Antithetic hTERT Regulation by Androgens in Prostate Cancer Cells: hTERT Inhibition Is Mediated by the ING1 and ING2 Tumor Suppressors

Simple Summary The expression of the catalytic subunit of the human telomerase reverse transcriptase subunit (hTERT) is hormonally controlled. Androgen treatment suppresses the hTERT expression at a transcriptional level in prostate cancer cells. Here, we identified the responsive promoter element that mediates the androgen receptor induced transrepression of hTERT. The negative androgen response element (nARE) is identified as 62 bp located in the core promoter of hTERT. Chromatin immunoprecipitations indicate an androgen-dependent recruitment of the androgen receptor (AR) ING1 and ING2 to the hTERT promoter. Interestingly, the androgen-induced transrepression is mediated by the class II tumor suppressors inhibitor of growth 1 and 2, namely ING1 and ING2, respectively. The human telomerase is a key factor during tumorigenesis in prostate cancer (PCa). The androgen receptor (AR) is a key drug target controlling PCa growth and regulates hTERT expression, but is described to either inhibit or to activate. Here, we reveal that androgens repress and activate hTERT expression in a concentration-dependent manner. Physiological low androgen levels activate, while, notably, supraphysiological androgen levels (SAL), used in bipolar androgen therapy (BAT), repress hTERT expression. We confirmed the SAL-mediated gene repression of hTERT in PCa cell lines, native human PCa samples derived from patients treated ex vivo, as well as in cancer spheroids derived from androgen-dependent or castration resistant PCa (CRPC) cells. Interestingly, chromatin immuno-precipitation (ChIP) combined with functional assays revealed a positive (pARE) and a negative androgen response element (nARE). The nARE was narrowed down to 63 bp in the hTERT core promoter region. AR and tumor suppressors, inhibitor of growth 1 and 2 (ING1 and ING2, respectively), are androgen-dependently recruited. Mechanistically, knockdown indicates that ING1 and ING2 mediate AR-regulated transrepression. Thus, our data suggest an oppositional, biphasic function of AR to control the hTERT expression, while the inhibition of hTERT by androgens is mediated by the AR co-repressors ING1 and ING2.

Automated summary

The expression of human telomerase reverse transcriptase subunit (hTERT) is hormonally controlled, with androgen treatment suppressing hTERT expression in prostate cancer cells. This inhibition and activation of hTERT by androgens is mediated by androgen receptor (AR) co-repressors ING1 and ING2. This reveals a dual role of AR in controlling hTERT expression during prostate cancer tumorigenesis.