2. Academic Validation
  3. Polycomb deficiency drives a FOXP2-high aggressive state targetable by epigenetic inhibitors

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

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. cfbrainson@uky.edu.
  • 9 Markey Cancer Center, University of Kentucky, Lexington, KY, 40536, USA. cfbrainson@uky.edu.
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.

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