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Targeting bivalency de-represses Indian Hedgehog and inhibits self-renewal of colorectal cancer-initiating cells

Author

Listed:
  • Evelyne Lima-Fernandes

    (University of Toronto
    University Health Network)

  • Alex Murison

    (University Health Network)

  • Tiago da Silva Medina

    (University Health Network)

  • Yadong Wang

    (University Health Network)

  • Anqi Ma

    (Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai)

  • Cherry Leung

    (University Health Network)

  • Genna M. Luciani

    (University of Toronto
    University Health Network)

  • Jennifer Haynes

    (University Health Network)

  • Aaron Pollett

    (University of Toronto
    Lunenfeld-Tanenbaum Research Institute Toronto)

  • Constanze Zeller

    (University Health Network)

  • Shili Duan

    (University of Toronto)

  • Antonija Kreso

    (University Health Network)

  • Dalia Barsyte-Lovejoy

    (University of Toronto)

  • Bradly G. Wouters

    (University Health Network
    University of Toronto
    University of Toronto)

  • Jian Jin

    (Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai)

  • Daniel D. De Carvalho

    (University Health Network
    University of Toronto)

  • Mathieu Lupien

    (University Health Network
    University of Toronto
    Ontario Institute for Cancer Research)

  • Cheryl H. Arrowsmith

    (University of Toronto
    University Health Network
    University of Toronto)

  • Catherine A. O’Brien

    (University Health Network
    University of Toronto
    University of Toronto
    University of Toronto)

Abstract

In embryonic stem cells, promoters of key lineage-specific differentiation genes are found in a bivalent state, having both activating H3K4me3 and repressive H3K27me3 histone marks, making them poised for transcription upon loss of H3K27me3. Whether cancer-initiating cells (C-ICs) have similar epigenetic mechanisms that prevent lineage commitment is unknown. Here we show that colorectal C-ICs (CC-ICs) are maintained in a stem-like state through a bivalent epigenetic mechanism. Disruption of the bivalent state through inhibition of the H3K27 methyltransferase EZH2, resulted in decreased self-renewal of patient-derived C-ICs. Epigenomic analyses revealed that the promoter of Indian Hedgehog (IHH), a canonical driver of normal colonocyte differentiation, exists in a bivalent chromatin state. Inhibition of EZH2 resulted in de-repression of IHH, decreased self-renewal, and increased sensitivity to chemotherapy in vivo. Our results reveal an epigenetic block to differentiation in CC-ICs and demonstrate the potential for epigenetic differentiation therapy of a solid tumour through EZH2 inhibition.

Suggested Citation

  • Evelyne Lima-Fernandes & Alex Murison & Tiago da Silva Medina & Yadong Wang & Anqi Ma & Cherry Leung & Genna M. Luciani & Jennifer Haynes & Aaron Pollett & Constanze Zeller & Shili Duan & Antonija Kre, 2019. "Targeting bivalency de-represses Indian Hedgehog and inhibits self-renewal of colorectal cancer-initiating cells," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09309-4
    DOI: 10.1038/s41467-019-09309-4
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