title: Induction of the transcriptional repressor ZBTB4 in prostate cancer cells by drug-induced targeting of microRNA-17-92/106b-25 clusters.
abstract: Androgen-insensitive DU145 and PC3 human prostate cancer cells express high levels of specificity protein (Sp) transcription factors Sp1, Sp3, and Sp4, and treatment of cells with methyl 2-cyano-3,11-dioxo-18β-olean-1,12-dien-30-oate (CDODA-Me) inhibited cell growth and downregulated Sp1, Sp3, and Sp4 expression. CDODA-Me (15 mg/kg/d) was a potent inhibitor of tumor growth in a mouse xenograft model (PC3 cells) and also decreased expression of Sp transcription factors in tumors. CDODA-Me-mediated downregulation of Sp1, Sp3, and Sp4 was due to induction of the transcriptional repressor ZBTB4, which competitively binds and displaces Sp transcription factors from GC-rich sites in Sp1-, Sp3-, Sp4-, and Sp-regulated gene promoters. ZBTB4 levels are relatively low in DU145 and PC3 cells due to suppression by miR paralogs that are members of the miR-17-92 (miR-20a/17-5p) and miR-106b-25 (miR-106b/93) clusters. Examination of publically available prostate cancer patient array data showed an inverse relationship between ZBTB4 and miRs-20a/17-5p/106b/93 expression, and increased ZBTB4 in patients with prostate cancer was a prognostic factor for increased survival. CDODA-Me induces ZBTB4 in prostate cancer cells through disruption of miR-ZBTB4 interactions, and this results in downregulation of pro-oncogenic Sp transcription factors and Sp-regulated genes.
authors: Institute of Biosciences and Technology, Texas A&M Health Science Center, MD Anderson Cancer Center, The University of Texas, Houston, USA.
authors: Kyounghyun
authors: K
authors: Kim
authors: Gayathri
authors: G
authors: Chadalapaka
authors: Satya S
authors: SS
authors: Pathi
authors: Un-Ho
authors: UH
authors: Jin
authors: Ju-Seog
authors: JS
authors: Lee
authors: Yun-Yong
authors: YY
authors: Park
authors: Sung-Gook
authors: SG
authors: Cho
authors: Sudhakar
authors: S
authors: Chintharlapalli
authors: Stephen
authors: S
authors: Safe
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017930:Genes, Reporter; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics; D005810:Multigene Family; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D051703:Sp Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C542541:MIRN106 microRNA, human; C524941:MIRN17 microRNA, human; C543351:MIRN25 microRNA, human; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; D012097:Repressor Proteins; D051703:Sp Transcription Factors; C508974:ZBTB4 protein, human; C543611:methyl 2-cyano-3,11-dioxo-18beta-olean-1,12-dien-30-oate; D008156:Luciferases; D006034:Glycyrrhetinic Acid