p300/CBP是Ewing肉瘤致病性增强子活性和基因表达的重要驱动因子。

IF 6.2 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

EMBO Reports Pub Date : 2025-09-01 DOI:10.1038/s44319-025-00552-z

Laura C Godfrey, Brandon Regalado, Sydney R Schweber, Charles Hatton, Daniela V Wenge, Yanhe Wen, Meaghan Boileau, Maria Wessels, Jun Qi, Christopher J Ott, Kimberly Stegmaier, Miguel N Rivera, Scott A Armstrong

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引用次数: 0

摘要

t（11;22）易位编码EWS::FLI1融合癌蛋白，这是Ewing肉瘤的主要驱动因素。EWS::FLI1产生独特的、全新的致病增强子，驱动基因表达，是肿瘤发生的核心机制。哪些染色质调节蛋白对这一机制至关重要尚不清楚。在这里，我们比较分析了染色质复合物MLL3/4和p300/CBP在EWS:: fli1介导的基因调控中的功能。利用EWS::FLI1降解模型，我们定义了一个EWS::FLI1敏感增强子子集，其活性与p300/CBP功能相关。我们干扰了这两个染色质复合物，以确定与MLL3/4相反，p300/CBP是EWS:: fli1驱动的增强子活性和下游基因表达的关键调节因子。我们还发现p300/CBP小分子抑制在体内减缓肿瘤生长。我们的工作强调了致癌增强子染色质蛋白活性的环境依赖性，并揭示了p300/CBP是尤因肉瘤的重要调节因子。

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p300/CBP is an essential driver of pathogenic enhancer activity and gene expression in Ewing sarcoma.

The t(11;22) translocation encodes the EWS::FLI1 fusion oncoprotein which is the primary driver of Ewing sarcoma. EWS::FLI1 creates unique, de novo pathogenic enhancers that drive gene expression and are a central mechanism of oncogenesis. Which chromatin regulatory proteins are critical to this mechanism is understudied. Here, we perform a comparative analysis of the function of the chromatin complexes MLL3/4 and p300/CBP in EWS::FLI1-mediated gene regulation. Using EWS::FLI1 degradation models, we define a subset of EWS::FLI1-sensitive enhancers whose activity correlates with p300/CBP function. We perturb both chromatin complexes to establish that in contrast to MLL3/4, p300/CBP is a critical regulator of EWS::FLI1-driven enhancer activity and downstream gene expression. We also show that p300/CBP small-molecule inhibition decelerates tumor growth in vivo. Our work highlights the context-dependent nature of chromatin protein activity at oncogenic enhancers and reveals p300/CBP as an important regulator of Ewing sarcoma.

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来源期刊

EMBO Reports 生物-生化与分子生物学

CiteScore

11.20

自引率

1.30%

发文量

267

审稿时长

1 months

期刊介绍： EMBO Reports is a scientific journal that specializes in publishing research articles in the fields of molecular biology, cell biology, and developmental biology. The journal is known for its commitment to publishing high-quality, impactful research that provides novel physiological and functional insights. These insights are expected to be supported by robust evidence, with independent lines of inquiry validating the findings. The journal's scope includes both long and short-format papers, catering to different types of research contributions. It values studies that: Communicate major findings: Articles that report significant discoveries or advancements in the understanding of biological processes at the molecular, cellular, and developmental levels. Confirm important findings: Research that validates or supports existing knowledge in the field, reinforcing the reliability of previous studies. Refute prominent claims: Studies that challenge or disprove widely accepted ideas or hypotheses in the biosciences, contributing to the correction and evolution of scientific understanding. Present null data: Papers that report negative results or findings that do not support a particular hypothesis, which are crucial for the scientific process as they help to refine or redirect research efforts. EMBO Reports is dedicated to maintaining high standards of scientific rigor and integrity, ensuring that the research it publishes contributes meaningfully to the advancement of knowledge in the life sciences. By covering a broad spectrum of topics and encouraging the publication of both positive and negative results, the journal plays a vital role in promoting a comprehensive and balanced view of scientific inquiry.