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Cited by 67Prostate Cancer Treatment and ResearchFOXO transcription factor regulationSperm and Testicular Function

A transcription-independent function of FOXO1 in inhibition of androgen-independent activation of the androgen receptor in prostate cancer cells.

Open access
Liu, Ping, Li, Shangwei, Gan, Lu, Kao, Timothy P., Huang, Haojie·2008·Cancer Research
DOI 10.1158/0008-5472.can-08-2038
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Abstract

Increasing evidence suggests that aberrant activation of the androgen receptor (AR) plays a pivotal role in the development and progression of androgen depletion-independent prostate cancer (PCa) after androgen deprivation therapy. Here, we show that loss of the PTEN tumor suppressor gene is associated with hyperactivation of the AR in human PCa cell lines. This effect is mediated primarily by its downstream effector FOXO1. In addition to the inhibition of androgenic activation of the AR, forced expression of FOXO1 in PTEN-negative PCa cells also inhibits androgen-independent activation of the AR in a manner independent of FOXO1 transcriptional function. In contrast, silencing of FOXO1 in PTEN-positive cells not only increases the basal activity of the AR in the absence of androgens, it also markedly sensitizes the AR activation by low levels of androgens or nonandrogenic factors such as interleukin-6. FOXO1-mediated inhibition of the AR is partially attenuated by the histone deacetylase (HDAC) inhibitor trichostatin A. Accordingly, FOXO1 interacts with HDAC3 as shown by coimmunoprecipitation assays, and cotransfection of cells with FOXO1 and HDAC3, but not HDAC1 and HDAC2, results in a greater inhibition of AR activity than in cells transfected with FOXO1 or HDAC3 individually. Together, our findings define a novel corepressor function of FOXO1 in inhibition of androgen-independent activation of the AR.

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  • Silencing of FOXO1 in PTEN-positive cells increases the basal activity of the AR and can sensitize the receptor to lower levels of androgens and to IL-6.

    “Interestingly, silencing of FOXO1 in PTEN-positive cells increases the basal activity of the AR and can sensitize the receptor to lower levels of androgens and by IL-6 (52).”

    From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [52]

  • Ectopic expression of FOXO1 in PTEN-null prostate cancer cells inhibits androgen-independent activation of the AR.

    “Ectopic expression of FOXO1 in PTEN-null prostate cancer cells inhibits androgen-independent activation of the AR (52).”

    From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [52]

  • Histone deacetylase 3 cooperates with FOXO1 to inhibit androgen receptor-mediated transcription in LNCaP cells.

    “Recently, histone deacetylase 3 was demonstrated to cooperate with FOXO1 to inhibit AR-mediated transcription in LNCaP cells and suggests a mechanism by which FOXO1 can promote AR activity in the absence of ligand (52).”

    From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [52]

  • The cooperation of HDAC3 with FOXO1 suggests a mechanism by which FOXO1 can promote androgen receptor activity in the absence of ligand.

    “Recently, histone deacetylase 3 was demonstrated to cooperate with FOXO1 to inhibit AR-mediated transcription in LNCaP cells and suggests a mechanism by which FOXO1 can promote AR activity in the absence of ligand (52).”

    From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [52]

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Research works printed but not linked: 2

  1. Roy-Burman P, Tindall DJ, Robins DM, et al. Andro- gens and prostate cancer: are the descriptors valid? Cancer Biol Ther 2005;4:4-5.
  2. Fan W, Yanase T, Morinaga H, et al. IGF1/insulin signaling activates androgen signaling through direct interactions of FOXO1 with androgen receptor. J Biol Chem 2007;282:7329-38.

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Authors
Liu, P., Li, S., Gan, L., Kao, T. P., & Huang, H.
Affiliations
University of Minnesota (US)
ORCID
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2008-12-15
Volume
68
Issue
24
Pages
10290-10299
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.can-08-2038
OpenAlex
W2146866082
Cited by
67
References
40
Citations by year
2026: 1 · 2025: 1 · 2024: 4 · 2022: 2 · 2021: 3 · 2020: 7 · 2019: 3 · 2018: 3 · 2017: 5 · 2016: 4 · 2015: 7 · 2014: 5 · 2013: 5 · 2012: 5
FWCI
3.68
Type
journal article
Language
en
Open access
Locations
  • Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Defense (W81XWH, W81XWH0710137)
  • University of Minnesota
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
  • Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
Keywords
FOXO1, androgen receptor, prostate cancer, PTEN, HDAC3, trichostatin A, interleukin-6, androgen deprivation therapy
MeSH terms
Forkhead Box Protein O1, Androgen Antagonists, Androgens, Cell Nucleus, Histone Deacetylases, Humans, Male, Prostatic Neoplasms, Receptors, Androgen, RNA, Messenger, Transcription, Genetic, Transfection, Transcriptional Activation, Prostate-Specific Antigen, RNA, Small Interfering, Cell Line, Tumor, PTEN Phosphohydrolase, Forkhead Transcription Factors, Androgen Receptor Antagonists

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