Abstract
Epigenetic dysregulation is one of many factors that contribute to cancer development and progression. Numerous epigenetic alterations have been identified in urologic cancers including histone modifications, DNA methylation changes, and microRNA expression. Since these changes are reversible, efforts are being made to develop epigenetic drugs that restore the normal epigenetic patterns of cells, and many clinical trials are already underway to test their clinical potential. In this review we analyze multiple clinical trials (n=51) that test the efficacy of these drugs in patients with urologic cancers. The most frequently used epigenetic drugs were histone deacetylase inhibitors followed by antisense oligonucleotides, DNA methyltransferase inhibitors and histone demethylase inhibitors, the last of which are only being tested in prostate cancer. In more than 50% of the clinical trials considered, epigenetic drugs were used as part of combination therapy, which achieved the best results. The epigenetic regulation of some cancers is still matter of research but will undoubtedly open a window to new therapeutic approaches in the era of personalized medicine. The future of therapy for urological malignancies is likely to include multidrug regimens in which epigenetic modifying drugs will play an important role.
Highlights
IntroductionThe establishment and progression of malignancy involves broad changes in gene expression that are determined by both genetic and epigenetic events
HISTONE MODIFICATIONSUrologic cancers account for approximately 10% of all cancer deaths in the USA and include bladder, kidney, prostate and testicular cancers [1].The establishment and progression of malignancy involves broad changes in gene expression that are determined by both genetic and epigenetic events
The most frequently used epigenetic drugs were histone deacetylase inhibitors followed by antisense oligonucleotides, DNA methyltransferase inhibitors and histone demethylase inhibitors, the last of which are only being tested in prostate cancer
Summary
The establishment and progression of malignancy involves broad changes in gene expression that are determined by both genetic and epigenetic events. Genetic events include chromosome rearrangements and duplications as well as translocations, deletions, and single base pair mutations. Epigenetic modifications are somatically heritable changes that modify gene expression without altering the DNA sequence. Among these are histone modifications, DNA methylation, and miRNA expression [2]. Post-translational modification of the histone protein N terminal tails can alter the structure of the nucleosome and change the compaction state of chromatin. Acetylation, phosphorylation, ubiquitylation and sumoylation [2]. Histone acetylation and methylation are best described in cancer epigenetic dysregulation [2]
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