Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer.
The evolution of prostate cancer from an androgen-dependent state to one that is androgen-independent marks its lethal progression. The androgen receptor (AR) is essential in both, though its function in androgen-independent cancers is poorly understood. We have defined the direct AR-dependent target genes in both androgen-dependent and -independent cancer cells by generating AR-dependent gene expression profiles and AR cistromes. In contrast to what is found in androgen-dependent cells, AR selectively upregulates M-phase cell-cycle genes in androgen-independent cells, including UBE2C, a gene that inactivates the M-phase checkpoint. We find that epigenetic marks at the UBE2C enhancer, notably histone H3K4 methylation and FoxA1 transcription factor binding, are present in androgen-independent cells and direct AR-enhancer binding and UBE2C activation. Thus, the role of AR in androgen-independent cancer cells is not to direct the androgen-dependent gene expression program without androgen, but rather to execute a distinct program resulting in androgen-independent growth.
Wang
Qianben
Q
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
Li
Wei
W
Zhang
Yong
Y
Yuan
Xin
X
Xu
Kexin
K
Yu
Jindan
J
Chen
Zhong
Z
Beroukhim
Rameen
R
Wang
Hongyun
H
Lupien
Mathieu
M
Wu
Tao
T
Regan
Meredith M
MM
Meyer
Clifford A
CA
Carroll
Jason S
JS
Manrai
Arjun Kumar
AK
Jänne
Olli A
OA
Balk
Steven P
SP
Mehra
Rohit
R
Han
Bo
B
Chinnaiyan
Arul M
AM
Rubin
Mark A
MA
True
Lawrence
L
Fiorentino
Michelangelo
M
Fiore
Christopher
C
Loda
Massimo
M
Kantoff
Philip W
PW
Liu
X Shirley
XS
Brown
Myles
M
D000728:Androgens / Q000378:metabolism; D002455:Cell Division; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D015533:Transcriptional Activation; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism
C410798:AR protein, human; D000728:Androgens; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D006657:Histones; D011944:Receptors, Androgen; C105156:UBE2C protein, human; D044763:Ubiquitin-Conjugating Enzymes