PT - JOURNAL ARTICLE AU - Kim, KyoungHyun AU - Chadalapaka, Gayathri AU - Pathi, Satya S. AU - Jin, Un-Ho AU - Lee, Ju-Seog AU - Park, Yun-Yong AU - Cho, Sung-Gook AU - Chintharlapalli, Sudhakar AU - Safe, Stephen TI - Induction of the Transcriptional Repressor ZBTB4 in Prostate Cancer Cells by Drug-Induced Targeting of MicroRNA-17-92/106b-25 Clusters AID - 10.1158/1535-7163.MCT-12-0181 DP - 2012 Sep 01 TA - Molecular Cancer Therapeutics PG - 1852--1862 VI - 11 IP - 9 4099 - http://mct.aacrjournals.org/content/11/9/1852.short 4100 - http://mct.aacrjournals.org/content/11/9/1852.full SO - Mol Cancer Ther2012 Sep 01; 11 AB - 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. Mol Cancer Ther; 11(9); 1852–62. ©2012 AACR.