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.

中文翻译：

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DiPRO1 可以明显地重新编程肌肉和间质癌细胞。


我们最近发现，未表征的 ZNF555 蛋白是参与面肩肱营养不良症 4qA 基因座病态功能的生产性复合物的一个组成部分。随后命名为 DiPRO1（死亡、分化和增殖相关蛋白 1），我们的研究提供了其在人类成肌细胞分化和增殖中的作用的实质性证据。 DiPRO1 通过 SIX1（肌生成的主要调节因子）的调节结合区域发挥作用。它的相关性扩展到间充质肿瘤，例如横纹肌肉瘤 (RMS) 和尤文肉瘤，其中 DiPRO1 通过表观遗传调节因子 TIF1B 和 UHRF1 充当阻遏蛋白，维持顺式调节元件和基因启动子的甲基化。 DiPRO1 的缺失模仿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。这能够根除癌细胞，通过 NF-kappaB 信号传导控制 TNF-α，重新编程针对炎症和/或细胞凋亡的细胞决策平衡。最后，我们的结果强调了间充质癌肿瘤对基于 si/shDiPRO1 的纳米药物的脆弱性，将 DiPRO1 定位为潜在的治疗靶点。