Epigenetics in prostate cancer

Abstract

Prostate cancer (PC) is the most commonly diagnosed nonskin malignancy and the second most common cause of cancer death among men in the United States. Epigenetics is the study of heritable changes in gene expression caused by mechanisms other than changes in the underlying DNA sequences. Two common epigenetic mechanisms, DNA methylation and histone modification, have demonstrated critical roles in prostate cancer growth and metastasis. DNA hypermethylation of cytosine-guanine (CpG) rich sequence islands within gene promoter regions is widespread during neoplastic transformation of prostate cells, suggesting that treatment-induced restoration of a "normal" epigenome could be clinically beneficial. Histone modification leads to altered tumor gene function by changing chromosome structure and the level of gene transcription. The reversibility of epigenetic aberrations and restoration of tumor suppression gene function have made them attractive targets for prostate cancer treatment with modulators that demethylate DNA and inhibit histone deacetylases.

Figure 1

Epigenetic mechanism of gene expression silencing. (a) In unmethylated DNA (depicted by white hollow circles on left) transcription factors (TF) are free to bind gene promotor regions. In hypermethylated DNA (depicted in red filled-in circles on the right) TF are blocked from binding to gene promotor regions leading to functional silencing of gene expression. (b) Histone deacetylation by methyl-CpG-binding domain protein (MPD)/histone deacetylase (HDAC) complexes promotes a condensed structure which inhibit normal gene transcription. (With permission from [4].)

Figure 2

(a) The mutation of EZH2 usually turns on gene transcription. (b) Overexpression of EZH2 in cancer trimethylates H3K27 to inhibit gene expression, especially among tumor suppressor genes. (c) Cyclin-dependent kinase 1/2 phophorylates EZH2 at Th350 which results in deregulating tumor suppressor genes by increasing H3K27-trimethylation levels at promoters of EZH2 targeted genes. (d) Proposed anti-tumor mechanisms of action of CDK1/2 and EZH2/Th350 inhibitors.