title: Integrative genomics analysis reveals silencing of beta-adrenergic signaling by polycomb in prostate cancer.
abstract: The Polycomb group (PcG) protein EZH2 possesses oncogenic properties for which the underlying mechanism is unclear. We integrated in vitro cell line, in vivo tumor profiling, and genome-wide location data to nominate key targets of EZH2. One of the candidates identified was ADRB2 (Adrenergic Receptor, Beta-2), a critical mediator of beta-adrenergic signaling. EZH2 is recruited to the ADRB2 promoter and represses ADRB2 expression. ADRB2 inhibition confers cell invasion and transforms benign prostate epithelial cells, whereas ADRB2 overexpression counteracts EZH2-mediated oncogenesis. ADRB2 is underexpressed in metastatic prostate cancer, and clinically localized tumors that express lower levels of ADRB2 exhibit a poor prognosis. Taken together, we demonstrate the power of integrating multiple diverse genomic data to decipher targets of disease-related genes.
authors.affiliation: Department of Pathology, Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Jindan
authors.initials: J
authors.lastname: Yu
authors.forename: Qi
authors.initials: Q
authors.lastname: Cao
authors.forename: Rohit
authors.initials: R
authors.lastname: Mehra
authors.forename: Bharathi
authors.initials: B
authors.lastname: Laxman
authors.forename: Jianjun
authors.initials: J
authors.lastname: Yu
authors.forename: Scott A
authors.initials: SA
authors.lastname: Tomlins
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.forename: Saravana M
authors.initials: SM
authors.lastname: Dhanasekaran
authors.forename: Ronglai
authors.initials: R
authors.lastname: Shen
authors.forename: Guoan
authors.initials: G
authors.lastname: Chen
authors.forename: David S
authors.initials: DS
authors.lastname: Morris
authors.forename: Victor E
authors.initials: VE
authors.lastname: Marquez
authors.forename: Rajal B
authors.initials: RB
authors.lastname: Shah
authors.forename: Debashis
authors.initials: D
authors.lastname: Ghosh
authors.forename: Sooryanarayana
authors.initials: S
authors.lastname: Varambally
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins / Q000378:metabolism*; D000071221:Enhancer of Zeste Homolog 2 Protein; D020868:Gene Silencing; D023281:Genomics; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D009368:Neoplasm Transplantation; D063151:Polycomb Repressive Complex 2; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D018343:Receptors, Adrenergic, beta-2; D014157:Transcription Factors; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2