Global Levels of Specific Histone Modifications and an Epigenetic Gene Signature Predict Prostate Cancer Progression and Development

Tina Bianco-Motto, Karen Chiam, Grant Buchanan, Shalini Jindal, Tanya Day, Mervyn Thomas, Marie Pickering, Melissa O'Loughlin, Natalie Ryan, Wendy Raymond, Lisa Horvath, James Kench, Phillip Stricker, Villis Marshall, Robert Sutherland, Susan Henshall, William Gerald, H Scher, Gail Risbridger, Judith ClementsL Butler, Wayne Tilley, David Horsfall, Carmela Ricciardelli

    Research output: Contribution to journalArticlepeer-review

    91 Citations (Scopus)

    Abstract

    Background: Epigenetic alterations are common in prostate cancer, yet how these modifications contribute to carcinogenesis is poorly understood. We investigated whether specific histone modifications are prognostic for prostate cancer relapse, and whether the expression of epigenetic genes is altered in prostate tumorigenesis. Methods: Global levels of histone H3 lysine-18 acetylation (H3K18Ac) and histone H3 lysine-4 dimethylation (H3K4diMe) were assessed immunohistochemically in a prostate cancer cohort of 279 cases. Epigenetic gene expression was investigated in silico by analysis of microarray data from 23 primary prostate cancers (8 with biochemical recurrence and 15 without) and 7 metastatic lesions. Results: H3K18Ac and H3K4diMe are independent predictors of relapse-free survival, with high global levels associated with a 1.71-fold (P < 0.0001) and 1.80-fold (P = 0.006) increased risk of tumor recurrence, respectively. High levels of both histone modifications were associated with a 3-fold increased risk of relapse (P < 0.0001). Epigenetic gene expression profiling identified a candidate gene signature (DNMT3A, MBD4, MLL2, MLL3, NSD1, and SRCAP), which significantly discriminated nonmalignant from prostate tumor tissue (P = 0.0063) in an independent cohort. Conclusions: This study has established the importance of histone modifications in predicting prostate cancer relapse and has identified an epigenetic gene signature associated with prostate tumorigenesis. Impact: Our findings suggest that targeting the epigenetic enzymes specifically involved in a particular solid tumor may be a more effective approach. Moreover, testing for aberrant expression of epigenetic genes such as those identified in this study may be beneficial in predicting individual patient response to epigenetic therapies.

    Original languageEnglish
    Pages (from-to)2611-2622
    Number of pages12
    JournalCancer Epidemiology Biomarkers and Prevention
    Volume19
    Issue number10
    DOIs
    Publication statusPublished - 2010

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