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Methyltransferase inhibitor adenosine dialdehyde suppresses androgen receptor expression and prostate cancer growth
Masaki Shiota1, Ario Takeuchi, Akira Yokomizo
1Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
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.
Insights
The methyltransferase inhibitor adenosine dialdehyde effectively reduces prostate cancer cell growth by decreasing histone H3 lysine 9 methylation and androgen receptor expression. This compound shows promise as a novel therapeutic for both androgen-dependent and castration-resistant prostate cancer.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Prostate cancer often becomes castration-resistant after initial androgen deprivation therapy.
- Novel therapeutic strategies are crucial for treating advanced prostate cancer.
- Increased histone H3 lysine 9 methylation is observed in prostate cancer.
Purpose of the Study:
- To investigate the effects of the methyltransferase inhibitor adenosine dialdehyde on histone H3 lysine 9 methylation and androgen receptor (AR) gene expression.
- To evaluate the therapeutic potential of adenosine dialdehyde against prostate cancer.
Main Methods:
- Quantitative real-time polymerase chain reaction and Western blot were used to assess histone H3 lysine 9 methylation and AR gene expression.
- Chromatin immunoprecipitation assays compared histone H3 lysine 9 methylation at the AR promoter in different prostate cancer types.
- In vitro and in vivo studies evaluated the cytotoxic effects of adenosine dialdehyde on prostate cancer.
Main Results:
- Adenosine dialdehyde suppressed monomethylation and dimethylation of histone H3 lysine 9.
- The compound inhibited Twist1 and androgen receptor expression, crucial for cancer cell survival.
- Adenosine dialdehyde demonstrated cytotoxic effects on androgen-dependent, sensitive, and castration-resistant prostate cancer cells in vitro and suppressed tumor growth in vivo.
Conclusions:
- Adenosine dialdehyde effectively targets key pathways in prostate cancer progression.
- The methyltransferase inhibitor shows significant potential as a novel therapeutic agent for prostate cancer.
- Further investigation into adenosine dialdehyde is warranted for clinical application in prostate cancer treatment.
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