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Nat Commun. 2019 Mar 29;10(1):1436. doi: 10.1038/s41467-019-09309-4.

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

Author information

1
Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G1L7, Canada.
2
Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G1L7, Canada.
3
Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
4
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, M5S1A8, Canada.
5
Lunenfeld-Tanenbaum Research Institute Toronto, Toronto, ON, M5G1X5, Canada.
6
Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G1L7, Canada.
7
Department of Radiation Oncology, University of Toronto, Toronto, ON, M5G1L7, Canada.
8
Ontario Institute for Cancer Research, Toronto, ON, M5G1L7, Canada.
9
Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G1L7, Canada. carrow@uhnresearch.ca.
10
Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G1L7, Canada. carrow@uhnresearch.ca.
11
Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G1L7, Canada. carrow@uhnresearch.ca.
12
Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G1L7, Canada. Catherine.OBrien@uhnresearch.ca.
13
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, M5S1A8, Canada. Catherine.OBrien@uhnresearch.ca.
14
Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G1L7, Canada. Catherine.OBrien@uhnresearch.ca.
15
Department of Physiology, University of Toronto, Toronto, ON, M5G1L7, Canada. Catherine.OBrien@uhnresearch.ca.
16
Department of Surgery, Toronto General Hospital, Toronto, ON, M5G2C4, Canada. Catherine.OBrien@uhnresearch.ca.

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.

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