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

Waryah, C; Cursons, J; Foroutan, M; Pflueger, C; Wang, E; Molania, R; Woodward, E; Sorolla, A; Wallis, C; Moses, C; Glas, I; Magalh&#227;es, L; Thompson, EW; Fearnley, LG; Chaffer, CL; Davis, M; Papenfuss, AT; Redfern, A; Lister, R; Esteller, M; Blancafort, P

Author(s): Waryah, C; Cursons, J; Foroutan, M; Pflueger, C; Wang, E; Molania, R; Woodward, E; Sorolla, A; Wallis, C; Moses, C; Glas, I; Magalhães, L; Thompson, EW; Fearnley, LG; Chaffer, CL; Davis, M; Papenfuss, AT; Redfern, A; Lister, R; Esteller, M; Blancafort, P;
Details: Publication Year 2023-05-22,Volume 10,Issue #22,Page e2301802
Journal Title: Advanced Science
Abstract: 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.
Publisher: Wiley
Keywords: CRISPR/dCas9 repression; Zeb1; cancer epigenetics; epithelial-mesenchymal transition; triple negative breast cancer
Research Division(s): Bioinformatics; Population Health And Immunity
PubMed ID: 37217832
Publisher's Version: https://doi.org/10.1002/advs.202301802
Open Access at Publisher's Site: https://doi.org/10.1002/advs.202301802
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-12-13 10:19:47

Last Modified: 2023-12-13 10:22:01