title: MYC-induced epigenetic activation of GATA4 in lung adenocarcinoma.
abstract: Human lung cancer is a disease with high incidence and accounts for most cancer-related deaths in both men and women. Metastasis is a common event in non-small cell lung carcinoma (NSCLC), diminishing the survival chance of the patients with this type of tumor. It has been shown that MYC is involved in the development of metastasis from NSCLC, but the mechanism underlying this switch remained to be identified. Here, we focus on GATA4 as a MYC target in the development of metastasis with origin in lung adenocarcinoma, the most common type of NSCLC. Epigenetic alterations at the GATA4 promoter level were observed after MYC expression in lung adenocarcinoma in vivo and in vitro. Such alterations include site-specific demethylation that accompanies the displacement of the MYC-associated zinc finger protein (MAZ) from the GATA4 promoter, which leads to GATA4 expression. Histone modification analysis of the GATA4 promoter revealed a switch from repressive histone marks to active histone marks after MYC binding, which corresponds to active GATA4 expression. Our results thus identify a novel epigenetic mechanism by which MYC activates GATA4 leading to metastasis in lung adenocarcinoma, suggesting novel potential targets for the development of antimetastatic therapy.
authors.affiliation: Biocenter, Department of Microbiology, University of Würzburg, Würzburg, Germany.
authors.forename: Inês C
authors.initials: IC
authors.lastname: Castro
authors.forename: Achim
authors.initials: A
authors.lastname: Breiling
authors.forename: Katharina
authors.initials: K
authors.lastname: Luetkenhaus
authors.forename: Fatih
authors.initials: F
authors.lastname: Ceteci
authors.forename: Simone
authors.initials: S
authors.lastname: Hausmann
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kress
authors.forename: Frank
authors.initials: F
authors.lastname: Lyko
authors.forename: Thomas
authors.initials: T
authors.lastname: Rudel
authors.forename: Ulf R
authors.initials: UR
authors.lastname: Rapp
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D002448:Cell Adhesion / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D050991:GATA4 Transcription Factor / Q000096:biosynthesis / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D055262:Mucin-2 / Q000235:genetics; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D014157:Transcription Factors / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; C117307:KRAS protein, human; C489427:MYC protein, human; D055262:Mucin-2; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; C076035:c-MYC-associated zinc finger protein; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins