# MicroRNA-379 Modulates Prostate-Specific Antigen Expression Through Targeting the Androgen Receptor in Prostate Cancer

## TL;DR

This study shows that microRNA-379 reduces prostate cancer spread to bones by lowering androgen receptor levels, which in turn lowers prostate-specific antigen.

## Contribution

The novel finding is that miR-379 indirectly regulates PSA by targeting the androgen receptor, not directly.

## Key findings

- miR-379 reduces androgen receptor levels, leading to decreased PSA production in prostate cancer cells.
- Higher miR-379 levels in prostate cancer patients correlate with lower PSA levels and reduced AR activity.
- miR-379 targets the 3′-UTR of AR, suppressing its expression and PSA transcription.

## Abstract

We have previously found that microRNA-379 (miR-379) may reduce the metastatic spread of prostate cancer to bone. In this study, we discovered that miR-379 affects how much prostate-specific antigen (PSA), the clinically used prostate cancer marker, is released by prostate cancer cells. However, miR-379 does not control PSA directly. Instead, our results indicate miR-379 reduces the levels of the androgen receptor (AR), which in turn reduces PSA production. In prostate cancer patient samples, higher miR-379 levels were linked to lower PSA levels and less AR activity. These findings suggest that miR-379 may help prevent prostate cancer from spreading to bones by regulating AR and PSA.

Background: MicroRNA-379 (miR-379) has been reported to play a tumour-suppressing role in several cancer types. Our previous work demonstrated that miR-379 overexpression attenuates the metastatic spread of prostate cancer (PCa) both in vitro and in vivo. However, the underlying mechanisms remain poorly understood. Methods: To elucidate the mechanisms by which miR-379 affects metastases, we performed a cytokine array to identify secreted proteins modulated by miR-379 dysregulation in a bone microenvironment model. We then assessed the levels of the key candidate, and performed functional studies, including reporter assays, of the transcriptional regulation. Results: Prostate-specific antigen (PSA)—the clinically widely used blood biomarker for PCa—emerged as the most significantly affected secreted protein. We observed that PSA secretion increased following miR-379 inhibition and decreased with miR-379 overexpression, with parallel changes in intracellular PSA levels. However, our data suggests that miR-379 does not directly regulate PSA expression. Instead, miR-379 appears to downregulate androgen receptor (AR) expression by targeting its 3′-untranslated region (3′-UTR), thereby indirectly reducing PSA transcription through diminished AR-mediated promoter activation. Supporting this indirect mechanism, analysis of clinical samples from prostate cancer patients revealed an inverse correlation between expression of miR-379 in prostatic tissue and serum PSA levels. Furthermore, reduced miR-379 expression was associated with increased levels of AR immunostaining in malignant tissues. Conclusions: Taken together, these findings suggest that miR-379 negatively regulates PSA secretion indirectly via suppression of AR, and that the interplay between miR-379, AR, and PSA may contribute to the metastatic progression of PCa to bone.