FOXO1 binds to the TAU5 motif and inhibits constitutively active androgen receptor splice variants
Version of Record online: 6 FEB 2013
Copyright © 2013 Wiley Periodicals, Inc.
Volume 73, Issue 10, pages 1017–1027, July 2013
How to Cite
Bohrer, L. R., Liu, P., Zhong, J., Pan, Y., Angstman, J., Brand, L. J., Dehm, S. M. and Huang, H. (2013), FOXO1 binds to the TAU5 motif and inhibits constitutively active androgen receptor splice variants. Prostate, 73: 1017–1027. doi: 10.1002/pros.22649
- Issue online: 30 MAY 2013
- Version of Record online: 6 FEB 2013
- Manuscript Accepted: 8 JAN 2013
- Manuscript Received: 26 OCT 2012
- National Institutes of Health. Grant Numbers: CA134514, CA130908, CA141011
- Department of Defense. Grant Numbers: W81XWH-09-1-622, W81XWH-10-1-0353
- Prostate Cancer Foundation
- androgen receptor;
- prostate cancer;
Aberrant activation of the androgen receptor (AR) is a major factor highly relevant to castration-resistant progression of prostate cancer (PCa). FOXO1, a key downstream effector of PTEN, inhibits androgen-independent activation of the AR. However, the underlying mechanism remains elusive.
The inhibitory effect of FOXO1 on full-length and constitutively active splice variants of the AR was examined by luciferase reporter assays and real-time reverse transcription polymerase chain reaction (RT-qPCR). In vitro protein binding assays and western blot analyses were used to determine the regions in FOXO1 and AR responsible for their interaction.
We found that a putative transcription repression domain in the NH2-terminus of FOXO1 is dispensable for FOXO1 inhibition of the AR. In vitro protein binding assays showed that FOXO1 binds to the transcription activation unit 5 (TAU5) motif in the AR NH2-terminal domain (NTD), a region required for recruitment of p160 activators including SRC-1. Ectopic expression of SRC-1 augmented transcriptional activity of some, but not all AR splice variants examined. Forced expression of FOXO1 blocked the effect of SRC-1 on AR variants' transcriptional activity by decreasing the binding of SRC-1 to the AR NTD. Ectopic expression of FOXO1 inhibited expression of endogenous genes activated primarily by alternatively spliced AR variants in human castration-resistant PCa 22Rv1 cells.
FOXO1 binds to the TAU5 motif in the AR NTD and inhibits ligand-independent activation of AR splice variants, suggesting the PTEN/FOXO1 pathway as a potential therapeutic target for inhibition of aberrant AR activation and castration-resistant PCa growth. Prostate 73: 1017–1027, 2013. © 2013 Wiley Periodicals, Inc.