Abstract B61: c-Myc is regulated and therapeutically targetable via the miR-1207-3p/FNDC1/FN1/AR pathway in aggressive prostate cancer in men of African ancestry

Prostate cancer is the 2nd most common cancer in the world for men. For reasons still unclear, aggressive PCa disproportionately affects males of African ancestry (MoAA). Incidence and mortality rates are highest in MoAA as they have consistently shown a 2.3-3.0-fold higher risk of mortality compared to Caucasian men (CM). This aggressiveness of PCa may be due to specific biologic factors. Located downstream of c-Myc at chromosome 8q24 is PVT1, which encodes miR-1207-3p. Studies have shown that PVT1/MYC cooperation is a fundamental feature in all cancers with 8q24 amplification, and 98% of the 8q24 amplicons contained concurrent amplification of the MYC and PVT1 loci. Moreover, MYC has been linked to PCa aggressiveness and has been reported to be downstream of AR in some PCa. However, the mechanisms regulating c-MYC have never been studied in MoAA. We recently demonstrated that miR-1207-3p directly binds to FNDC1 to regulate a novel FNDC1/FN1/AR pathway upregulated in metastatic prostate cancer (PCa). However, the mechanisms regulating c-Myc in PCa remain unclear, and the relevance of our novel and clinically significant miR-1207-3p molecular pathway in PCa in MoAA is unknown. The aim of this study was to determine if c-Myc is regulated and therapeutically targetable via the miR-1207-3p/FNDC1/FN1/AR pathway in aggressive PCa in MoAA. We used qPCR, immunoblotting, RNA pulldown, proliferation, migration, and apoptosis assays to evaluate miR-1207-3p regulation of c-Myc in aggressive PCa in MoAA. Also, miR-1207-3p, FNDC1, FN1, AR, and c-Myc expression was analyzed in prostate tissues (normal = 21; benign = 41; tumor = 26) of patients who received prostatectomy or transrectal ultrasound-guided biopsies at the University College Hospital, Ibadan, Nigeria, a sub-Saharan Black African population. Seventeen patients had tumor tissues with Gleason score ≥ 8. Tissues were collected in compliance with Institutional Review Board-approved protocols. ANOVA, student's t-test, and Tukey post-hoc tests were used for statistical analysis. Prostate tissue analysis revealed that underexpression of miR-1207-3p and the overexpression of FNDC1, FN1, AR, and c-Myc is significantly associated with aggressive PCa in MoAA. Also, miR-1207-3p was underexpressed while FNDC1 and c-MYC were overexpressed in tumors with Gleason score ≥8 in comparison to those with Gleason score