Jinchang Lu , Yang Shao , Sanjay Saw , Hui Fang , Guohui Song , Yan Chen , Qinglian Tang , Geoffrey Wood , Jin Wang , Paul Waterhouse , Jingnan Shen , Rama Khokha
{"title":"组蛋白赖氨酸甲基转移酶NSD3通过灭活ARID3A驱动骨肉瘤形成。","authors":"Jinchang Lu , Yang Shao , Sanjay Saw , Hui Fang , Guohui Song , Yan Chen , Qinglian Tang , Geoffrey Wood , Jin Wang , Paul Waterhouse , Jingnan Shen , Rama Khokha","doi":"10.1016/j.canlet.2025.218045","DOIUrl":null,"url":null,"abstract":"<div><div>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 <em>RUNX2</em>, <em>MMP13</em>, <em>OCT4</em> and <em>NANOG</em> 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.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"633 ","pages":"Article 218045"},"PeriodicalIF":10.1000,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"The histone lysine methyltransferase NSD3 drives osteosarcomagenesis by inactivating ARID3A\",\"authors\":\"Jinchang Lu , Yang Shao , Sanjay Saw , Hui Fang , Guohui Song , Yan Chen , Qinglian Tang , Geoffrey Wood , Jin Wang , Paul Waterhouse , Jingnan Shen , Rama Khokha\",\"doi\":\"10.1016/j.canlet.2025.218045\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>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 <em>RUNX2</em>, <em>MMP13</em>, <em>OCT4</em> and <em>NANOG</em> 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.</div></div>\",\"PeriodicalId\":9506,\"journal\":{\"name\":\"Cancer letters\",\"volume\":\"633 \",\"pages\":\"Article 218045\"},\"PeriodicalIF\":10.1000,\"publicationDate\":\"2025-09-17\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cancer letters\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0304383525006172\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer letters","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0304383525006172","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
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.
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.