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Abstract
The epigenetic writer lysine-specific demethylase 1 (LSD1) is aberrantly upregulated in many cancer types and its overexpression correlates with poor survival and tumor progression. In this study, we analysed LSD1 function in non-small cell lung cancer adenocarcinomas. Expression profiling of 182 cases of lung adenocarcinoma proved a significant correlation of LSD1 overexpression with lung adenocarcinoma progression and metastasis. KRAS-mutated lung cancer cell clones were stably silenced for LSD1 expression. RNA-seq and comprehensive pathway analysis revealed, that genes related to a recently described non-canonical integrin β3 pathway, were significantly downregulated by LSD1 silencing. Hence, invasion and self-renewal capabilities were strongly decreased. Notably, this novel defined LSD1/integrin β3 axis, was also detected in human lung adenocarcinoma specimens. Furthermore, the linkage of LSD1 to an altered expression pattern of lung-lineage specific transcription factors and genes, which are involved in alveolar epithelial differentiation, was demonstrated. Thus, our findings point to a LSD1-integrin β3 axis, conferring attributes of invasiveness and tumor progression to lung adenocarcinoma.
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1 Institute of Pathology, University Hospital of Cologne, Cologne, Germany; The Center for Molecular Medicine Cologne (CMMC), Cologne, Germany
2 Institute of Pathology, University Hospital of Cologne, Cologne, Germany; Center of Integrative Oncology, University Clinic of Cologne and Bonn, Cologne, Germany
3 Functional Epigenomics, University of Cologne, Cologne, Germany
4 Institute of Pathology, University Hospital of Cologne, Cologne, Germany
5 Center of Integrative Oncology, University Clinic of Cologne and Bonn, Cologne, Germany; Department of Translational Genomics, Medical Faculty, University of Cologne, Cologne, Germany; Centre Léon Bérard, Lyon, France
6 Center of Integrative Oncology, University Clinic of Cologne and Bonn, Cologne, Germany; Department of Translational Genomics, Medical Faculty, University of Cologne, Cologne, Germany
7 Institute of Pathology, University Hospital of Cologne, Cologne, Germany; Center of Integrative Oncology, University Clinic of Cologne and Bonn, Cologne, Germany; Lung Cancer Group Cologne, University Hospital of Cologne, Cologne, Germany
8 Center of Integrative Oncology, University Clinic of Cologne and Bonn, Cologne, Germany; Lung Cancer Group Cologne, University Hospital of Cologne, Cologne, Germany; Clinic for Internal Medicine, University Hospital of Cologne, Cologne, Germany
9 Max Planck Institute for Molecular Genetics, Berlin, Germany
10 Institute of Pathology, University Hospital of Cologne, Cologne, Germany; Center of Integrative Oncology, University Clinic of Cologne and Bonn, Cologne, Germany; Department of Translational Genomics, Medical Faculty, University of Cologne, Cologne, Germany; German Cancer Research Center, German Cancer Consortium (DKTK), Heidelberg, Germany
11 Institute of Pathology, University Hospital of Cologne, Cologne, Germany; The Center for Molecular Medicine Cologne (CMMC), Cologne, Germany; Center of Integrative Oncology, University Clinic of Cologne and Bonn, Cologne, Germany; Lung Cancer Group Cologne, University Hospital of Cologne, Cologne, Germany
12 Institute of Pathology, University Hospital of Cologne, Cologne, Germany; The Center for Molecular Medicine Cologne (CMMC), Cologne, Germany; Lung Cancer Group Cologne, University Hospital of Cologne, Cologne, Germany