EMT transcription factor ZEB1 alters the epigenetic landscape of colorectal cancer cells.
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
24 02 2020
24 02 2020
Historique:
received:
12
04
2019
accepted:
06
12
2019
revised:
05
12
2019
entrez:
26
2
2020
pubmed:
26
2
2020
medline:
10
4
2021
Statut:
epublish
Résumé
Epigenetic deregulation remarkably triggers mechanisms associated with tumor aggressiveness like epithelial-mesenchymal transition (EMT). Since EMT is a highly complex, but also reversible event, epigenetic processes such as DNA methylation or chromatin alterations must be involved in its regulation. It was recently described that loss of the cell cycle regulator p21 was associated with a gain in EMT characteristics and an upregulation of the master EMT transcription factor ZEB1. In this study, in silico analysis was performed in combination with different in vitro and in vivo techniques to identify and verify novel epigenetic targets of ZEB1, and to proof the direct transcriptional regulation of SETD1B by ZEB1. The chorioallantoic-membrane assay served as an in vivo model to analyze the ZEB1/SETD1B interaction. Bioinformatical analysis of CRC patient data was used to examine the ZEB1/SETD1B network under clinical conditions and the ZEB1/SETD1B network was modeled under physiological and pathological conditions. Thus, we identified a self-reinforcing loop for ZEB1 expression and found that the SETD1B associated active chromatin mark H3K4me3 was enriched at the ZEB1 promoter in EMT cells. Moreover, clinical evaluation of CRC patient data showed that the simultaneous high expression of ZEB1 and SETD1B was correlated with the worst prognosis. Here we report that the expression of chromatin modifiers is remarkably dysregulated in EMT cells. SETD1B was identified as a new ZEB1 target in vitro and in vivo. Our study demonstrates a novel example of an activator role of ZEB1 for the epigenetic landscape in colorectal tumor cells.
Identifiants
pubmed: 32094334
doi: 10.1038/s41419-020-2340-4
pii: 10.1038/s41419-020-2340-4
pmc: PMC7040187
doi:
Substances chimiques
ZEB1 protein, human
0
Zinc Finger E-box-Binding Homeobox 1
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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