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- Title
Polycomb deficiency drives a FOXP2-high aggressive state targetable by epigenetic inhibitors.
- Authors
Chen, Fan; Byrd, Aria L.; Liu, Jinpeng; Flight, Robert M.; DuCote, Tanner J.; Naughton, Kassandra J.; Song, Xiulong; Edgin, Abigail R.; Lukyanchuk, Alexsandr; Dixon, Danielle T.; Gosser, Christian M.; Esoe, Dave-Preston; Jayswal, Rani D.; Orkin, Stuart H.; Moseley, Hunter N. B.; Wang, Chi; Brainson, Christine Fillmore
- Abstract
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. Delineating the specific role of Polycomb Repressive Complex 2 (PRC2) in various cancer systems is desirable as inhibitors for EZH2 inhibitors are approved for some cancers. Here the authors show haplo- and full-insufficiency of EZH2 drive divergent phenotypes in lung cancer. 3D tumoroids recapitulate transcriptional profiles, including FOXP2 derepression, and drug responses of in vivo tumors.
- Subjects
AGGRESSIVE driving; LUNGS; EPIGENETICS; GENETIC models; LUNG cancer; DEMETHYLASE
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-35784-x