Polycomb deficiency drives a FOXP2-high aggressive state targetable by epigenetic inhibitors

Fan Chen, Aria L. Byrd, Jinpeng Liu, Robert M. Flight, Tanner J. DuCote, Kassandra J. Naughton, Xiulong Song, Abigail R. Edgin, Alexsandr Lukyanchuk, Danielle T. Dixon, Christian M. Gosser, Dave-Preston Esoe, Rani D. Jayswal, Stuart H. Orkin, Hunter N. B. Moseley, Chi Wang and Christine Fillmore Brainson ()
Additional contact information
Fan Chen: University of Kentucky
Aria L. Byrd: University of Kentucky
Jinpeng Liu: University of Kentucky
Robert M. Flight: University of Kentucky
Tanner J. DuCote: University of Kentucky
Kassandra J. Naughton: University of Kentucky
Xiulong Song: University of Kentucky
Abigail R. Edgin: University of Kentucky
Alexsandr Lukyanchuk: University of Kentucky
Danielle T. Dixon: University of Kentucky
Christian M. Gosser: University of Kentucky
Dave-Preston Esoe: University of Kentucky
Rani D. Jayswal: Markey Cancer Center Biostatistics and Bioinformatics Shared Resource Facility
Stuart H. Orkin: Boston Children’s Hospital
Hunter N. B. Moseley: University of Kentucky
Chi Wang: University of Kentucky
Christine Fillmore Brainson: University of Kentucky

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-35784-x

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