Prostate cancer is amongst the most prevalent causes of death in the US. As such, despite great progress in our understanding of this disease, there still remains a dire need to explore the molecular mechanisms involved in prostate tumorigenesis that will ultimately help to improve the clinical management of this cancer. KDM4A is a histone demethylase that is involved in epigenetic regulation. Moreover, we recently reported that KDM4A is overexpressed especially in aggressive human prostate tumors and that KDM4A transgenic mice develop prostatic intraepithelial neoplasia. In addition, KDM4A overexpression synergizes with the overexpression of the ETS transcription factor ETV1 and ablation of the tumor suppressor PTEN to induce prostatic adenocarcinomas. However, it has remained unresolved why KDM4A becomes overexpressed in prostate tumors and how KDM4A is functionally regulated. Here, we demonstrate that SET7/9 methylates KDM4A on six lysine residues and that SET7/9 ablation diminishes KDM4A expression. These data suggest that one function of SET7/9-mediated methylation is the stabilization of KDM4A in prostate cancer. Consistently, SET7/9 itself is overexpressed in prostate tumors and correlates with KDM4A expression. Moreover, our preliminary data indicate that methylation of KDM4A affects its ability to interact with the ETV1 transcription factor. Based on these preliminary data, we posit that SET7/9-dependent methylation of KDM4A enhances its oncogenic potential. To test this hypothesis, we propose two specific aims of research: (i) To determine how methylation modulates the KDM4A molecule. (ii) To reveal how KDM4A methylation affects prostate cancer cells. Completion of these studies will greatly advance our molecular understanding of KDM4A and SET7/9 as well as their roles in prostate tumorigenesis. This progress in knowledge will also point out that interfering with SET7/9-mediated methylation of KDM4A could represent a valid novel approach to fight prostate cancer.

Public Health Relevance

More than 27,000 patients die each year from prostate cancer in the US, indicating the urgent need for innovative new avenues of therapeutic intervention. Our studies will uncover how the KDM4A enzyme, which has oncogenic properties, is regulated by methylation of lysine residues. Such knowledge may point out novel ways to combat prostate cancer by interfering with the posttranslational modification of KDM4A or to improve prognosis.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Small Research Grants (R03)
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Special Emphasis Panel (ZCA1)
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Okano, Paul
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University of Oklahoma Health Sciences Center
Anatomy/Cell Biology
Schools of Medicine
Oklahoma City
United States
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