Yuning J. Tang, Haiqing Xu, Nicholas W. Hughes, Paloma Ruiz, Samuel H. Kim, Emily G. Shuldiner, Steven S. Lopez, Jess D. Hebert, Saswati Karmakar, Laura Andrejka, Deniz Nesli Dolcen, Gabor Boross, Pauline Chu, Christian A. Kunder, Colin Detrick, Sarah E. Pierce, Emily L. Ashkin, William J. Greenleaf, Anne K. Voss, Tim Thomas, Matt van de Rijn, Dmitri A. Petrov, Monte M. Winslow
{"title":"Functional mapping of epigenomic regulators uncovers coordinated tumor suppression by the HBO1 and MLL1 complexes","authors":"Yuning J. Tang, Haiqing Xu, Nicholas W. Hughes, Paloma Ruiz, Samuel H. Kim, Emily G. Shuldiner, Steven S. Lopez, Jess D. Hebert, Saswati Karmakar, Laura Andrejka, Deniz Nesli Dolcen, Gabor Boross, Pauline Chu, Christian A. Kunder, Colin Detrick, Sarah E. Pierce, Emily L. Ashkin, William J. Greenleaf, Anne K. Voss, Tim Thomas, Matt van de Rijn, Dmitri A. Petrov, Monte M. Winslow","doi":"10.1158/2159-8290.cd-24-1565","DOIUrl":null,"url":null,"abstract":"Epigenomic dysregulation is widespread in cancer. However, the specific epigenomic regulators and the processes they control to drive cancer phenotypes are poorly understood. We employed a novel high-throughput in vivo method to perform iterative functional screens of >250 epigenomic regulators within autochthonous oncogenic KRAS-driven lung tumors. We identified many previously unappreciated epigenomic tumor-suppressor and tumor-dependency genes. We show that a specific HBO1 complex and MLL1 complex are robust tumor suppressors in lung adenocarcinoma. Histone modifications generated by HBO1 complex are frequently reduced in human lung adenocarcinomas and are associated with worse clinical features. HBO1 and MLL1 complexes co-occupy shared genomic regions, impact chromatin accessibility, and control the expression of canonical tumor suppressor genes and lineage fidelity. The HBO1 complex is epistatic with the MLL1 complex and other tumor suppressor genes in lung adenocarcinoma development. Collectively, these results provide a phenotypic roadmap of epigenomic regulators in lung tumorigenesis in vivo.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"99 1","pages":""},"PeriodicalIF":33.3000,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer discovery","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/2159-8290.cd-24-1565","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Epigenomic dysregulation is widespread in cancer. However, the specific epigenomic regulators and the processes they control to drive cancer phenotypes are poorly understood. We employed a novel high-throughput in vivo method to perform iterative functional screens of >250 epigenomic regulators within autochthonous oncogenic KRAS-driven lung tumors. We identified many previously unappreciated epigenomic tumor-suppressor and tumor-dependency genes. We show that a specific HBO1 complex and MLL1 complex are robust tumor suppressors in lung adenocarcinoma. Histone modifications generated by HBO1 complex are frequently reduced in human lung adenocarcinomas and are associated with worse clinical features. HBO1 and MLL1 complexes co-occupy shared genomic regions, impact chromatin accessibility, and control the expression of canonical tumor suppressor genes and lineage fidelity. The HBO1 complex is epistatic with the MLL1 complex and other tumor suppressor genes in lung adenocarcinoma development. Collectively, these results provide a phenotypic roadmap of epigenomic regulators in lung tumorigenesis in vivo.
期刊介绍:
Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.