Inhibitors of the Polycomb Repressive Complex 2 (PRC2) histone methyltransferase EZH2 are approved for certain cancers, but realizing their wider utility relies upon understanding PRC2 biology in each cancer system. Using a genetic model to delete Ezh2 in KRAS-driven lung adenocarcinomas, we observed that Ezh2 haplo-insufficient tumors were less lethal and lower grade than Ezh2 fully-insufficient tumors, which were poorly differentiated and metastatic. Using three-dimensional cultures and in vivo experiments, we determined that EZH2-deficient tumors were vulnerable to H3K27 demethylase or BET inhibitors. PRC2 loss/inhibition led to de-repression of FOXP2, a transcription factor that promotes migration and stemness, and FOXP2 could be suppressed by BET inhibition. Poorly differentiated human lung cancers were enriched for an H3K27me3-low state, representing a subtype that may benefit from BET inhibition as a single therapy or combined with additional EZH2 inhibition. These data highlight diverse roles of PRC2 in KRAS-driven lung adenocarcinomas, and demonstrate the utility of three-dimensional cultures for exploring epigenetic drug sensitivities for cancer.
|State||Published - Dec 2023|
Bibliographical noteFunding Information:
The authors thank Dave Powell in the Markey Cancer Center Small Animal Imaging Facility (MCCSAIF) for extensive help with the MRI scanning, the Yang and Orren laboratories at the University of Kentucky for sharing cell lines, Aveo Pharmaceuticals and the Kuperwasser laboratory for sharing vectors, Dr. Roderick Bronson of Harvard Medical School for assessing tumor sections, and Joanne M. Berry and Yanming Zhao for assistance with mice. This work was supported in part by NCI K22 CA201036, Kentucky Lung Cancer Research Program, V Foundation Scholar Award, American Cancer Society Grants IRG-85-001-25 and 133123-RSG-19-081-01-TBG, NCI R01 CA237643, the American Institute for Cancer Research, and American Association for Cancer Research-Bayer Innovation and Discovery Grant (C.F.B.), NIGMS P20 GM121327-03 (C.F.B. and H.N.B.M.), NIEHS T32 5T32ES007266 (T.J.D. and A.L.B.), and NHLBI F31 HL151111 (A.L.B.). This research was also supported by the Biostatistics & Bioinformatics Shared Resource Facility, Oncogenomics Shared Resource Facility, Biospecimen Procurement & Translational Pathology Shared Resource Facility and Flow Cytometry & Immune Monitoring Shared Resource Facility of the University of Kentucky Markey Cancer Center (P30CA177558). Finally, the Markey Cancer Center’s Research Communications Office assisted with manuscript preparation.
© 2023, The Author(s).
ASJC Scopus subject areas
- Physics and Astronomy (all)
- Chemistry (all)
- Biochemistry, Genetics and Molecular Biology (all)