bosco, Jocelyn;Chang, Cindy Y.;Tamayo, Pablo;Galili, Naomi;Raza, Azra;Root, David E.;Attar, Eyal;Ellis, Steven R.;Golub, Todd R.
通讯作者：
Golub, Todd R.