Co-regulators of androgen receptor transcriptional activity as a novel therapeutic target for advanced prostate cancer
Schaarschuch, Kevin Fernando
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Currently advanced prostate cancer (PCa) is in need of novel therapies as current treatment options are not curative. Topoisomerases are highly conserved enzymes involved in key biological processes including DNA replication and transcription. Specifically, topoisomerase II alpha (TOP2A) has been demonstrated to be associated with worse prognosis in prostate cancer studies. More importantly, the isozyme TOP2B is linked to DNA double strand breaks induced by androgen receptor (AR) signaling leading to genomic rearrangements and gene fusions, which are a hallmark of cancer. Enhancer of zeste homolog 2 (EZH2) is also shown to be up regulated in metastatic PCa, and associated with disease progression. EZH2 can epigenetically silence genes via its catalytic activity involving the tri-methylation of histone H3 lysine 27 (H3K27me3). Utilizing a spontaneous syngeneic transplant mouse model of PCa, we performed a RNA-sequencing study of primary vs. metastatic murine PCa tissues. We observed an increase in TOP2A mRNA expression in metastatic tissue samples. Increased TOP2A mRNA expression was validated in independent tumor samples via qRT-PCR. Publically available data from clinical samples indicated that increased TOP2A mRNA could select for patients with worse disease free survival. Further investigation revealed a significant positive correlation between TOP2A and EZH2 mRNA expression. For this reason we investigated the potential of combining the TOP2 inhibitor Etoposide with the EZH2 inhibitor, GSK126 in PCa cell line models. The goal of this study is to stratify patients based on gene signatures and tailor personalized medicine strategies. Here we utilize a combination of VP-16 (Topoisomerase poison) and GSK126 (EZH2 inhibitor) to induce greater cytotoxicity and reduced AR transcriptional activity in vitro . Our data shows that combination of non-cytoxic doses of both drugs in combination indeed induces a greater cell death in viability assays. The combination of both drugs in addition of cycling synthetic androgen also reduces androgen receptor transcriptional activity as well as protein expression levels of AR, EZH2 and H3K27me3.