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Review
. 2013 Dec;73(16):1721-30.
doi: 10.1002/pros.22716. Epub 2013 Sep 2.

Epigenetic susceptibility factors for prostate cancer with aging

N A Damaschke  1 , B Yang, S Bhusari, J P Svaren, D F Jarrard
Affiliations
Review

Epigenetic susceptibility factors for prostate cancer with aging

N A Damaschke et al. Prostate. 2013 Dec.

Abstract

Background: Increasing age is a significant risk factor for prostate cancer. The prostate is exposed to environmental and endogenous stress that may underlie this remarkable incidence. DNA methylation, genomic imprinting, and histone modifications are examples of epigenetic factors known to undergo change in the aging and cancerous prostate. In this review we examine the data linking epigenetic alterations in the prostate with aging to cancer development.

Methods: An online search of current and past peer reviewed literature on epigenetic changes with cancer and aging was performed. Relevant articles were analyzed.

Results: Epigenetic changes are responsible for modifying expression of oncogenes and tumor suppressors. Several of these changes may represent a field defect that predisposes to cancer development. Focal hypermethylation occurs at CpG islands in the promoters of certain genes including GSTP1, RARβ2, and RASSF1A with both age and cancer, while global hypomethylation is seen in prostate cancer and known to occur in the colon and other organs. A loss of genomic imprinting is responsible for biallelic expression of the well-known Insulin-like Growth Factor 2 (IGF2) gene. Loss of imprinting (LOI) at IGF2 has been documented in cancer and is also known to occur in benign aging prostate tissue marking the presence of cancer. Histone modifications have the ability to dictate chromatin structure and direct gene expression.

Conclusions: Epigenetic changes with aging represent molecular mechanisms to explain the increased susceptibly of the prostate to develop cancer in older men. These changes may provide an opportunity for diagnostic and chemopreventive strategies given the epigenome can be modified.

Keywords: aging; epigenetics; imprinting; methylation; prostate cancer.

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Figures

Fig. 1
Fig. 1
Igf2 imprinting. A: Schematic of Igf2-H19 imprint regulation. The imprinted Igf2/H19 locus contains an intergenic imprint control region (ICR) along with shared enhancers that collectively coordinate gene expression. Normal imprinting in this region is characterized by CpG methylation on the paternal allele (lower) within the ICR. This CpG methylation blocks CTCF, a chromatin insulator, binding to Igf2 and facilitates enhancer binding to the Igf2 promoter leading to expression of the gene. CTCF binds hypomethylated CpGs on the maternal allele (upper) at the ICR blocking enhancer binding to the Igf2 promoter and silencing of gene expression. Aging is associated with decreased CTCF levels and altered methylation at the ICR. B: Model of Igf2 imprinting in the human prostate. The perhipheral zone demonstrates the regional loss of imprinting associated with prostate disease that is age-dependent. Cancers commonly form in this region and also demonstrate a loss of imprinting. In the central zone, benign prostatic hyperplasia (BPH) is found. Igf2 imprinting is maintained in this region.
Fig. 2
Fig. 2
Age related epigenetic alterations inducing susceptibility (AREAS) in the prostate. Specific epigenetic alterations, including loss of imprinting, gene methylation, and histone modifications, are either stable (1) or erode (2) over time in the epithelium (or stroma) of the prostate that does not develop cancer. Alternately, in the prostate gland that develops cancer epigenetic alterations occurring during aging result in gene expression changes that confer a selective advantage to early neoplastic changes (3). These changes represent a field of susceptibility and may be accelerated by environmental insults. These epigenetic changes that occur in aging tissues are frequently selected for in tumors (4). Other cancer specific epigenetic alterations arise within the tumor and are age-independent (5).
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