Wild-type but not mutant androgen receptor inhibits expression of the hTERT telomerase subunit: a novel role of AR mutation for prostate cancer development.
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.
Moehren
Udo
U
Division of Biochemistry, University of Leuven, Leuven, Belgium.
Papaioannou
Maria
M
Reeb
Christina A
CA
Grasselli
Annalisa
A
Nanni
Simona
S
Asim
Mohammad
M
Roell
Daniela
D
Prade
Ina
I
Farsetti
Antonella
A
Baniahmad
Aria
A
D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008297:Male; D009154:Mutation; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics*; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation
D021122:Protein Subunits; D011944:Receptors, Androgen; C509186:TERT protein, human; D019098:Telomerase