Integrative genomics analysis reveals silencing of beta-adrenergic signaling by polycomb in prostate cancer.
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.
Yu
Jindan
J
Department of Pathology, Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Cao
Qi
Q
Mehra
Rohit
R
Laxman
Bharathi
B
Yu
Jianjun
J
Tomlins
Scott A
SA
Creighton
Chad J
CJ
Dhanasekaran
Saravana M
SM
Shen
Ronglai
R
Chen
Guoan
G
Morris
David S
DS
Marquez
Victor E
VE
Shah
Rajal B
RB
Ghosh
Debashis
D
Varambally
Sooryanarayana
S
Chinnaiyan
Arul M
AM
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*
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