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DiPRO1 显著重编程肌肉和间充质癌细胞。

DiPRO1 distinctly reprograms muscle and mesenchymal cancer cells.

机构信息

UMR8126 CNRS, Gustave Roussy Cancer campus, Université Paris-Saclay, Villejuif, France.

INSERM U1016, CNRS UMR 8104, Institut Cochin, Université Paris-Cité, Paris, France.

出版信息

EMBO Mol Med. 2024 Aug;16(8):1840-1885. doi: 10.1038/s44321-024-00097-z. Epub 2024 Jul 15.

DOI:10.1038/s44321-024-00097-z
PMID:39009887
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11319797/
Abstract

We have recently identified the uncharacterized ZNF555 protein as a component of a productive complex involved in the morbid function of the 4qA locus in facioscapulohumeral dystrophy. Subsequently named DiPRO1 (Death, Differentiation, and PROliferation related PROtein 1), our study provides substantial evidence of its role in the differentiation and proliferation of human myoblasts. DiPRO1 operates through the regulatory binding regions of SIX1, a master regulator of myogenesis. Its relevance extends to mesenchymal tumors, such as rhabdomyosarcoma (RMS) and Ewing sarcoma, where DiPRO1 acts as a repressor via the epigenetic regulators TIF1B and UHRF1, maintaining methylation of cis-regulatory elements and gene promoters. Loss of DiPRO1 mimics the host defense response to virus, awakening retrotransposable repeats and the ZNF/KZFP gene family. This enables the eradication of cancer cells, reprogramming the cellular decision balance towards inflammation and/or apoptosis by controlling TNF-α via NF-kappaB signaling. Finally, our results highlight the vulnerability of mesenchymal cancer tumors to si/shDiPRO1-based nanomedicines, positioning DiPRO1 as a potential therapeutic target.

摘要

我们最近发现了一个未被描述的 ZNF555 蛋白，它是一个参与面肩肱型肌营养不良症 4qA 基因座病理性功能的有效复合物的组成部分。随后将其命名为 DiPRO1（与死亡、分化和增殖相关的蛋白 1），我们的研究为其在人类成肌细胞分化和增殖中的作用提供了充分的证据。DiPRO1 通过 SIX1 的调节结合区域发挥作用，SIX1 是成肌调节的主要调控因子。它的相关性扩展到间叶肿瘤，如横纹肌肉瘤（RMS）和尤文肉瘤，其中 DiPRO1 通过表观遗传调节剂 TIF1B 和 UHRF1 作为抑制剂发挥作用，维持顺式调节元件和基因启动子的甲基化。DiPRO1 的缺失模拟了宿主对病毒的防御反应，唤醒了逆转录转座重复序列和 ZNF/KZFP 基因家族。这使得能够消灭癌细胞，通过 NF-kappaB 信号通路控制 TNF-α，使细胞决策平衡向炎症和/或细胞凋亡重新编程。最后，我们的结果强调了间叶性癌症肿瘤对基于 si/shDiPRO1 的纳米药物的脆弱性，将 DiPRO1 定位为一个有潜力的治疗靶点。

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