An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression.
Chromosomal rearrangements fusing the androgen-regulated gene TMPRSS2 to the oncogenic ETS transcription factor ERG occur in approximately 50% of prostate cancers, but how the fusion products regulate prostate cancer remains unclear. Using chromatin immunoprecipitation coupled with massively parallel sequencing, we found that ERG disrupts androgen receptor (AR) signaling by inhibiting AR expression, binding to and inhibiting AR activity at gene-specific loci, and inducing repressive epigenetic programs via direct activation of the H3K27 methyltransferase EZH2, a Polycomb group protein. These findings provide a working model in which TMPRSS2-ERG plays a critical role in cancer progression by disrupting lineage-specific differentiation of the prostate and potentiating the EZH2-mediated dedifferentiation program.
Yu
Jindan
J
Michigan Center for Translational Pathology, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Yu
Jianjun
J
Mani
Ram-Shankar
RS
Cao
Qi
Q
Brenner
Chad J
CJ
Cao
Xuhong
X
Wang
Xiaoju
X
Wu
Longtao
L
Li
James
J
Hu
Ming
M
Gong
Yusong
Y
Cheng
Hong
H
Laxman
Bharathi
B
Vellaichamy
Adaikkalam
A
Shankar
Sunita
S
Li
Yong
Y
Dhanasekaran
Saravana M
SM
Morey
Roger
R
Barrette
Terrence
T
Lonigro
Robert J
RJ
Tomlins
Scott A
SA
Varambally
Sooryanarayana
S
Qin
Zhaohui S
ZS
Chinnaiyan
Arul M
AM
D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000235:genetics*; D018450:Disease Progression; D000071221:Enhancer of Zeste Homolog 2 Protein; D050939:Gene Fusion; D006801:Humans; D008297:Male; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D063151:Polycomb Repressive Complex 2; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D011944:Receptors, Androgen / Q000235:genetics*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics*
D004268:DNA-Binding Proteins; D015514:Oncogene Proteins, Fusion; D011944:Receptors, Androgen; C515553:TMPRSS2-ERG fusion protein, human; D014157:Transcription Factors; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2