Interleukin-4 activates androgen receptor through CBP/p300.
BACKGROUND
Aberrant activation of androgen receptor (AR) plays an important role in the progression of castration resistant prostate cancer. Interleukin-4 (IL-4) enhances AR activation in the absence of androgen and stimulates castration resistant growth of androgen-sensitive prostate cancer cells. However, the mechanism of IL-4 mediated AR activation has not yet been revealed.


METHODS
The effect of IL-4 on CBP/p300 expression was examined by Western blot analysis. The effect of IL-4 on the interactions of AR and CBP/p300 was examined by co-immunoprecipitation and ChIP assays. CBP/p300 siRNA was used to knockdown CBP/p300 expression to examine the role of CBP/p300 expression on IL-4 mediated AR activation.


RESULTS
We found that IL-4 increases CBP/p300 protein expression and enhances interaction of AR with CBP/p300 proteins through an increase in the recruitment of CBP/p300 protein to the androgen responsive elements in the promoters of androgen responsive genes. Down regulation of CBP/p300 expression using CBP/p300 specific siRNA abolished IL-4 mediated AR activation, suggesting that CBP/p300 is responsible for AR activation induced by IL-4. Furthermore, AR activation can be enhanced by AR acetylation induced by IL-4 in prostate cancer cells. The IL-4 mediated AR acetylation can be blocked by knocking down CBP/p300 expression using CBP/p300 specific siRNA.


CONCLUSIONS
These results suggest that IL-4 activates AR through enhanced expression of CBP/p300 and its histone acetyltransferase activity.
Lee
Soo Ok
SO
Department of Urology and Cancer Center, University of California Davis Medical Center, Sacramento, California 95817, USA.
Chun
Jae Yeon
JY
Nadiminty
Nagalakshmi
N
Lou
Wei
W
Feng
Siting
S
Gao
Allen C
AC
D001665:Binding Sites; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000502:physiology*; D016384:Consensus Sequence; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051548:Histone Acetyltransferases / Q000235:genetics; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology*; D008297:Male; D011471:Prostatic Neoplasms; D011944:Receptors, Androgen / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D050880:p300-CBP Transcription Factors / Q000502:physiology*
D011944:Receptors, Androgen; D015847:Interleukin-4; D051548:Histone Acetyltransferases; D050880:p300-CBP Transcription Factors