Synthetic Epigenetic Reprogramming of Mesenchymal to Epithelial States Using the CRISPR/dCas9 Platform in Triple Negative Breast Cancer
Waryah, Charlene (University of Western Australia)
Cursons, Joseph (Monash University, Australia)
Foroutan, Momeneh (Department of Biochemistry and Molecular Biology. Monash University, Australia)
Pflueger, Christian (University of Western Australia)
Wang, Edina (University of Western Australia)
Molania, Ramyar (University of Melbourne, Australia)
Woodward, Eleanor (Harry Perkins Institute of Medical Research, Australia)
Sorolla, Anabel (University of Western Australia)
Wallis, Christopher (University of Western Australia)
Moses, Colette (University of Amsterdam, The Netherlands)
Glas, Irina (Harry Perkins Institute of Medical Research, Australia)
Magalhães, Leandro (University of Pará, Brazil)
Thompson, Erik W. (Queensland University of Technology, Brisbane, Australia)
Fearnley, Liam G. (University of Melbourne, Australia)
Chaffer, Christine L. (St Vincent's Clinical School. UNSW Medicine, Australia)
Davis, Melissa (University of Melbourne, Australia)
Papenfuss, Anthony T. (University of Melbourne, Australia)
Redfern, Andrew (University of Western Australia)
Lister, Ryan (The University of Western Australia)
Esteller, M (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Blancafort, Pilar (University of Western Australia)

Fecha:	2023
Resumen:	Epithelial-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.
Nota:	Altres ajuts: National Health and Medical Research Council (NHMRC) grant APP1147528; NHMRC grants APP1165208 and APP1187328; National Breast Cancer Foundation IIRS-22-044; Cancer Council New South Wales APP2013068; Cancer Council Western Australia APP2004608
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Cancer epigenetics ; CRISPR/dCas9 repression ; Epithelial-mesenchymaltransition ; Triple negative breast cancer ; ZEB1
Publicado en:	Advanced science, Vol. 10 Núm. 22 (august 2023) , ISSN 2198-3844

DOI: 10.1002/advs.202301802
PMID: 37217832

22 p, 8.7 MB

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Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Instituto de Investigación contra la Leucemia Josep Carreras
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