Epigenetic mechanisms for progression of prostate cancer

Epigenetic mechanisms may be the main driving force for critical changes in gene expression that are responsible for progression of prostate cancers. The three most extensively characterized mechanisms for epigenetic gene-reg ulation are (i) changing patterns of DNA methylation, (ii) histone acetylat ions/deacetylations, and (iii) alterations in regulatory feedback loops for growth factors. Several studies have indicated that DNA hypermethylation i s an important mechanism in prostate cancer for inactivation of key regulat ory genes such as E-cadherin, pi-class glutathione S-transferase, the tumor suppressors CDKN2 and PTEN, and IGF-II. Similarly, histone acetylations an d deacetylations are frequently associated respectively with transcriptiona l activation (e.g. IGFBP-2 and p21) and repression (e.g. Mad:Max dimers) of genes linked to prostate cancer progression. Recently, histone acetyltrans ferase and deacetylase activities have been shown to be intrinsic with tran scriptional coregulator proteins that bind to steroid receptors (e.g. SRC-1 and PCAF). Changes in regulatory feedback loops for growth factors with pr ostate cancer progression tend toward shifts from paracrine to autocrine co ntrol where the receptor and ligand are produced by the same cell. While th ere are several examples of this progression pattern in prostate tumors suc h as with IGF, FGF, TGF-alpha and their respective receptors, the precise m echanism (i.e. epigenetic or mutational) is less certain. In the context of treatment options, the contribution of mutational versus epigenetic events to prostate cancer progression is an improtant consideration. Irreversible genetic changes are likely to be less amenable to therapeutic control than are epigenetic ones.