title: High-Throughput Screen for Inhibitors of Androgen Receptor-RUNX2 Transcriptional Regulation in Prostate Cancer.
abstract: Runt-related transcription factor 2 (RUNX2) plays a critical role in prostate cancer progression. RUNX2 interacts with the androgen receptor (AR) and modulates its transcriptional activity in a locus-specific manner. RUNX2 and AR synergistically stimulate a subset of genes, including the pro-oncogene snail family zinc finger 2 (SNAI2). AR-RUNX2 signaling cooperatively induces invasiveness of prostate cancer cells via SNAI2; and coexpression of AR, RUNX2, and SNAI2 in prostate cancer biopsy samples predicts disease recurrence. Competitive inhibition of AR alone could not disrupt the synergistic activation of SNAI2. We therefore established a phenotypic cell-based screening assay for compounds that could inhibit AR-RUNX2 synergistic activity either directly or indirectly. This assay was used to screen 880 compounds as a proof of concept, resulting in identification of several compounds that disrupted the synergistic stimulation of genes. Further investigation suggested the involvement of epidermal growth factor receptor (EGFR) signaling in AR/RUNX2 synergistic activity. Our assay is amenable to high-throughput screening and can be used to identify inhibitors of the AR-RUNX2 interaction in prostate cancer cells.
authors.affiliation: Beckman Research Institute, City of Hope, Duarte, California (W.V., B.Y.T., J.O.J.); Keck School of Medicine, University of Southern California, Los Angeles, California (G.H.L., B.F.).
authors.forename: Winston
authors.initials: W
authors.lastname: Vuong
authors.affiliation: Beckman Research Institute, City of Hope, Duarte, California (W.V., B.Y.T., J.O.J.); Keck School of Medicine, University of Southern California, Los Angeles, California (G.H.L., B.F.).
authors.forename: Ben Y
authors.initials: BY
authors.lastname: Tew
authors.affiliation: Beckman Research Institute, City of Hope, Duarte, California (W.V., B.Y.T., J.O.J.); Keck School of Medicine, University of Southern California, Los Angeles, California (G.H.L., B.F.).
authors.forename: Gillian H
authors.initials: GH
authors.lastname: Little
authors.affiliation: Beckman Research Institute, City of Hope, Duarte, California (W.V., B.Y.T., J.O.J.); Keck School of Medicine, University of Southern California, Los Angeles, California (G.H.L., B.F.).
authors.forename: Baruch
authors.initials: B
authors.lastname: Frenkel
authors.affiliation: Beckman Research Institute, City of Hope, Duarte, California (W.V., B.Y.T., J.O.J.); Keck School of Medicine, University of Southern California, Los Angeles, California (G.H.L., B.F.) jjones@coh.org.
authors.forename: Jeremy O
authors.initials: JO
authors.lastname: Jones
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics* / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D057166:High-Throughput Screening Assays; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000473:pathology*; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D000071250:Snail Family Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects*; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D050659:Core Binding Factor Alpha 1 Subunit; D011944:Receptors, Androgen; C000604408:SNAI2 protein, human; D000071250:Snail Family Transcription Factors