Identification of Endoglin as an epigenetically regulated tumour-suppressor gene in lung cancer

• Published in: British journal of cancer Vol. 113; no. 6; pp. 970 - 978
• Main Authors: O’Leary, K, Shia, A, Cavicchioli, F, Haley, V, Comino, A, Merlano, M, Mauri, F, Walter, K, Lackner, M, Wischnewsky, M B, Crook, T, Lo Nigro, C, Schmid, P
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.09.2015; Nature Publishing Group
• Subjects: 692/699/67/1612/1350; 692/699/67/581; 692/699/67/68/2486; Antigens, CD - genetics; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - mortality; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Disease Progression; Down-Regulation; Drug Resistance; Endoglin; Epidemiology; Gene Silencing; Genes, Tumor Suppressor; Genetics & Genomics; genetics-and-genomics; Genome-Wide Association Study; Humans; Lung Neoplasms - genetics; Lung Neoplasms - mortality; Lung Neoplasms - pathology; Methylation; Molecular Medicine; Oncology; Promoter Regions, Genetic; Protein Array Analysis; Receptors, Cell Surface - genetics; Sequence Analysis, DNA - methods; lung cancer; Endoglin; epigenetic; tumour suppressor; EMT
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2015.302

Background: The transforming growth factor-beta (TGF- β ) pathway has been implicated in proliferation, migration and invasion of various cancers. Endoglin is a TGF- β accessory receptor that modulates signalling. We identified Endoglin as an epigenetically silenced tumour-suppressor gene in lung cancer by means of a genome-wide screening approach, then sought to characterise its effect on lung cancer progression. Methods: Methylation microarray and RNA sequencing were carried out on lung cancer cell lines. Epigenetic silencing of Endoglin was confirmed by methylation and expression analyses. An expression vector and a 20-gene expression panel were used to evaluate Endoglin function. Pyrosequencing was carried out on two independent cohorts comprising 112 and 202 NSCLC cases, respectively, and the impact of Endoglin methylation on overall survival (OS) was evaluated. Results: Methylation in the promoter region resulted in silencing of Endoglin, which could be reactivated by demethylation. Increased invasion coupled with altered EMT marker expression was observed in cell lines with an epithelial-like, but not those with a mesenchymal-like, profile when Endoglin was absent. Methylation was associated with decreased OS in stage I but not in stages II–III disease. Conclusions: We show that Endoglin is a common target of epigenetic silencing in lung cancer. We reveal a link between Endoglin silencing and EMT progression that might be associated with decreased survival in stage I disease.