Specific changes in the expression of imprinted genes in prostate cancer--implications for cancer progression and epigenetic regulation

Abstract

Epigenetic dysregulation comprising DNA hypermethylation and hypomethylation, enhancer of zeste homologue 2 (EZH2) overexpression and altered patterns of histone modifications is associated with the progression of prostate cancer. DNA methylation, EZH2 and histone modifications also ensure the parental-specific monoallelic expression of at least 62 imprinted genes. Although it is therefore tempting to speculate that epigenetic dysregulation may extend to imprinted genes, expression changes in cancerous prostates are only well documented for insulin-like growth factor 2 (IGF2). A literature and database survey on imprinted genes in prostate cancer suggests that the expression of most imprinted genes remains unchanged despite global disturbances in epigenetic mechanisms. Instead, selective genetic and epigenetic changes appear to lead to the inactivation of a sub-network of imprinted genes, which might function in the prostate to limit cell growth induced via the PI3K/Akt pathway, modulate androgen responses and regulate differentiation. Whereas dysregulation of IGF2 may constitute an early change in prostate carcinogenesis, inactivation of this imprinted gene network is rather associated with cancer progression.

Figure 1.

A network of imprinted genes. On the basis of 116 mouse microarray experiments, Varrault et al. discovered significant co-expression of selected imprinted genes. The figure shows a simplified version of the original Pajek network representation of coregulated imprinted genes disregarding the exact degree of co-expression and omitting non-imprinted genes. The enlarged circles represent the central imprinted genes of the network (modified from Ref. 60). The genes indicated in bold are deregulated in prostate cancer according to our analysis (Table 1). Note that IGF2R is not imprinted in humans. IGF2, insulin-like growth factor 2.

Figure 2.

A sketch of the relationship between IGF signalling, the PI3K pathway and androgen responses in the prostate. IGF, insulin-like growth factor.

Figure 3.

An overview of signalling pathways and cellular regulatory systems influenced by and acting upon imprinted genes with altered expression in prostate cancer.

Figure 4.

A hypothesis on the role of imprinted genes in prostate cancer initiation and progression. IGF2, insulin-like growth factor 2.