Synthetic Epigenetic Reprogramming of Mesenchymal to Epithelial States Using the CRISPR/dCas9 Platform in Triple Negative Breast Cancer

Author:

Waryah Charlene12,Cursons Joseph34,Foroutan Momeneh34,Pflueger Christian56,Wang Edina12,Molania Ramyar78,Woodward Eleanor1,Sorolla Anabel12,Wallis Christopher12,Moses Colette19,Glas Irina1,Magalhães Leandro110,Thompson Erik W.1112,Fearnley Liam G.713,Chaffer Christine L.1415,Davis Melissa78,Papenfuss Anthony T.713,Redfern Andrew16,Lister Ryan56,Esteller Manel17181920,Blancafort Pilar12ORCID

Affiliation:

1. Cancer Epigenetics Group Harry Perkins Institute of Medical Research Perth WA 6009 Australia

2. Centre for Medical Research University of Western Australia Perth WA 6009 Australia

3. Monash Biomedicine Discovery Institute Monash University Melbourne VIC 3800 Australia

4. Department of Biochemistry and Molecular Biology Monash University Melbourne VIC 3800 Australia

5. Australian Research Council Centre of Excellence in Plant Energy Biology School of Molecular Sciences University of Western Australia Perth WA 6009 Australia

6. Harry Perkins Institute of Medical Research QEII Medical Centre and Centre for Medical Research, The University of Western Australia 6 Verdun St Perth WA 6009 Australia

7. Population Health and Immunity Division Bioinformatics Division Walter and Eliza Hall Institute of Medical Research Melbourne VIC 3052 Australia

8. Department of Biochemistry and Molecular Biology Faculty of Medicine Dentistry and Health Sciences University of Melbourne Melbourne VIC 3010 Australia

9. Evolutionary Neurogenomics Swammerdam Institute for Life Sciences University of Amsterdam Amsterdam XH 1098 The Netherlands

10. Postgraduate Program of Genetics and Molecular Biology Institute of Biological Sciences Federal University of Pará Belém 66075‐110 Brazil

11. School of Biomedical Sciences Queensland University of Technology Brisbane QLD 4000 Australia

12. Translational Research Institute Brisbane QLD 4102 Australia

13. Department of Medical Biology University of Melbourne Melbourne VIC 3800 Australia

14. The Kinghorn Cancer Centre Garvan Institute of Medical Research Darlinghurst NSW 2010 Australia

15. St Vincent's Clinical School UNSW Medicine Darlinghurst NSW 2010 Australia

16. School of Medicine University of Western Australia Perth WA 6009 Australia

17. Josep Carreras Leukemia Research Institute (IJC) Badalona Barcelona 08916 Spain

18. Centro de Investigacion Biomedica en Red Cancer (CIBERONC) Madrid 28029 Spain

19. Institucio Catalana de Recerca i Estudis Avançats (ICREA) Barcelona Catalonia 08010 Spain

20. Physiological Sciences Department School of Medicine and Health Sciences University of Barcelona (UB) Barcelona Catalonia 08007 Spain

Abstract

AbstractEpithelial‐mesenchymal transition (EMT) is a reversible transcriptional program invoked by cancer cells to drive cancer progression. Transcription factor ZEB1 is a master regulator of EMT, driving disease recurrence in poor‐outcome triple negative breast cancers (TNBCs). Here, this work silences ZEB1 in TNBC models by CRISPR/dCas9‐mediated epigenetic editing, resulting in highly‐specific and nearly complete suppression of ZEB1 in vivo, accompanied by long‐lasting tumor inhibition. Integrated “omic” changes promoted by dCas9 linked to the KRAB domain (dCas9‐KRAB) enabled the discovery of a ZEB1‐dependent‐signature of 26 genes differentially‐expressed and ‐methylated, including the reactivation and enhanced chromatin accessibility in cell adhesion loci, outlining epigenetic reprogramming toward a more epithelial state. In the ZEB1 locus transcriptional silencing is associated with induction of locally‐spread heterochromatin, significant changes in DNA methylation at specific CpGs, gain of H3K9me3, and a near complete erasure of H3K4me3 in the ZEB1 promoter. Epigenetic shifts induced by ZEB1‐silencing are enriched in a subset of human breast tumors, illuminating a clinically‐relevant hybrid‐like state. Thus, the synthetic epi‐silencing of ZEB1 induces stable “lock‐in” epigenetic reprogramming of mesenchymal tumors associated with a distinct and stable epigenetic landscape. This work outlines epigenome‐engineering approaches for reversing EMT and customizable precision molecular oncology approaches for targeting poor outcome breast cancers.

Funder

National Health and Medical Research Council

National Breast Cancer Foundation

Cancer Council NSW

Cancer Council Western Australia

Australian Genome Research Facility

Publisher

Wiley

Subject

General Physics and Astronomy,General Engineering,Biochemistry, Genetics and Molecular Biology (miscellaneous),General Materials Science,General Chemical Engineering,Medicine (miscellaneous)

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