P300/CBP 的药理靶向揭示了 EWS::FLI1 在尤文肉瘤中介导的衰老逃避。

IF 27.7 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Cancer Pub Date : 2024-10-05 DOI:10.1186/s12943-024-02115-7
Erdong Wei, Ana Mitanoska, Quinn O'Brien, Kendall Porter, MacKenzie Molina, Haseeb Ahsan, Usuk Jung, Lauren Mills, Michael Kyba, Darko Bosnakovski
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引用次数: 0

摘要

尤文肉瘤(ES)的主要致癌因子EWS::FLI1很难靶向治疗,这给治疗带来了巨大挑战。我们的研究表明,通过抑制 P300/CBP 对 EWS::FLI1 转录复合物进行药理学靶向,能产生与直接敲除 EWS::FLI1 相似的全局转录结果,并能进一步产生影响 ES 患者预后的风险因素。我们发现,EWS::FLI1通过ES细胞和EWS::FLI1允许的间充质干细胞中重复的GGAA图案识别和乙酰化代码上调LMNB1,当P300抑制逆转时会导致ES细胞衰老。然后,P300抑制的衰老ES细胞可通过靶向PI3K信号通路的衰老剂消除。ES 细胞易受这种联合疗法的影响,这为未来的治疗探索提供了一种有吸引力的协同策略。
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Pharmacological targeting of P300/CBP reveals EWS::FLI1-mediated senescence evasion in Ewing sarcoma.

Ewing sarcoma (ES) poses a significant therapeutic challenge due to the difficulty in targeting its main oncodriver, EWS::FLI1. We show that pharmacological targeting of the EWS::FLI1 transcriptional complex via inhibition of P300/CBP drives a global transcriptional outcome similar to direct knockdown of EWS::FLI1, and furthermore yields prognostic risk factors for ES patient outcome. We find that EWS::FLI1 upregulates LMNB1 via repetitive GGAA motif recognition and acetylation codes in ES cells and EWS::FLI1-permissive mesenchymal stem cells, which when reversed by P300 inhibition leads to senescence of ES cells. P300-inhibited senescent ES cells can then be eliminated by senolytics targeting the PI3K signaling pathway. The vulnerability of ES cells to this combination therapy suggests an appealing synergistic strategy for future therapeutic exploration.

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来源期刊
Molecular Cancer
Molecular Cancer 医学-生化与分子生物学
CiteScore
54.90
自引率
2.70%
发文量
224
审稿时长
2 months
期刊介绍: Molecular Cancer is a platform that encourages the exchange of ideas and discoveries in the field of cancer research, particularly focusing on the molecular aspects. Our goal is to facilitate discussions and provide insights into various areas of cancer and related biomedical science. We welcome articles from basic, translational, and clinical research that contribute to the advancement of understanding, prevention, diagnosis, and treatment of cancer. The scope of topics covered in Molecular Cancer is diverse and inclusive. These include, but are not limited to, cell and tumor biology, angiogenesis, utilizing animal models, understanding metastasis, exploring cancer antigens and the immune response, investigating cellular signaling and molecular biology, examining epidemiology, genetic and molecular profiling of cancer, identifying molecular targets, studying cancer stem cells, exploring DNA damage and repair mechanisms, analyzing cell cycle regulation, investigating apoptosis, exploring molecular virology, and evaluating vaccine and antibody-based cancer therapies. Molecular Cancer serves as an important platform for sharing exciting discoveries in cancer-related research. It offers an unparalleled opportunity to communicate information to both specialists and the general public. The online presence of Molecular Cancer enables immediate publication of accepted articles and facilitates the presentation of large datasets and supplementary information. This ensures that new research is efficiently and rapidly disseminated to the scientific community.
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