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Cited by 92Prostate Cancer Treatment and ResearchEstrogen and related hormone effectsSperm and Testicular Function

p300 regulates androgen receptor-independent expression of prostate-specific antigen in prostate cancer cells treated chronically with interleukin-6.

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Debes, Jose D., Comuzzi, Barbara, Schmidt, Lucy J., Dehm, Scott M., Culig, Zoran, Tindall, Donald J.·2005·Cancer Research
DOI 10.1158/0008-5472.can-04-2837

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Abstract

Prostate cancer is the most frequent non-skin cancer in men. Although the mechanisms involved in the progression of prostate cancer are not entirely understood, androgen receptor has been shown to play an important role. Androgen receptor is expressed in both early and late-stage prostate cancer. Also, androgen-regulated pathways are thought to be active as evidenced by elevated levels of prostate-specific antigen (PSA). In addition, several androgen receptor coactivators and cytokines are involved in prostate cancer progression. In this regard, we have shown previously that the coactivator p300 plays a major role in the androgen-independent activation of PSA by interleukin 6 (IL-6), a cytokine involved in late-stage prostate cancer. In this study, we investigated the role of p300 and its homologue CREB-binding protein in prostate cancer cells treated chronically with IL-6. We found that p300 but not CREB-binding protein induced activation of PSA in these cells and that the histone acetyltransferase activity of p300 was critical. This effect was independent of the presence of androgens or antiandrogens. Moreover, we found markedly reduced levels of androgen receptor in these cells and p300 transfection did not affect those levels, suggesting that the p300 effect on PSA could be bypassing the androgen receptor. Transfection with exogenous androgen receptor showed minimal response of PSA to androgens but higher response to p300. We found similar effects of p300 on the androgen response element III, which mediates the androgen receptor-dependent activation of PSA. Finally, we showed that p300 alone regulates expression of the endogenous PSA gene in the IL-6-treated cells. These findings reveal a new insight in the progression of prostate cancer, suggesting that coactivators, such as p300, play more important roles in late-stage prostate cancer, and could regulate androgen-dependent genes in the absence or with very low levels of androgen receptor.

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  • Chronic stimulation of LNCaP cells with IL-6 results in stimulation of AR via STAT signaling, inducing PSA expression even in the absence of androgen.

    “In contrast, chronic stimulation of LNCaP cells with IL-6 results in stimulation of AR via STAT signaling, thus inducing PSA expression, even in the absence of androgen (22).”

    From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [22]

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Research works printed but not linked: 2

  1. Drachenberg DE, Elgamal AA, Rowbotham R, Peterson M, Murphy GP. Circulating levels of interleukin-6 in patients with hormone refractory prostate cancer. Prostate 1999;41:127-33.
  2. Prescott JL, Blok L, Tindall DJ. Isolation and androgen regulation of the human homeobox cDNA, NKX3.1. Prostate 1998;35:71-80.

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Authors
Debes, J. D., Comuzzi, B., Schmidt, L. J., Dehm, S. M., Culig, Z., & Tindall, D. J.
Affiliations
  • 1Departments of Urology, Biochemistry, and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota and
  • Innsbruck Medical University (AT)
  • Mayo Clinic (US)
  • 2Department of Urology, Innsbruck Medical University, Innsbruck, Austria
ORCID
Dehm, Scott M.
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2005-07-01
Volume
65
Issue
13
Pages
5965-5973
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.can-04-2837
OpenAlex
W1988049837
Cited by
92
References
39
Citations by year
2024: 1 · 2023: 3 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 1 · 2018: 2 · 2017: 1 · 2016: 3 · 2015: 5 · 2014: 6 · 2013: 7 · 2012: 7
FWCI
9.06
Type
journal article
Language
en
Open access
Locations
  • Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Prostate Cancer Foundation
  • Terry Fox Foundation
  • Oesterreichische Nationalbank
  • National Institutes of Health (CA91956)
  • National Cancer Institute (CA 70892, CA 91956, P50CA091956)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK65236, DK60920, R01DK060920)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
  • Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
Keywords
P300, CREB-binding protein, prostate-specific antigen, prostate cancer, interleukin-6, histone acetyltransferase activity, androgen receptor coactivator
MeSH terms
Androgens, Humans, Male, Nuclear Proteins, Prostatic Neoplasms, Receptors, Androgen, RNA, Messenger, Transfection, Trans-Activators, Interleukin-6, Gene Expression Regulation, Neoplastic, Prostate-Specific Antigen, Cell Line, Tumor

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