KDM4C and ATF4 Cooperate in Transcriptional Control of Amino Acid Metabolism.
KDM4C and ATF4 Cooperate in Transcriptional Control of Amino Acid Metabolism.
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KDM4C和ATF4在氨基酸代谢的转录控制方面合作。
DOI：
10.1016/j.celrep.2015.12.053
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发表时间：
2016-01-26
期刊：
影响因子：
8.8
通讯作者：
Ding HF
中科院分区：
文献类型：
--
作者：
Zhao E;Ding J;Xia Y;Liu M;Ye B;Choi JH;Yan C;Dong Z;Huang S;Zha Y;Yang L;Cui H;Ding HF
组蛋白赖氨酸去甲基化酶KDM4C主要通过基因扩增在癌症中过度表达。KDM4C在肿瘤发生中的分子机制尚不明确。在这里，我们报道KDM4C转录激活氨基酸的生物合成和运输，导致细胞内氨基酸水平显著增加。对丝氨酸-甘氨酸合成途径的研究表明，KDM4C通过去除抑制组蛋白修饰H3赖氨酸9 （H3K9）三甲基化，在稳态和丝氨酸剥夺条件下表观遗传地激活了该途径基因。KDM4C的这种作用需要ATF4，一种氨基酸代谢和应激反应的转录主调节因子。KDM4C激活ATF4转录，并与ATF4相互作用，靶向丝氨酸途径基因进行转录激活。我们进一步提出了KDM4C在氨基酸代谢和细胞增殖的转录协调中的证据。这些发现表明，kdm4c介导的H3K9去甲基化和atf4介导的转激活在癌细胞增殖的氨基酸代谢重编程中的分子机制。
The histone lysine demethylase KDM4C is often overexpressed in cancers primarily through gene amplification. The molecular mechanisms of KDM4C action in tumorigenesis are not well defined. Here we report that KDM4C transcriptionally activates amino acid biosynthesis and transport, leading to a significant increase in intracellular amino acid levels. Examination of the serine-glycine synthesis pathway reveals that KDM4C epigenetically activates the pathway genes under steady-state and serine deprivation conditions by removing the repressive histone modification H3 lysine 9 (H3K9) trimethylation. This action of KDM4C requires ATF4, a transcriptional master regulator of amino acid metabolism and stress responses. KDM4C activates ATF4 transcription and interacts with ATF4 to target serine pathway genes for transcriptional activation. We further present evidence for KDM4C in transcriptional coordination of amino acid metabolism and cell proliferation. These findings suggest a molecular mechanism linking KDM4C-mediated H3K9 demethylation and ATF4-mediated transactivation in reprogramming amino acid metabolism for cancer cell proliferation.