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NEDD4 介导的 H3 泛素化调控 H3 乙酰化和肿瘤发生。

H3 ubiquitination by NEDD4 regulates H3 acetylation and tumorigenesis.

机构信息

Department of Cancer Biology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157, USA.

Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

出版信息

Nat Commun. 2017 Mar 16;8:14799. doi: 10.1038/ncomms14799.

DOI:10.1038/ncomms14799
PMID:28300060
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5357315/
Abstract

Dynamic changes in histone modifications under various physiological cues play important roles in gene transcription and cancer. Identification of new histone marks critical for cancer development is of particular importance. Here we show that, in a glucose-dependent manner, E3 ubiquitin ligase NEDD4 ubiquitinates histone H3 on lysine 23/36/37 residues, which specifically recruits histone acetyltransferase GCN5 for subsequent H3 acetylation. Genome-wide analysis of chromatin immunoprecipitation followed by sequencing reveals that NEDD4 regulates glucose-induced H3 K9 acetylation at transcription starting site and enhancer regions. Integrative analysis of ChIP-seq and microarray data sets also reveals a consistent role of NEDD4 in transcription activation and H3 K9 acetylation in response to glucose. Functionally, we show that NEDD4-mediated H3 ubiquitination, by transcriptionally activating IL1α, IL1β and GCLM, is important for tumour sphere formation. Together, our study reveals the mechanism for glucose-induced transcriptome reprograming and epigenetic regulation in cancer by inducing NEDD4-dependent H3 ubiquitination.

摘要

各种生理信号下组蛋白修饰的动态变化在基因转录和癌症中发挥重要作用。鉴定对癌症发生至关重要的新组蛋白标记物尤为重要。在这里，我们发现，E3 泛素连接酶 NEDD4 以葡萄糖依赖的方式在赖氨酸 23/36/37 残基上泛素化组蛋白 H3，从而特异性招募组蛋白乙酰转移酶 GCN5 进行随后的 H3 乙酰化。通过测序的染色质免疫沉淀的全基因组分析揭示了 NEDD4 调节葡萄糖诱导的转录起始位点和增强子区域的 H3 K9 乙酰化。ChIP-seq 和微阵列数据集的综合分析也揭示了 NEDD4 在转录激活和响应葡萄糖的 H3 K9 乙酰化中的一致作用。在功能上，我们表明，NEDD4 介导的 H3 泛素化通过转录激活 IL1α、IL1β 和 GCLM，对于肿瘤球形成是重要的。总之，我们的研究揭示了通过诱导 NEDD4 依赖性 H3 泛素化，在癌症中诱导葡萄糖诱导的转录组重编程和表观遗传调控的机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a7b9/5357315/ccd6b71d29a1/ncomms14799-f7.jpg
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