Acetylation of FOXM1 is essential for its transactivation and tumor growth stimulation.
Acetylation of FOXM1 is essential for its transactivation and tumor growth stimulation.
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FOXM1 的乙酰化对其反式激活和肿瘤生长刺激至关重要
DOI：
10.18632/oncotarget.11332
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发表时间：
2016-09-13
期刊：
影响因子：
--
通讯作者：
Tong T
中科院分区：
文献类型：
--
作者：
Lv C;Zhao G;Sun X;Wang P;Xie N;Luo J;Tong T
叉头盒转录因子M1 （FOXM1）通过调控靶基因的表达，在包括细胞增殖和分化、细胞周期和肿瘤发生在内的一系列生物过程中起着至关重要的作用。FOXM1的高表达在许多恶性肿瘤中经常被观察到。在体内，我们发现FOXM1可以被p300/CBP在赖氨酸K63、K422、K440、K603和K614位点乙酰化。这种修饰对于其在靶基因上的转激活是必不可少的。FOXM1的乙酰化在S期增加，并在G2和M期保持高水平，此时需要FOXM1的转录活性。我们发现，与野生型FOXM1相比，乙酰化缺陷FOXM1突变体活性较低，致瘤活性明显较弱。机制上，FOXM1的乙酰化通过增加其DNA结合亲和力、蛋白质稳定性和磷酸化敏感性来增强其转录活性。此外，我们证明了nad依赖性组蛋白去乙酰化酶SIRT1在体内与FOXM1物理结合并去乙酰化。SIRT1对FOXM1的去乙酰化降低了其转录活性，降低了其蛋白稳定性。总之，我们的研究结果表明，p300/CBP和SIRT1对FOXM1的可逆乙酰化调节了其转激活功能。
Forkhead box transcription factor M1 (FOXM1) plays crucial roles in a wide array of biological processes, including cell proliferation and differentiation, the cell cycle, and tumorigenesis by regulating the expression of its target genes. Elevated expression of FOXM1 is frequently observed in a multitude of malignancies. Here we show that FOXM1 can be acetylated by p300/CBP at lysines K63, K422, K440, K603 and K614 in vivo. This modification is essential for its transactivation on the target genes. Acetylation of FOXM1 increases during the S phase and remains high throughout the G2 and M phases, when FOXM1 transcriptional activity is required. We find that the acetylation-deficient FOXM1 mutant is less active and exhibits significantly weaker tumorigenic activities compared to wild-type FOXM1. Mechanistically, the acetylation of FOXM1 enhances its transcriptional activity by increasing its DNA binding affinity, protein stability, and phosphorylation sensitivity. In addition, we demonstrate that NAD-dependent histone deacetylase SIRT1 physically binds to and deacetylates FOXM1 in vivo. The deacetylation of FOXM1 by SIRT1 attenuates its transcriptional activity and decreases its protein stability. Together, our findings demonstrate that the reversible acetylation of FOXM1 by p300/CBP and SIRT1 modulates its transactivation function.