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RING1B 招募 EWSR1-FLI1 并共同重塑染色质，这对于尤文肉瘤的肿瘤发生是必要的。

RING1B recruits EWSR1-FLI1 and cooperates in the remodeling of chromatin necessary for Ewing sarcoma tumorigenesis.

机构信息

Developmental Tumor Biology Laboratory, Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, 08950 Barcelona, Spain.

Center for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, 08003 Barcelona, Spain.

出版信息

Sci Adv. 2020 Oct 23;6(43). doi: 10.1126/sciadv.aba3058. Print 2020 Oct.

DOI:10.1126/sciadv.aba3058
PMID:33097530
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7608835/
Abstract

Ewing sarcoma (EwS) is an aggressive tumor that affects adolescents and young adults. EwS is defined by a chromosomal translocation, EWSR1-FLI1 being the most common, that causes genome reprogramming through remodeling of enhancers. Here, we describe an unexpected function of RING1B, which is highly expressed in EwS. While retaining its repressive activity at Polycomb developmental regulated genes, RING1B colocalizes with EWSR1-FLI1 at active enhancers. We demonstrate that RING1B is necessary for the expression of key EWSR1-FLI1 targets by facilitating oncogene recruitment to their enhancers. Knockdown of RING1B impairs growth of tumor xenografts and expression of genes regulated by EWSR1-FLI1 bound enhancers. Pharmacological inhibition of AURKB with AZD1152 increases H2Aub levels causing down-regulation of RING1B/EWSR1-FLI1 common targets. Our findings demonstrate that RING1B is a critical modulator of EWSR1-FLI1-induced chromatin remodeling, and its inhibition is a potential therapeutic strategy for the treatment of these tumors.

摘要

尤因肉瘤 (EwS) 是一种侵袭性肿瘤，影响青少年和年轻人。EwS 是由染色体易位定义的，其中 EWSR1-FLI1 最为常见，它通过重塑增强子来导致基因组重编程。在这里，我们描述了 RING1B 的一个意外功能，它在 EwS 中高度表达。虽然 RING1B 在 Polycomb 发育调控基因上保持其抑制活性，但它与 EWSR1-FLI1 在活性增强子上共定位。我们证明 RING1B 通过促进癌基因募集到它们的增强子上来表达关键的 EWSR1-FLI1 靶基因是必需的。RING1B 的敲低会损害肿瘤异种移植物的生长和受 EWSR1-FLI1 结合增强子调控的基因的表达。用 AZD1152 抑制 AURKB 会增加 H2Aub 水平，从而下调 RING1B/EWSR1-FLI1 的常见靶基因。我们的研究结果表明，RING1B 是 EWSR1-FLI1 诱导的染色质重塑的关键调节剂，其抑制是治疗这些肿瘤的潜在治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d40/7608835/4dea086397dc/aba3058-F6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d40/7608835/071e57111ddf/aba3058-F1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d40/7608835/f467eb4bd134/aba3058-F2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d40/7608835/52b188b55128/aba3058-F3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d40/7608835/4dd81ae5f810/aba3058-F4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d40/7608835/1d628ed8a689/aba3058-F5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d40/7608835/4dea086397dc/aba3058-F6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d40/7608835/071e57111ddf/aba3058-F1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d40/7608835/f467eb4bd134/aba3058-F2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d40/7608835/52b188b55128/aba3058-F3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d40/7608835/4dd81ae5f810/aba3058-F4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d40/7608835/1d628ed8a689/aba3058-F5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d40/7608835/4dea086397dc/aba3058-F6.jpg

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本文引用的文献

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The Bivalent Genome: Characterization, Structure, and Regulation.二倍体基因组：特征、结构和调控。
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High-throughput Chemical Screening Identifies Focal Adhesion Kinase and Aurora Kinase B Inhibition as a Synergistic Treatment Combination in Ewing Sarcoma.
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