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

Nat Commun. 2019 Mar 29;10(1):1436
Evelyne Lima-Fernandes 1 , Alex Murison 1 , Tiago da Silva Medina 1 , Yadong Wang 1 , Anqi Ma 2 , Cherry Leung 1 , Genna M Luciani 1 , Jennifer Haynes 1 , Aaron Pollett 3 , Constanze Zeller 1 , Shili Duan 4 , Antonija Kreso 1 , Dalia Barsyte-Lovejoy 5 , Bradly G Wouters 6 , Jian Jin 2 , Daniel D De Carvalho 4 , Mathieu Lupien 7 , Cheryl H Arrowsmith 8 , Catherine A O'Brien 9
Evelyne Lima-Fernandes 1 , Alex Murison 1 , Tiago da Silva Medina 1 , Yadong Wang 1 , Anqi Ma 2 , Cherry Leung 1 , Genna M Luciani 1 , Jennifer Haynes 1 , Aaron Pollett 3 , Constanze Zeller 1 , Shili Duan 4 , Antonija Kreso 1 , Dalia Barsyte-Lovejoy 5 , Bradly G Wouters 6 , Jian Jin 2 , Daniel D De Carvalho 4 , Mathieu Lupien 7 , Cheryl H Arrowsmith 8 , Catherine A O'Brien 9
+ et al

[No authors listed]

Author information
  • 1 Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G1L7, Canada.
  • 2 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.
  • 3 Lunenfeld-Tanenbaum Research Institute Toronto, Toronto, ON, M5G1X5, Canada.
  • 4 Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G1L7, Canada.
  • 5 Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G1L7, Canada.
  • 6 Department of Radiation Oncology, University of Toronto, Toronto, ON, M5G1L7, Canada.
  • 7 Ontario Institute for Cancer Research, Toronto, ON, M5G1L7, Canada.
  • 8 Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G1L7, Canada. carrow@uhnresearch.ca.
  • 9 Department of Surgery, Toronto General Hospital, Toronto, ON, M5G2C4, Canada. Catherine.OBrien@uhnresearch.ca.

摘要

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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