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

Author

Listed:
  • Fan Chen

    (University of Kentucky
    Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University)

  • Aria L. Byrd

    (University of Kentucky)

  • Jinpeng Liu

    (University of Kentucky)

  • Robert M. Flight

    (University of Kentucky
    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
    University of Kentucky)

  • Chi Wang

    (University of Kentucky
    University of Kentucky)

  • Christine Fillmore Brainson

    (University of Kentucky
    University of Kentucky)

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.

Suggested Citation

  • 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 &, 2023. "Polycomb deficiency drives a FOXP2-high aggressive state targetable by epigenetic inhibitors," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-35784-x
    DOI: 10.1038/s41467-023-35784-x
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    References listed on IDEAS

    as
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