Methyltransferase inhibitor adenosine dialdehyde suppresses androgen receptor expression and prostate cancer growth.

Abstract

PURPOSE:

Although most prostate cancers regress after androgen deprivation therapy is given at diagnosis, they eventually regrow in a castration resistant manner, spread systemically and end fatally. Thus, novel therapeutic compounds are needed for prostate cancer. We previously reported that methylation at histone H3 lysine 9 was increased in prostate cancer. In this study we examined the effects of the methyltransferase inhibitor adenosine dialdehyde (Sigma®) on the methylation state of histone H3 lysine 9 and AR gene expression as well as its possible usefulness for prostate cancer.

MATERIALS AND METHODS:

The effect of adenosine dialdehyde on the methylation state of histone H3 lysine 9 and AR gene expression was examined by quantitative real-time polymerase chain reaction and Western blot. We compared methylation at histone H3 lysine 9 at the AR promoter region between androgen dependent and castration resistant prostate cancer by chromatin immunoprecipitation assay. The cytotoxic effect of adenosine dialdehyde on prostate cancer was also evaluated in vitro and in vivo.

RESULTS:

Adenosine dialdehyde suppressed the monomethylation and dimethylation of histone H3 lysine 9 and inhibited Twist1 as well as androgen receptor expression, which are critical for the survival and growth of androgen dependent, androgen sensitive and castration resistant prostate cancer cells in which monomethylated histone H3 lysine 9 increased at the 5' untranslated region of the AR gene. As a result, adenosine dialdehyde had a cytotoxic effect on androgen dependent, androgen sensitive and castration resistant prostate cancer cells in vitro. Adenosine dialdehyde also suppressed prostate cancer growth in vivo in a mouse xenograft model.

CONCLUSIONS:

Results indicate that the methyltransferase inhibitor adenosine dialdehyde is a promising, novel therapeutic compound for prostate cancer.

• Authors: Masaki Shiota, Ario Takeuchi, Akira Yokomizo, Eiji Kashiwagi, Katsunori Tatsugami, Seiji Naito
• Journal: The Journal of urology (J Urol) Vol. 188 Issue 1 Pg. 300-6 (Jul 2012) ISSN: 1527-3792 [Electronic] United States
• PMID: 22608750 (Publication Type: Journal Article)
• Copyright: Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Chemical References

• Androgens
• RNA, Neoplasm
• Receptors, Androgen
• periodate-oxidized adenosine
• Methyltransferases
• Adenosine

Topics

• Adenosine (analogs & derivatives, therapeutic use)
• Androgens (therapeutic use)
• Animals
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Male
• Methyltransferases (antagonists & inhibitors, metabolism)
• Mice
• Mice, Nude
• Neoplasms, Experimental
• Promoter Regions, Genetic
• Prostatic Neoplasms (drug therapy, genetics, metabolism)
• RNA, Neoplasm (genetics)
• Real-Time Polymerase Chain Reaction
• Receptors, Androgen (biosynthesis, genetics)
• Tumor Cells, Cultured