title: ABCB4 is frequently epigenetically silenced in human cancers and inhibits tumor growth.
abstract: Epigenetic silencing through promoter hypermethylation is an important hallmark for the inactivation of tumor-related genes in carcinogenesis. Here we identified the ATP-binding cassette sub-family B member 4 (ABCB4) as a novel epigenetically silenced target gene. We investigated the epigenetic regulation of ABCB4 in 26 human lung, breast, skin, liver, head and neck cancer cells lines and in primary cancers by methylation and expression analysis. Hypermethylation of the ABCB4 CpG island promoter occurred in 16 out of 26 (62%) human cancer cell lines. Aberrant methylation of ABCB4 was also revealed in 39% of primary lung cancer and in 20% of head and neck cancer tissues. In 37% of primary lung cancer samples, ABCB4 expression was absent. For breast cancer a significant hypermethylation occurred in tumor tissues (41%) compared to matching normal samples (0%, p = 0.002). Silencing of ABCB4 was reversed by 5-aza-2'-deoxycytidine and zebularine treatments leading to its reexpression in cancer cells. Overexpression of ABCB4 significantly suppressed colony formation and proliferation of lung cancer cells. Hypermethylation of Abcb4 occurred also in murine cancer, but was not found in normal tissues. Our findings suggest that ABCB4 is a frequently silenced gene in different cancers and it may act tumor suppressivly in lung cancer.
authors.affiliation: Institute for Genetics; Justus-Liebig-University; Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research; 35392 Giessen, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Kiehl
authors.affiliation: Institute for Genetics; Justus-Liebig-University; Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research; 35392 Giessen, Germany.
authors.forename: Stefanie C
authors.initials: SC
authors.lastname: Herkt
authors.affiliation: Institute for Genetics; Justus-Liebig-University; Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research; 35392 Giessen, Germany.
authors.forename: Antje M
authors.initials: AM
authors.lastname: Richter
authors.affiliation: Molecular Mechanisms in Lung Cancer, Max Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research; 61231 Bad Nauheim, Germany.
authors.forename: Liesa
authors.initials: L
authors.lastname: Fuhrmann
authors.affiliation: Molecular Mechanisms in Lung Cancer, Max Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research; 61231 Bad Nauheim, Germany.
authors.forename: Nefertiti
authors.initials: N
authors.lastname: El-Nikhely
authors.affiliation: Molecular Mechanisms in Lung Cancer, Max Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research; 61231 Bad Nauheim, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.affiliation: Molecular Mechanisms in Lung Cancer, Max Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research; 61231 Bad Nauheim, Germany.
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Savai
authors.affiliation: Institute for Genetics; Justus-Liebig-University; Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research; 35392 Giessen, Germany.
authors.forename: Reinhard H
authors.initials: RH
authors.lastname: Dammann
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; C095122:multidrug resistance protein 3