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

  • Nat Commun. 2023 Jan 20;14(1):336. doi: 10.1038/s41467-023-35784-x.
Fan Chen  1  2 ,  Aria L Byrd  1 ,  Jinpeng Liu  3 ,  Robert M Flight  4  5 ,  Tanner J DuCote  1 ,  Kassandra J Naughton  1 ,  Xiulong Song  1 ,  Abigail R Edgin  1 ,  Alexsandr Lukyanchuk  1 ,  Danielle T Dixon  1 ,  Christian M Gosser  1 ,  Dave-Preston Esoe  1 ,  Rani D Jayswal  6 ,  Stuart H Orkin  7 ,  Hunter N B Moseley  4  5 ,  Chi Wang  3  5 ,  Christine Fillmore Brainson  8  9
Affiliations
  • 1. Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, 40536, USA.
  • 2. Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, 510060, Guangzhou, P. R. China.
  • 3. Department of Internal Medicine, University of Kentucky, Lexington, KY, 40536, USA.
  • 4. Department of Molecular & Cellular Biochemistry, University of Kentucky, Lexington, KY, 40536, USA.
  • 5. Markey Cancer Center, University of Kentucky, Lexington, KY, 40536, USA.
  • 6. Markey Cancer Center Biostatistics and Bioinformatics Shared Resource Facility, Lexington, KY, 40536, USA.
  • 7. Department of Hematology/Oncology, Boston Children's Hospital, Boston, MA, 02115, USA.
  • 8. Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, 40536, USA. [email protected].
  • 9. Markey Cancer Center, University of Kentucky, Lexington, KY, 40536, USA. [email protected].
PMID: 36670102 DOI: 10.1038/s41467-023-35784-x
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.

Products