PI3K/AKT Signaling Regulates H3K4 Methylation in Breast Cancer.
PI3K/AKT Signaling Regulates H3K4 Methylation in Breast Cancer.
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DOI：
10.1016/j.celrep.2016.05.046
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发表时间：
2016-06-21
期刊：
影响因子：
8.8
通讯作者：
Brown M
中科院分区：
文献类型：
--
作者：
Spangle JM;Dreijerink KM;Groner AC;Cheng H;Ohlson CE;Reyes J;Lin CY;Bradner J;Zhao JJ;Roberts TM;Brown M
翻译后组蛋白H3修饰调节转录能力。表观基因组响应致癌信号的调节机制仍不清楚。在这里，我们显示了在乳腺肿瘤中由激活的PIK 3CA等位基因驱动的体内H3 K4 me 3增加，并且抑制PI 3 K/AKT信号传导减少了人乳腺癌细胞中启动子相关的H3 K4 me 3。我们表明，H3 K4去甲基化酶KDM 5A是一个AKT的目标和KDM 5A的磷酸化调节其核定位和启动子占用。支持KDM 5A在介导PI 3 K/AKT转录效应中的作用，响应于与不良临床结果相关的细胞周期基因子集的AKT抑制的表达降低被KDM 5A沉默减弱。我们的数据确定了PI 3 K/AKT信号通过控制H3 K4甲基化调节癌症表观基因组的机制，并表明KDM 5A亚细胞定位和基因组占用可能是目前临床开发的PI 3 K/AKT抑制剂活性的药效学标志物。
Posttranslational histone H3 modifications regulate transcriptional competence. The mechanisms by which the epigenome is regulated in response to oncogenic signaling remain unclear. Here we show increased H3K4me3 in vivo in breast tumors driven by an activated PIK3CA allele and inhibition of PI3K/AKT signaling reduces promoter-associated H3K4me3 in human breast cancer cells. We show that the H3K4 demethylase KDM5A is an AKT target and that phosphorylation of KDM5A regulates its nuclear localization and promoter occupancy. Supporting a role for KDM5A in mediating PI3K/AKT transcriptional effects, the decreased expression in response to AKT inhibition of a subset of cell cycle genes associated with poor clinical outcome is blunted by KDM5A silencing. Our data identify a mechanism by which PI3K/AKT signaling modulates the cancer epigenome through controlling H3K4 methylation and suggest that KDM5A subcellular localization and genome occupancy may be pharmacodynamic markers of the activity of PI3K/AKT inhibitors currently in clinical development.
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影响因子：
7.3
作者：
Liu Y;Liu F;Yu H;Zhao X;Sashida G;Deblasio A;Harr M;She QB;Chen Z;Lin HK;Di Giandomenico S;Elf SE;Yang Y;Miyata Y;Huang G;Menendez S;Mellinghoff IK;Rosen N;Pandolfi PP;Hedvat CV;Nimer SD
通讯作者：
Nimer SD
影响因子：
64.5
作者：
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通讯作者：
Greenberg, ME
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
64.5
作者：
Klose, Robert J.;Yan, Qin;Kaelin, William G., Jr.
通讯作者：
Kaelin, William G., Jr.
影响因子：
4.8
作者：
Ge, Zheng;Li, Wenjuan;Xu, Dawei
通讯作者：
Xu, Dawei