title: miR-124 and Androgen Receptor Signaling Inhibitors Repress Prostate Cancer Growth by Downregulating Androgen Receptor Splice Variants, EZH2, and Src.
abstract: miR-124 targets the androgen receptor (AR) transcript, acting as a tumor suppressor to broadly limit the growth of prostate cancer. In this study, we unraveled the mechanisms through which miR-124 acts in this setting. miR-124 inhibited proliferation of prostate cancer cells in vitro and sensitized them to inhibitors of androgen receptor signaling. Notably, miR-124 could restore the apoptotic response of cells resistant to enzalutamide, a drug approved for the treatment of castration-resistant prostate cancer. We used xenograft models to examine the effects of miR-124 in vivo when complexed with polyethylenimine-derived nanoparticles. Intravenous delivery of miR-124 was sufficient to inhibit tumor growth and to increase tumor cell apoptosis in combination with enzalutamide. Mechanistic investigations revealed that miR-124 directly downregulated AR splice variants AR-V4 and V7 along with EZH2 and Src, oncogenic targets that have been reported to contribute to prostate cancer progression and treatment resistance. Taken together, our results offer a preclinical rationale to evaluate miR-124 for cancer treatment.
authors.affiliation: Department of Urology, School of Medicine, University of California at Davis, Sacramento, California. ralph.devere-white@ucdmc.ucdavis.edu xbshi@ucdavis.edu.
authors.forename: Xu-Bao
authors.initials: XB
authors.lastname: Shi
authors.affiliation: Department of Urology, School of Medicine, University of California at Davis, Sacramento, California.
authors.forename: Ai-Hong
authors.initials: AH
authors.lastname: Ma
authors.affiliation: Department of Urology, School of Medicine, University of California at Davis, Sacramento, California.
authors.forename: Lingru
authors.initials: L
authors.lastname: Xue
authors.affiliation: Department of Urology, School of Medicine, University of California at Davis, Sacramento, California.
authors.forename: Meimei
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Urology, University of California, San Francisco, California.
authors.forename: Hao G
authors.initials: HG
authors.lastname: Nguyen
authors.affiliation: Department of Urology, School of Medicine, University of California at Davis, Sacramento, California.
authors.forename: Joy C
authors.initials: JC
authors.lastname: Yang
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine, University of California at Davis, Sacramento, California. UC Davis Comprehensive Cancer Center, University of California at Davis, Sacramento, California.
authors.forename: Clifford G
authors.initials: CG
authors.lastname: Tepper
authors.affiliation: Department of Pathology, School of Medicine, University of California at Davis, Sacramento, California.
authors.forename: Regina
authors.initials: R
authors.lastname: Gandour-Edwards
authors.affiliation: Department of Urology, School of Medicine, University of California at Davis, Sacramento, California. UC Davis Comprehensive Cancer Center, University of California at Davis, Sacramento, California.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Evans
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine, University of California at Davis, Sacramento, California. UC Davis Comprehensive Cancer Center, University of California at Davis, Sacramento, California.
authors.forename: Hsing-Jien
authors.initials: HJ
authors.lastname: Kung
authors.affiliation: Department of Urology, School of Medicine, University of California at Davis, Sacramento, California. UC Davis Comprehensive Cancer Center, University of California at Davis, Sacramento, California. ralph.devere-white@ucdmc.ucdavis.edu xbshi@ucdavis.edu.
authors.forename: Ralph W
authors.initials: RW
authors.lastname: deVere White
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015536:Down-Regulation; D000071221:Enhancer of Zeste Homolog 2 Protein; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D063151:Polycomb Repressive Complex 2 / Q000096:biosynthesis*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020033:Protein Isoforms; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000096:biosynthesis*
chemical_list: C509207:MIRN124 microRNA, human; D035683:MicroRNAs; D020033:Protein Isoforms; D011944:Receptors, Androgen; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D019061:src-Family Kinases