The Homeobox Transcription Factor NKX3.1 Displays an Oncogenic Role in Castration-Resistant Prostate Cancer Cells

Background/Objectives: Prostate cancer (PCa) is the second leading cause of cancer-related death in men. The increase in incidence rates of more advanced and aggressive forms of the disease year-to-year fuels urgency to find new therapeutic interventions and bolster already established ones. PCa is a uniquely targetable disease in that it is fueled by male hormones (androgens) that drive tumorigenesis via the androgen receptor or AR. Current standard-of-care therapies directly target AR and its aberrant signaling axis but resistance to these therapies commonly arises, and the mechanisms behind the onset of therapy-resistance are still elusive. Research has shown that even with resistant disease, AR remains the main driver of growth and survival of PCa, and AR target genes and cofactors may help mediate resistance to therapy. Here, we focused on a homeobox transcription factor that exhibits a close relationship with AR-NKX3.1. Though NKX3.1 is traditionally thought of as a tumor suppressor, it has been previously reported to promote cancer cell survival by cooperating with AR. The role of NKX3.1 as a tumor suppressor perhaps in early-stage disease also contradicts its profile as a diagnostic biomarker for advanced prostate cancer. Methods: We investigated the physical interaction between NKX3.1 and AR, a modulated NKX3.1 expression in prostate cancer cells via overexpression and knockdown and assayed subsequent viability and downstream target gene expression. Results: We find that the expression of NKX3.1 is maintained in advanced PCa, and it is often elevated because of aberrant AR activity. Transient knockdown experiments across various PCa cell line models reveal NKX3.1 expression is necessary for survival. Similarly, stable overexpression of NKX3.1 in PCa cell lines reveals an androgen insensitive phenotype, suggesting NKX3.1 is sufficient to promote growth in the absence of an AR ligand. Conclusions: Our work provides new insight into NKX3.1's oncogenic influence on PCa and the molecular interplay of these transcription factors in models of late-stage prostate cancer.