PCAF-primed EZH2 acetylation regulates its stability and promotes lung adenocarcinoma progression.
PCAF-primed EZH2 acetylation regulates its stability and promotes lung adenocarcinoma progression.
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PCAF 引发的 EZH2 乙酰化可调节其稳定性并促进肺腺癌进展。
DOI：
10.1093/nar/gkv238
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发表时间：
2015-04-20
影响因子：
14.9
通讯作者：
Zhang H
中科院分区：
文献类型：
--
作者：
Wan J;Zhan J;Li S;Ma J;Xu W;Liu C;Xue X;Xie Y;Fang W;Chin YE;Zhang H
zeste同源物2增强子（Enhancer of zeste homolog 2, EZH2）是催化H3K27三甲基化的关键表观遗传调控因子，并通过翻译后修饰（post-translational modified, PTMs）进行调控。然而，EZH2 PTMs的精确调控仍然难以捉摸。我们在此报道了EZH2被乙酰转移酶P300/ cbp相关因子（PCAF）乙酰化，并被去乙酰化酶SIRT1去乙酰化。我们发现PCAF主要在赖氨酸348位点（K348）与EZH2相互作用并使其乙酰化。在机制上，K348乙酰化降低了EZH2在T345和T487位点的磷酸化，增加了EZH2的稳定性，而不破坏polycomb inhibition complex 2 （PRC2）的形成。功能上，EZH2 K348乙酰化可增强其抑制靶基因的能力，促进肺癌细胞迁移和侵袭。此外，肺腺癌患者EZH2 K348乙酰化水平升高预示预后不良。我们的研究结果通过将EZH2乙酰化与其磷酸化联系起来，确定了EZH2调节的新机制，从而稳定EZH2并促进肺腺癌的进展。
Enhancer of zeste homolog 2 (EZH2) is a key epigenetic regulator that catalyzes the trimethylation of H3K27 and is modulated by post-translational modifications (PTMs). However, the precise regulation of EZH2 PTMs remains elusive. We, herein, report that EZH2 is acetylated by acetyltransferase P300/CBP-associated factor (PCAF) and is deacetylated by deacetylase SIRT1. We identified that PCAF interacts with and acetylates EZH2 mainly at lysine 348 (K348). Mechanistically, K348 acetylation decreases EZH2 phosphorylation at T345 and T487 and increases EZH2 stability without disrupting the formation of polycomb repressive complex 2 (PRC2). Functionally, EZH2 K348 acetylation enhances its capacity in suppression of the target genes and promotes lung cancer cell migration and invasion. Further, elevated EZH2 K348 acetylation in lung adenocarcinoma patients predicts a poor prognosis. Our findings define a new mechanism underlying EZH2 modulation by linking EZH2 acetylation to its phosphorylation that stabilizes EZH2 and promotes lung adenocarcinoma progression.
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影响因子：
3.7
作者：
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