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

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 Kreso, Dalia Barsyte-Lovejoy, Bradly G. Wouters, Jian Jin, Daniel D. De Carvalho, Mathieu Lupien, Cheryl H. Arrowsmith () and Catherine A. O’Brien ()
Additional contact information
Evelyne Lima-Fernandes: University of Toronto
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
Jennifer Haynes: University Health Network
Aaron Pollett: University of 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
Jian Jin: Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
Daniel D. De Carvalho: University Health Network
Mathieu Lupien: University Health Network
Cheryl H. Arrowsmith: University of Toronto
Catherine A. O’Brien: University Health Network

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09309-4

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