These results also suggested that the tumour-specific targeting of de novo methylation is pre-programmed by an established epigenetic system that normally has a role in marking embryonic genes for repression. It is thought that lifestyle and environmental or dietary exposure may contribute to cancer risk through epigenetic mechanisms. Although little data relate directly to prostate cancer, examination of other systems provides strong evidence that the occurrence of epigenetic changes is age related.
Ageing is associated with global hypomethylation together with hypermethylation of specific genes, in the same way as in cancer. Inactivation of specific genes by DNA methylation in the ageing colonic mucosa has been proposed to be one of the earliest events in the development of cancer at this site Issa et al, Analysis of monozygotic identical twins demonstrate that they are epigenetically indistinguishable in early life.
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However with ageing, differences in DNA methylation patterns, histone modification and gene expression pattern are observed. These differences were most pronounced when the twins had lived apart, suggesting a role for diet and environment Fraga et al, b. SirT1 and IGF signalling, both linked to epigenetic mechanisms, have each been implicated in controlling the ageing process. A variety of dietary and environmental factors have been linked to epigenetic changes: these include smoking, alcohol consumption, drinking green tea, dietary selenium levels, folate and methionine deficiencies, and the presence of resversatrol and dihydrocoumarins; high selenium consumption is known to be associated with lower risk of developing prostate cancer.
Resversatrol a molecule present in several plants including purple grapes and dihydrocoumarins found in sweet clover inhibit SirT1. Prostate cancer frequently progresses very slowly, and for many cases, treatments that delay the development or progression of this disease, even marginally, could have a significant clinical impact. If epigenetic alterations occur gradually through ageing or under the influence of dietary factors as the first step in cancer development, they may provide an excellent target for preventative strategies.
In this respect, it is worthy of note that the potential chemopreventive agents sulphoraphane, butyrate, and diallyl disulphide are all known to act as inhibitors of HDACs.
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Support for the idea that chemoprevention strategies can be successful comes from the study of patients with genetically determined hyperhomocysteinemia where treatment by folate supplementation can restore the normal DNA methylation and expression patterns of specific genes Ingrosso et al, Epigenetic marks may not always be erased by passage through the germ line, and in some cases can be inherited from one generation to the next.
The influence of maternal diet in this process is well documented. It is, however, now emerging that paternal transmission may also occur. This has been described in mice for the Axin Fu allele, and epidemiological evidence Pembrey et al, supports the view that epigenetic effects of smoking can be inherited thorough father-to-son transmission. The general failure to identify gene mutations that account for genetic inheritance in prostate cancer suggests that it may be appropriate to examine epigenetic mechanism of inheritance. The identification of such genes represents a significant technical challenge, although technologies for the genome-wide screening of DNA-methylation patterns and histone marks that would be required for target gene identification are starting to become available see below.
Whole genome analysis of histone modifications and of proteins involved in epigenetic modulation can be performed using ChiP-based approaches Zhao et al, ; Roh and Zhao, A variety of strategies involving high-throughput DNA sequencing or hybridisation to oligonucleotide micorarray may be used for the genome-wide analysis of DNA methylation pattern reviewed by Zilberman and Henikoff, The specific applications of these technologies to prostate cancer represent an important area of future investigation.
[Full text] Vasectomy and prostate cancer risk: a historical synopsis of undulatin | RRU
Enzymes controlling epigenetic status and involved in cross talk between epigenetic systems are potential targets for cancer therapy. In principle, enzymes that modulate the activities of these proteins are also potential drug targets, as are proteins that bind methylated CpG sequences.
One strategy would be to try to use inhibitors of these proteins to reprogramme cells returning their epigenetic status to that reminiscent of a normal cell. A complication with this targeting strategy is that the effects of each individual targeted protein are most likely to be complex and difficult to predict. Several HDAC inhibitors have activity in the nanomolar range and have been demonstrated to inhibit growth of prostate cancer. Clinical trials have, however, been largely restricted to cancer types other than prostate Gallinari et al, The ability of 5-azacytidine and other nucleoside analogues to inhibit DNMTs, cause hypomethylation and alter gene transcription in cultured prostate cancer cells is well documented, but only limited clinical trials have been performed.
Epigenetics is now accepted as mainstream area of cancer research. However, many challenges remain both in understanding its importance in cancer development and in applying new knowledge to the benefit of prostate cancer patients. There is an urgent need to comprehensively assess epigenetic alterations on a genomic scale in a broad variety of normal cells, stem cells, and in corresponding cancer cells and to assess the importance of the role of small RNAs and their therapeutic potential. Oncogene 26 : — J Biol Chem : — Nat Genet 37 : — Cell Res 17 : — Nature : — Cancer Res 66 : — Lancet : — Nat Genet 7 : — Clin Cancer Res 1 : — Clin Cancer Res 10 : — Nat Genet 40 : — Biochem Biophys Res Commun : — Cancer Res 65 : — Br J Cancer 94 : — Curr Top Microbiol Immunol : — Am J Pathol : — Nat Genet 39 : — J Clin Oncol 25 : Eur J Hum Genet 14 : — PLoS Genet 2 : e De Marzo suspects that a breach in the armor might allow infection to enter the prostate.
PhIP is known to cause prostate and breast, and colon cancer in rats. Together, they found that chronic inflammation — in this case, caused by E.
Rats that had both E. When the scientists inoculated PhIP-fed rats with E. When the scientists fed rats tomatoes and broccoli along with PhIP, the rats lived longer and had fewer prostate neoplasms, intestinal cancers, and skin cancers than the rats that just ate the PhIP.
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Learn to love broccoli. So, if the barrier is broken — if the gate is stormed, like a medieval castle — can it be fixed? And is it possible to cool off the inflammation in the prostate? Tomatoes, green tea, and other foods have anti-inflammatory properties, as well. Note: Losing weight is another excellent way to remove some of the inflammatory fuel within the prostate. Published: Jul 4, Vol 12, No 2 Prostate cancer, hormone-dependent malignancy, prolactin and testosterone, citrate-producing acinar cells. Costello, L. Testosterone, prolactin, and oncogenic regulation of the prostate gland.
A new concept: Testosterone-independent malignancy is the development of prolactin-dependent malignancy!. Oncology Reviews , 12 2.