MicroRNAs as Epigenetic Determinants of Treatment Response and Potential Therapeutic Targets in Prostate Cancer

SIMPLE SUMMARY: Prostate cancer is one of the most common and lethal tumors in men worldwide. Due to the high heterogeneity of the disease, the optimal treatment choice for individual patients is very challenging, thus leading to treatment failure caused by poor responsiveness and/or tumor recurrence. Therefore, the identification of novel actionable targets involved in determining tumor treatment response is essential for developing patient-tailored therapeutic strategies. In this scenario, microRNAs, small endogenous RNA molecules able to epigenetically regulate cellular processes that are widely deregulated in cancer, have been proposed as potential treatment response modulators in many tumor types, including prostate cancer. In this review, we provide an overview on the main microRNAs involved in prostate cancer response to radiation and drug therapy, describing the mechanisms by which they concur to determine disease response, and illustrate whether they can be considered novel therapeutic targets/tools for improving treatment response in prostate cancer patients. ABSTRACT: Prostate cancer (PCa) is the second most common tumor in men worldwide, and the fifth leading cause of male cancer-related deaths in western countries. PC is a very heterogeneous disease, meaning that optimal clinical management of individual patients is challenging. Depending on disease grade and stage, patients can be followed in active surveillance protocols or undergo surgery, radiotherapy, hormonal therapy, and chemotherapy. Although therapeutic advancements exist in both radiatiotherapy and chemotherapy, in a considerable proportion of patients, the treatment remains unsuccessful, mainly due to tumor poor responsiveness and/or recurrence and metastasis. microRNAs (miRNAs), small noncoding RNAs that epigenetically regulate gene expression, are essential actors in multiple tumor-related processes, including apoptosis, cell growth and proliferation, autophagy, epithelial-to-mesenchymal transition, invasion, and metastasis. Given that these processes are deeply involved in cell response to anti-cancer treatments, miRNAs have been considered as key determinants of tumor treatment response. In this review, we provide an overview on main PCa-related miRNAs and describe the biological mechanisms by which specific miRNAs concur to determine PCa response to radiation and drug therapy. Additionally, we illustrate whether miRNAs can be considered novel therapeutic targets or tools on the basis of the consequences of their expression modulation in PCa experimental models.