CtBP2 modulates the androgen receptor to promote prostate cancer progression.

Abstract

The androgen receptor (AR) is the key driver of both early and advanced prostate cancer, making a complete understanding of its regulation important. Here, we report the identification of multiple AR-binding sites in the gene encoding the transcription factor CtBP2 (carboxyl terminal-binding protein), genetic variations of which have been associated with prostate cancer susceptibility. Notably, we found that SNPs in the human CTBP2 gene that were associated with prostate cancer development were correlated with AR-enhancer activity. High CtBP2 expression levels correlated with poor prognosis in patients, whereas CtBP2 silencing reduced tumor growth in a mouse xenograft model of human prostate cancer. Consistent with its function as a transcriptional corepressor, CtBP2 repressed tumor-suppressor genes and AR corepressors in prostate cancer cells, such as NCOR and RIP140, by binding with AR to the promoter enhancers of these genes. Global gene-expression analyses revealed a positive effect on androgen-mediated gene expression, and CtBP2 silencing was found to increase AR interactions with corepressors that limit histone modification. Overall, our results show how CtBP2 contributes to prostate cancer progression by modulating AR and oncogenic signaling.

• Authors: Ken-Ichi Takayama, Takashi Suzuki, Tetsuya Fujimura, Tomohiko Urano, Satoru Takahashi, Yukio Homma, Satoshi Inoue
• Journal: Cancer research (Cancer Res) Vol. 74 Issue 22 Pg. 6542-53 (Nov 15 2014) ISSN: 1538-7445 [Electronic] United States
• PMID: 25228652 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• AR protein, human
• Co-Repressor Proteins
• DNA-Binding Proteins
• FOXO1 protein, human
• Forkhead Box Protein O1
• Forkhead Transcription Factors
• Nerve Tissue Proteins
• Receptors, Androgen
• Alcohol Oxidoreductases
• CTBP2 protein, human
• C-terminal binding protein

Topics

• Aged
• Alcohol Oxidoreductases (physiology)
• Animals
• Binding Sites
• Co-Repressor Proteins
• DNA-Binding Proteins (physiology)
• Disease Progression
• Forkhead Box Protein O1
• Forkhead Transcription Factors (physiology)
• Genes, Tumor Suppressor
• Genetic Predisposition to Disease
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Middle Aged
• Neoplasm Invasiveness
• Nerve Tissue Proteins (physiology)
• Prognosis
• Prostatic Neoplasms (etiology, pathology)
• Receptors, Androgen (genetics, physiology)
• Transcriptional Activation