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

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 ZEB...

Descripción completa

Detalles Bibliográficos
Autores: Waryah, Charlene, Cursons, Joseph, Foroutan, Momeneh, Pflueger, Christian, Wang, Edina, Molania, Ramyar, Woodward, Eleanor, Sorolla, Anabel, Wallis, Christopher, Moses, Colette, Glas, Irina, Magalhães, Leandro, Thompson, Erik W., Fearnley, Liam G., Chaffer, Christine L., Davis, Melissa, Papenfuss, Anthony T., Redfern, Andrew, Lister, Ryan, Esteller, M.|||0000-0003-4490-6093, Blancafort, Pilar
Tipo de recurso: artículo
Fecha de publicación:2023
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:289212
Acceso en línea:https://ddd.uab.cat/record/289212
https://dx.doi.org/urn:doi:10.1002/advs.202301802
Access Level:acceso abierto
Palabra clave:Cancer epigenetics
CRISPR/dCas9 repression
Epithelial-mesenchymaltransition
Triple negative breast cancer
ZEB1
Descripción
Sumario: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.

Similares en LA Referencia