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: Kyounghyun Kim, Gayathri Chadalapaka, Satya S Pathi, Un-Ho Jin, Ju-Seog Lee, Yun-Yong Park, Sung-Gook Cho, Sudhakar Chintharlapalli, Stephen Safe
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 11 Issue 9 Pg. 1852-62 (Sep 2012) ISSN: 1538-8514 [Electronic] United States
• PMID: 22752225 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2012 AACR.

Chemical References

• Antineoplastic Agents
• MIRN106 microRNA, human
• MIRN17 microRNA, human
• MIRN25 microRNA, human
• MIRN92 microRNA, human
• MicroRNAs
• Repressor Proteins
• Sp Transcription Factors
• ZBTB4 protein, human
• methyl 2-cyano-3,11-dioxo-18beta-olean-1,12-dien-30-oate
• Luciferases
• Glycyrrhetinic Acid

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Gene Expression Regulation, Neoplastic (drug effects)
• Genes, Reporter
• Glycyrrhetinic Acid (analogs & derivatives, pharmacology, therapeutic use)
• Humans
• Luciferases (biosynthesis, genetics)
• Male
• Mice
• Mice, Nude
• MicroRNAs (genetics)
• Multigene Family
• Promoter Regions, Genetic
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• Repressor Proteins (genetics, metabolism)
• Sp Transcription Factors (genetics, metabolism)
• Transcriptional Activation
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays