Abstract
Simple SummaryThe 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.
Highlights
Prostate cancer (PCa) is the most commonly diagnosed cancer and the second leading cause of cancer mortality for males in the USA [1]
The identification of ING1 and ING2 tumor suppressors in the androgen receptor (AR)-mediated transrepression of hTERT provides some first insights into the link between tumor suppressors and the AR
ING1 and ING2 were shown to act as AR co-repressors that act on the androgen-activated AR [18,19]
Summary
Prostate cancer (PCa) is the most commonly diagnosed cancer and the second leading cause of cancer mortality for males in the USA [1]. The androgen receptor (AR) regulates the development and physiological function of the normal prostate, as well as the proliferation of cancerous prostate tissue. PCa is initially an androgen-sensitively growing tumor that eventually becomes castration-resistant (CRPC) and drug resistant [2]. While age is a major risk factor for this disease, androgen levels contribute to the growth of the tumor. AR represents a major drug target in the treatment of PCa. An important hormone therapy is androgen deprivation therapy (ADT) to reduce androgen production
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