Tumor and Stem Cell Biology Epigenetic Repression of miR-31 Disrupts Androgen Receptor Homeostasis and Contributes to Prostate Cancer Progression

Androgen receptor signaling plays a critical role in prostate cancer pathogenesis. Yet, the regulation of androgen receptor signaling remains elusive. Even with stringent androgen deprivation therapy, androgen receptor signaling persists. Here, our data suggest that there is a complex interaction between the expression of the tumor suppressor miRNA, miR-31, and androgen receptor signaling. We examined primary and metastatic prostate cancer and found that miR-31 expression was reduced as a result of promoter hypermethylation, and importantly, the levels of miR-31 expression were inversely correlated with the aggressiveness of the disease. As the expression of androgen receptor and miR-31 was inversely correlated in the cell lines, our study further suggested that miR-31 and androgen receptor could mutually repress each other. Upregulation of miR-31 effectively suppressed androgen receptor expression throughmultiplemechanisms and inhibited prostate cancer growth in vivo. Notably, we found that miR-31 targeted androgen receptor directly at a site located in the coding region, which was commonly mutated in prostate cancer. In addition, miR-31 suppressed cell-cycle regulators including E2F1, E2F2, EXO1, FOXM1, and MCM2. Together, our findings suggest a novel androgen receptor regulatory mechanismmediated through miR-31 expression. The downregulation of miR-31 may disrupt cellular homeostasis and contribute to the evolution and progression of prostate cancer. We provide implications for epigenetic treatment and support clinical development of detecting miR-31 promoter methylation as a novel biomarker. Cancer Res; 1–13. 2012 AACR. Introduction Prostate cancer represents a major public health problem among the aging Western population. It has the highest incidence rate of all noncutaneous malignancies in men, accounting for more than 241,000 new cases and 28,000 deaths in theUnited States in 2012 (1). Prostate cancer depends largely on androgen receptor (AR) signaling for growth and maintenance. Following the seminal observations by Huggins and Hodges over 60 years ago that prostate cancer responded dramatically to castration, androgen deprivation therapy (ADT) has become the standard first-line treatment for advanced hormone-na€ ve prostate cancer (2, 3). By reducing circulating androgen, ADT prevents signaling through androgen receptor and limits cancer growth. Unfortunately, the beneficial effect of ADT is short-lived and patients progress to castration-resistant prostate cancer (CRPC). The continued dysregulation of androgen receptor signaling in the face of ADT has been attributed to the acquisition of amplified or mutated androgen receptor; recent work using next-generation sequencing (NGS) suggests that androgen receptor gene amplification and mutations occur in up to 44% of CRPCs: 24% with copy number gain and 20% with point mutation (4). Perhaps the most important recent finding came when Chen and colleagues discovered that androgen receptor signaling persists under stringent ADT and that androgen receptor antagonists act as agonists at high androgen receptor levels (5). While these observations have led to the development of more efficacious therapeutic approaches for targeting androgen receptor signaling (6), CRPC still persists after treatment; therefore, other interventions are needed for androgen receptor regulation. Epigenetic aberrations arise during prostate cancer initiation and disease progression, which include promoter cytosine Authors' Affiliations: Departments of Pathology and Laboratory Medicine, Public Health, and Physiology and Biophysics, Graduate Program in Biochemistry & Structural Biology, Cell & Developmental Biology and Molecular Biology, Graduate School of Medical Sciences, HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Department of Urology and the LeFrak Center for Robotic Surgery, Department of Medicine, Hematology Oncology Division, Weill Cornell Medical College, New York, New York; Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut; and Centre for Integrative Biology, University of Trento, Trento, Italy Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Corresponding Author: Mark A. Rubin, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, 1300 York Avenue C-410A, New York, NY 10065. Phone: 212-746-6313; Fax: 212-746-8816; E-mail: [email protected] doi: 10.1158/0008-5472.CAN-12-2968 2012 American Association for Cancer Research. Cancer Research www.aacrjournals.org 1 on April 15, 2017. © 2013 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from Published OnlineFirst December 11, 2012; DOI: 10.1158/0008-5472.CAN-12-2968