EMT transcription factor ZEB1 alters the epigenetic landscape of colorectal cancer cells

Lindner P, Paul S, Eckstein M, Hampel C, Muenzner JK, Erlenbach-Wuensch K, Ahmed HP, Mahadevan V, Brabletz T, Hartmann A, Vera J, Schneider-Stock R (2020)

Publication Type: Journal article

Publication year: 2020

Journal

Cell Death & Disease Nature Publishing Group: Open Access Journals - Option B / Nature Publishing Group

Book Volume: 11

Article Number: 147

Journal Issue: 2

DOI: 10.1038/s41419-020-2340-4

Abstract

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.

Authors with CRIS profile

Pablo Lennert Institute of Pathology Markus Eckstein Institute of Pathology Thomas Brabletz Lehrstuhl für Experimentelle Medizin mit dem Schwerpunkt Molekulare Pathogeneseforschung Arndt Hartmann Lehrstuhl für Allgemeine Pathologie und Pathologische Anatomie Julio Vera González Professur für Tumorimmunologie (Schwerpunkt Systembiologie) Regine Schneider-Stock Professur für Experimentelle Tumorpathologie

Involved external institutions

Institute of Bioinformatics and Applied Biotechnology (IBAB) IN India (IN)

How to cite

APA:

Lindner, P., Paul, S., Eckstein, M., Hampel, C., Muenzner, J.K., Erlenbach-Wuensch, K.,... Schneider-Stock, R. (2020). EMT transcription factor ZEB1 alters the epigenetic landscape of colorectal cancer cells. Cell Death & Disease, 11(2). https://doi.org/10.1038/s41419-020-2340-4

MLA:

Lindner, Pablo, et al. "EMT transcription factor ZEB1 alters the epigenetic landscape of colorectal cancer cells." Cell Death & Disease 11.2 (2020).

BibTeX: Download