Oncotarget

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Epigenetic silencing of tumor suppressor candidate 3 confers adverse prognosis in early colorectal cancer

Elke Burgermeister, Patrick Höde, Johannes Betge, Tobias Gutting, Andreas Merkel, Wen Wu, Marc Tänzer, Maximilian Mossner, Daniel Nowak, Julia Magdeburg, Felix Rückert, Carsten Sticht, Katja Breitkopf-Heinlein, Nadine Schulte, Nicolai Härtel, Sebastian Belle, Stefan Post, Timo Gaiser, Barbara Ingold Heppner, Hans-Michael Behrens, Christoph Röcken and Matthias P.A. Ebert _

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Oncotarget. 2017; 8:84714-84728. https://doi.org/10.18632/oncotarget.20950

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Abstract

Elke Burgermeister1,*, Patrick Höde1,*, Johannes Betge1, Tobias Gutting1, Andreas Merkel1, Wen Wu1, Marc Tänzer2, Maximilian Mossner3, Daniel Nowak3, Julia Magdeburg4, Felix Rückert4, Carsten Sticht5, Katja Breitkopf-Heinlein1, Nadine Schulte1, Nicolai Härtel1, Sebastian Belle1, Stefan Post4, Timo Gaiser6, Barbara Ingold Heppner7, Hans-Michael Behrens8, Christoph Röcken8 and Matthias P.A. Ebert1

1 Department of Medicine II, University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

2 Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

3 Department of Medicine III, University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

4 Department of Surgery, University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

5 Center for Medical Research (ZMF), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

6 Institute of Pathology, University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

7 Institute of Pathology, University Hospital Charite, Berlin, Germany

8 Institute of Pathology, Christian-Albrechts University, Kiel, Germany

* These authors have contributed equally to this work

Correspondence to:

Matthias P.A. Ebert, email:

Keywords: TUSC3, colorectal cancer, prognosis, glycosylation, growth factor receptor

Received: March 14, 2017 Accepted: August 23, 2017 Published: September 15, 2017

Abstract

Colorectal cancer (CRC) is a biologically and clinically heterogeneous disease. Even though many recurrent genomic alterations have been identified that may characterize distinct subgroups, their biological impact and clinical significance as prognostic indicators remain to be defined. The tumor suppressor candidate-3 (TUSC3/N33) locates to a genomic region frequently deleted or silenced in cancers. TUSC3 is a subunit of the oligosaccharyltransferase (OST) complex at the endoplasmic reticulum (ER) which catalyzes bulk N-glycosylation of membrane and secretory proteins. However, the consequences of TUSC3 loss are largely unknown. Thus, the aim of the study was to characterize the functional and clinical relevance of TUSC3 expression in CRC patients’ tissues (n=306 cases) and cell lines. TUSC3 mRNA expression was silenced by promoter methylation in 85 % of benign adenomas (n=46 cases) and 35 % of CRCs (n =74 cases). Epidermal growth factor receptor (EGFR) was selected as one exemplary ER-derived target protein of TUSC3-mediated posttranslational modification. We found that TUSC3 inhibited EGFR-signaling and promoted apoptosis in human CRC cells, whereas TUSC3 siRNA knock-down increased EGFR-signaling. Accordingly, in stage I/II node negative CRC patients (n=156 cases) loss of TUSC3 protein expression was associated with poor overall survival. In sum, our data suggested that epigenetic silencing of TUSC3 may be useful as a molecular marker for progression of early CRC.


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