MIR-124 and androgen receptor signaling inhibitors repress prostate cancer growth by downregulating androgen receptor splice variants, EZH2, and Src

Xu Bao Shi, Ai Hong Ma, Lingru Xue, Meimei Li, Hao G. Nguyen, Joy C. Yang, Clifford G Tepper, Regina F Gandour-Edwards, Christopher P Evans, Hsing-Jien Kung, Ralph W deVere White

Research output: Contribution to journalArticle

32 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)5309-5317
Number of pages9
JournalCancer Research
Volume75
Issue number24
DOIs
StatePublished - Dec 15 2015

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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