Functional Mapping of Epigenomic Regulators Uncovers Coordinated Tumor Suppression by the HBO1 and MLL1 Complexes

Tang, YJ; CHU, P; Xu, H; Hughes, NW; Ruiz, P; Kim, SH; Shuldiner, EG; Lopez, SS; Hebert, JD; Karmakar, S; Andrejka, L; Dolcen, DN; Boross, G; Kunder, CA; Detrick, C; Pierce, SE; Ashkin, EL; Greenleaf, WJ; Voss, AK; Thomas, T; van de Rijn, M; Petrov, DA; Winslow, MM

Author(s): Tang, YJ; CHU, P; Xu, H; Hughes, NW; Ruiz, P; Kim, SH; Shuldiner, EG; Lopez, SS; Hebert, JD; Karmakar, S; Andrejka, L; Dolcen, DN; Boross, G; Kunder, CA; Detrick, C; Pierce, SE; Ashkin, EL; Greenleaf, WJ; Voss, AK; Thomas, T; van de Rijn, M; Petrov, DA; Winslow, MM;
Details: Publication Year 2025-12-02,Volume 15,Issue #12,Page 2554-2573
Journal Title: Cancer Discovery
Publication Type: Sep 26
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 used 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 the 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, affect 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. SIGNIFICANCE: Using a novel functional genomics method in vivo, we investigated epigenomic regulators in lung tumorigenesis. We discovered multiple novel genes that affect tumor growth. We show that the HBO1 and MLL1 complexes interact to suppress lung adenocarcinoma. Our findings provide broad insights into the epigenomic regulatory landscape of lung cancer.
Publisher: AACR
Keywords: Humans; *Myeloid-Lymphoid Leukemia Protein/metabolism/genetics; Animals; Mice; *Lung Neoplasms/genetics/pathology/metabolism; *Histone-Lysine N-Methyltransferase/metabolism/genetics; Adenocarcinoma of Lung/genetics/pathology; Gene Expression Regulation, Neoplastic; Epigenomics/methods; Genes, Tumor Suppressor; Cell Line, Tumor; Epigenesis, Genetic
Research Division(s): Genetics and Gene Regulation
PubMed ID: 40997327
Publisher's Version: https://doi.org/10.1158/2159-8290.CD-24-1565
Open Access at Publisher's Site: https://doi.org/10.1158/2159-8290.CD-24-1565
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-10-20 01:57:48

Last Modified: 2025-12-15 01:27:23