Basic Hallmarks of Urothelial Cancer Unleashed in Primary Uroepithelium by Interference with the Epigenetic Master Regulator ODC1.

Autor: Erichsen L; Epigenetics Core Laboratory, Institute of Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine University Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany., Seifert HH; Department of Urology, University Hospital Basel, Basel, Switzerland., Schulz WA; Department of Urology, Medical Faculty, Heinrich-Heine University Duesseldorf, Duesseldorf, Germany., Hoffmann MJ; Department of Urology, Medical Faculty, Heinrich-Heine University Duesseldorf, Duesseldorf, Germany., Niegisch G; Department of Urology, Medical Faculty, Heinrich-Heine University Duesseldorf, Duesseldorf, Germany., Araúzo-Bravo MJ; Group of Computational Biology and Systems Biomedicine, Biodonostia Health Research Institute, 20014, San Sebastián, Spain.; IKERBASQUE, Basque Foundation for Science, 48009, Bilbao, Spain., Bendhack ML; Department of Urology, University Hospital, Positivo University, Curitiba, Brazil., Poyet C; Department of Urology, University Hospital, University of Zurich, Zurich, Switzerland., Hermanns T; Department of Urology, University Hospital, University of Zurich, Zurich, Switzerland., Beermann A; Epigenetics Core Laboratory, Institute of Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine University Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany., Hassan M; Department of Surgery, Tulane University School of Medicine, New Orleans, LA, 70112, USA.; Institut National de la Santé et de la Recherché Médicale, University of Strasbourg, 67000, Strasbourg, France., Theis L; Epigenetics Core Laboratory, Institute of Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine University Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany., Mahmood W; Epigenetics Core Laboratory, Institute of Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine University Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany., Santourlidis S; Epigenetics Core Laboratory, Institute of Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine University Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany. simeon.santourlidis@med.uni-duesseldorf.de.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2020 Mar 02; Vol. 10 (1), pp. 3808. Date of Electronic Publication: 2020 Mar 02.
DOI: 10.1038/s41598-020-60796-8
Abstrakt: Urothelial carcinoma (UC) is a common disease causing significant morbidity and mortality as well as considerable costs for health systems. Extensive aberrant methylation of DNA is broadly documented in early UC, contributing to genetic instability, altered gene expression and tumor progression. However the triggers initiating aberrant methylation are unknown. Recently we discovered that several genes encoding key enzymes of methyl group and polyamine metabolism, including Ornithine Decarboxylase 1 (ODC1), are affected by DNA methylation in early stage UC. In this study, we investigated the hypothesis that these epigenetic alterations act in a feed-forward fashion to promote aberrant DNA methylation in UC. We demonstrate that siRNA-mediated knockdown of ODC1 expression elicits genome-wide LINE-1 demethylation, induction of LINE-1 transcripts and double-strand DNA breaks and decreases viability in primary cultured uroepithelial cells. Similarly, following siRNA-mediated knockdown of ODC1, UC cells undergo double-strand DNA breaks and apoptosis. Collectively, our findings provide evidence that ODC1 gene hypermethylation could be a starting point for the onset of genome-wide epigenetic aberrations in urothelial carcinogenesis. Furthermore, LINE-1 induction enabled by ODC1 interference provides a new experimental model to study mechanisms and consequences of LINE-1 activation in the etiology and progression of UC as well as presumably other cancers.
Databáze: MEDLINE
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