DNA methylation transcriptionally regulates the putative tumor cell growth suppressor ZNF677 in non-small cell lung cancers
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Gerwin Heller1,2, Corinna Altenberger1,2, Bianca Schmid1,2, Maximilian Marhold1,2, Erwin Tomasich1,2, Barbara Ziegler1,2, Leonhard Müllauer2,3, Christoph Minichsdorfer1,2, György Lang2,4,5, Adelheid End-Pfützenreuter2,4, Balazs Döme2,4,5,6, Britt-Madeleine Arns7, Kwun M. Fong8, Casey M. Wright8, Ian A. Yang8, Walter Klepetko2,4, Christoph C. Zielinski1,2, Sabine Zöchbauer-Müller1,2
1Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Vienna, Austria
2Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
3Department of Pathology, Medical University of Vienna, Vienna, Austria
4Division of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
5Department of Thoracic Surgery, National Institute of Oncology-Semmelweis University, Budapest, Hungary
6Department of Thoracic Oncology and Tumor Biology, National Koranyi Institute of Pulmonology, Budapest, Hungary
7Landesklinikum Thermenregion Hochegg, Grimmenstein, Austria
8University of Queensland, The Prince Charles Hospital, Queensland, Chermside, Australia
Sabine Zöchbauer-Müller, e-mail: firstname.lastname@example.org
Keywords: DNA methylation, microarray analysis, ZNF677, MS-HRM analysis, non-small cell lung cancer
Received: August 07, 2014 Accepted: November 04, 2014 Published: December 05, 2014
In our study, we investigated the role of ZNF677 in non-small cell lung cancers (NSCLC). By comparing ZNF677 expression in primary tumor (TU) and in the majority of cases also of corresponding non-malignant lung tissue (NL) samples from > 1,000 NSCLC patients, we found tumor-specific downregulation of ZNF677 expression (adjusted p-values < 0.001). We identified methylation as main mechanism for ZNF677 downregulation in NSCLC cells and we observed tumor-specific ZNF677 methylation in NSCLC patients (p < 0.0001). In the majority of TUs, ZNF677 methylation was associated with loss of ZNF677 expression. Moreover, ZNF677 overexpression in NSCLC cells was associated with reduced cell proliferation and cell migration. ZNF677 was identified to regulate expression of many genes mainly involved in growth hormone regulation and interferon signalling. Finally, patients with ZNF677 methylated TUs had a shorter overall survival compared to patients with ZNF677 not methylated TUs (p = 0.013). Overall, our results demonstrate that ZNF677 is trancriptionally regulated by methylation in NSCLCs, suggest that ZNF677 has tumor cell growth suppressing properties in NSCLCs and that ZNF677 methylation might serve as prognostic parameter in these patients.
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