Therapeutic Discovery Induction of the Transcriptional Repressor ZBTB4 in Prostate CancerCells byDrug-InducedTargeting ofMicroRNA-17-92/ 106b-25 Clusters

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-18b-olean1,12-dien-30-oate (CDODA-Me) inhibited cell growth and downregulated Sp1, Sp3, and Sp4 expression. CDODA-Me (15mg/kg/d)was a potent inhibitor of tumor growth in amouse xenograftmodel (PC3 cells) and alsodecreased expressionof Sp transcription factors in tumors.CDODA-Me–mediateddownregulation 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 inDU145 andPC3 cells due to suppression bymiRparalogs that aremembers 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 andmiRs-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.