组蛋白赖氨酸甲基转移酶NSD3通过灭活ARID3A驱动骨肉瘤形成。

IF 10.1 1区 医学 Q1 ONCOLOGY
Jinchang Lu , Yang Shao , Sanjay Saw , Hui Fang , Guohui Song , Yan Chen , Qinglian Tang , Geoffrey Wood , Jin Wang , Paul Waterhouse , Jingnan Shen , Rama Khokha
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引用次数: 0

摘要

骨肉瘤(OS)具有高度混乱的基因组,但其癌症驱动因素定义不清。利用跨物种OS基因组学,我们发现了NSD3(一种组蛋白赖氨酸甲基转移酶)的频繁扩增,并揭示了NSD3- arid3a轴是骨肉瘤形成的核心途径。利用CRISPR-Cas9和慢病毒系统进行的功能缺失和功能获得研究证实了NSD3在OS肿瘤生长和自发转移中的因果作用。NSD3特异性增强H3K27二甲基化以启动致癌重编程并使转录抑制因子ARID3A失活。这最终导致RUNX2、MMP13、OCT4和NANOG等指导性基因的表达改变,从而使骨肉瘤细胞分化向原始状态转变。在人类OS中,NSD3过表达在患者肿瘤中可见,并预示着不良的临床结果。我们的研究揭示了组蛋白赖氨酸甲基转移酶在骨肉瘤中至关重要的表观遗传失调,为表观遗传药物治疗开辟了新的可能性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The histone lysine methyltransferase NSD3 drives osteosarcomagenesis by inactivating ARID3A
Osteosarcomas (OS) have highly chaotic genomes, yet their cancer drivers are poorly defined. Leveraging cross-species OS genomics we identify the frequent amplification of NSD3, a histone lysine methyltransferase and expose the NSD3-ARID3A axis as a core pathway in osteosarcomagenesis. Loss- and gain-of-function studies with CRISPR-Cas9 and lentivirus systems establish the causal role of NSD3 in OS tumor growth and spontaneous metastasis. NSD3 specifically enhances H3K27 di-methylation to initiate oncogenic reprogramming and inactivates the transcriptional repressor ARID3A. This culminates in altered expression of instructive genes RUNX2, MMP13, OCT4 and NANOG generating a shift in osteosarcoma cell differentiation to a primitive state. In human OS, NSD3 overexpression is seen in patient tumors and predicts a poor clinical outcome. Our study uncovers the crucial epigenetic dysregulation of histone lysine methyltransferase in osteosarcoma, opening new possibilities for therapy with epigenetic drugs.
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来源期刊
Cancer letters
Cancer letters 医学-肿瘤学
CiteScore
17.70
自引率
2.10%
发文量
427
审稿时长
15 days
期刊介绍: Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.
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