title: Evidence for a functional role of epigenetically regulated midcluster HOXB genes in the development of Barrett esophagus.
abstract: Barrett esophagus (BE) is a human metaplastic condition that is the only known precursor to esophageal adenocarcinoma. BE is characterized by a posterior intestinal-like phenotype in an anterior organ and therefore it is reminiscent of homeotic transformations, which can occur in transgenic animal models during embryonic development as a consequence of mutations in HOX genes. In humans, acquired deregulation of HOX genes during adulthood has been linked to carcinogenesis; however, little is known about their role in the pathogenesis of premalignant conditions. We hypothesized that HOX genes may be implicated in the development of BE. We demonstrated that three midcluster HOXB genes (HOXB5, HOXB6, and HOXB7) are overexpressed in BE, compared with the anatomically adjacent normal esophagus and gastric cardia. The midcluster HOXB gene signature in BE is identical to that seen in normal colonic epithelium. Ectopic expression of these three genes in normal squamous esophageal cells in vitro induces markers of intestinal differentiation, such as KRT20, MUC2, and VILLIN. In BE-associated adenocarcinoma, the activation midcluster HOXB gene is associated with loss of H3K27me3 and gain of AcH3, compared with normal esophagus. These changes in histone posttranslational modifications correlate with specific chromatin decompaction at the HOXB locus. We suggest that epigenetically regulated alterations of HOX gene expression can trigger changes in the transcriptional program of adult esophageal cells, with implications for the early stages of carcinogenesis.
authors.affiliation: Medical Research Council Cancer Cell Unit, Hutchison Medical Research Council Research Centre, CB2 0XZ Cambridge,  United Kingdom.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: di Pietro
authors.forename: Pierre
authors.initials: P
authors.lastname: Lao-Sirieix
authors.forename: Shelagh
authors.initials: S
authors.lastname: Boyle
authors.forename: Andy
authors.initials: A
authors.lastname: Cassidy
authors.forename: Dani
authors.initials: D
authors.lastname: Castillo
authors.forename: Amel
authors.initials: A
authors.lastname: Saadi
authors.forename: Ragnhild
authors.initials: R
authors.lastname: Eskeland
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Fitzgerald
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D001471:Barrett Esophagus / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D003106:Colon / Q000166:cytology / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D004938:Esophageal Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D004947:Esophagus / Q000166:cytology / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D005801:Genes, Homeobox / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D046228:Microarray Analysis; D016133:Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; C489126:HOXB5 protein, human; C093252:HOXB6 protein, human; C490538:HOXB7 protein, human; D006657:Histones; D018398:Homeodomain Proteins