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SUN-002 Control of Metastasis by DAX-1 in Prostate Cancer Cells, an Androgen-Induced Orphan Nuclear Receptor

Abstract The ability of cancer cells to metastasize is the pivotal step that allows a primary tumor to become a life-threatening malignancy. This mechanism is coordinated by transcription factors driving cancer cells to acquire a mesenchymal state through a process called epithelial-mesenchymal transition (EMT). The study of potential therapeutic markers that can prevent or even reverse this phenomenon in metastatic cancers is crucial. To this effort, we have focused on studying the role of DAX-1 (Dosage-sensitive, sex-reversal, adrenal hypoplasia congenita, on the X chromosome, gene 1) as a transcriptional repressor of genes involved in EMT. DAX-1 is a member of the nuclear hormone receptor superfamily with key roles in adrenal and gonadal development. However, recent studies have focused on studying DAX-1 transcriptional regulation of genes involved in cancer progression. We hypothesize that DAX-1 is able to repress the transcription of genes involved in EMT leading to a reduction of metastatic rates in prostate cancer cells. We found that introducing DAX-1 into a prostate cancer cell line that lacks endogenous expression of DAX-1 was sufficient to repress the transcription of EMT markers and lead to a drastic reduction of metastatic rates. Parallel to these findings, we used a CRISPR KO model of DAX-1 to study its role in hormone-dependent prostate cancer. We have previously shown that treatment of hormone-dependent prostate cell lines with a non-aromatizable androgen leads to up-regulation of DAX-1 expression.  Here, we use the same mechanism to analyze DAX-1 and AR regulation of metastatic markers in an androgen induced DAX-1 model in parallel to an androgen stimulated DAX-1 KO model. Results have shown that DAX-1 is sufficient to repress the expression of metastatic markers and reduce metastatic rates in prostate cancer cells. These results shed light into the convoluted web of biological processes coordinating prostate cancer progression and could reveal new therapeutics for the treatment of prostate cancer.