Wild-type but not mutant androgen receptor inhibits expression of the hTERT telomerase subunit: a novel role of AR mutation for prostate cancer development

Moehren  U; Papaioannou  M; Reeb  CAGrassell  ANanni  SAsim  MRoell  DPrade  IFarsetti  ABaniahmad  A

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Wild-type but not mutant androgen receptor inhibits expression of the hTERT telomerase subunit: a novel role of AR mutation for prostate cancer development

机译：Wild-type but not mutant androgen receptor inhibits expression of the hTERT telomerase subunit: a novel role of AR mutation for prostate cancer development

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摘要

Androgens play a central role in prostate development and prostate cancer proliferation. Induction of telomerase is an early event in prostate carcinogenesis and is considered as a marker for both primary tumors and metastases. Interestingly, several reports suggest that telomerase activity is regulated by androgens in vivo. Here, we show that the wild-type (WT) human androgen receptor (AR) inhibits the expression of the human telomerase reverse transcriptase (hTERT) and telomerase activity via inhibition of hTERT promoter activity in the presence of androgen receptor agonists. However, pure androgen antagonists failed to repress hTERT transcription. The androgen-mediated repression of hTERT is abrogated in a human prostate cancer cell line exhibiting hormone-dependent growth, which expresses a mutant AR (T877A) frequently occurring in prostate cancer. We reveal that this single amino acid exchange is sufficient for the lack of transrepression. Interestingly, chromatin immunoprecipitation data suggest that, in contrast to the WT AR, the mutant AR is recruited less efficiently to the hTERT promoter in vivo, indicating that loss of transrepression results from reduced chromatin recruitment. Thus, our findings suggest that the WT AR inhibits expression of hTERT, which is indicative of a protective mechanism, whereas the T877A mutation of AR not only broadens the ligand spectrum of the receptor but abrogates this inhibitory mechanism in prostate cancer cells. This novel role of AR mutations in prostate cancer development suggests the benefit to a search for new AR antagonists that inhibit transactivation but allow transrepression.

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《The FASEB Journal》 |2008年第4期|1258-1267|共10页
作者
Moehren U; Papaioannou M; Reeb CAGrassell ANanni SAsim MRoell DPrade IFarsetti ABaniahmad A;
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作者单位

Inst Human Genet & Anthropol, Fac Med, D-07743 Jena, Germany;

Katholieke Univ Leuven, Div Biochem, Louvain, Belgium;

Regina Elena Inst Canc Res, Dept Expt Oncol, Mol Oncogenesis Lab, Rome, ItalyCNR, Inst Neurobiol & Mol Med, Rome, ItalyUniv Kuopio, Dept Biochem, FIN-70211 Kuopio, Finland;

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正文语种英语
中图分类生物化学;
关键词
transrepression; gene silencing; agonist; antagonist; chromatin; HORMONE REPLACEMENT THERAPY; CELLS IN-VITRO; TRANSCRIPTIONAL REGULATION; PROTEIN-INTERACTION; TESTOSTERONE LEVELS; TARGET; GENE; GROWTH; ANTAGONIST; MODULATION;

Wild-type but not mutant androgen receptor inhibits expression of the hTERT telomerase subunit: a novel role of AR mutation for prostate cancer development

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