Epigenomics
-
Reversible histone acetylation on lysine residues, regulated by the opposing activities of histone acetyltransferases and histone deacetylases (HDACs), plays an important role in the regulation of gene expression. Aberrant gene expression resulting from increased HDAC activity and histone hypoacetylation has been observed in human tumors and genetic knockdown studies support a role of HDACs in cancer. ⋯ Several HDAC inhibitors are in clinical development and show anti-tumor activity in cancer patients. Vorinostat (suberoylanilide hydroxamic acid) was the first HDAC inhibitor approved for the treatment of cancer and will be the focus of this article.
-
For the first time, the development of next-generation sequencing technologies has brought about tools to investigate epigenetic alterations in an unbiased, yet genome-wide approach. The importance of this innovative technology is undeniable since it has already been established that changes in DNA methylation play an important role in cancer initiation and progression. The first methylation maps have already been created, and it is only a matter of time until the complete epigenetic maps of healthy and diseased human genomes are available. In this review, we summarize the use of next-generation sequencing for diverse epigenetic technologies, give an overview of the status quo and outline future perspectives for its application in oncology and basic research.
-
The recent approval of azacitidine (Vidaza®), decitabine (Dacogen®) and vorinostat (Zolinza™) for myelodysplastic syndrome and cutaneous T-cell lymphoma has led to a wave of interest in epigenetic therapy. These DNA methylation inhibitors and the histone deacetylase inhibitor clearly have demonstrated activity in hematologic malignancies, but the future role of epigenetic therapy in solid tumors is still unknown. What is not commonly known is that azacitidine and decitabine were originally developed as cytotoxic nucleoside analogs and clinical trials were previously conducted in a variety of cancer types prior to the knowledge of their ability to inhibit DNA methylation. We review the experience of azacitidine and decitabine in early clinical trials and demonstrate the activity of epigenetic therapy in solid tumors.
-
There are numerous examples of enduring effects of early experience on gene transcription and neural function. We review the emerging evidence for epigenetics as a candidate mechanism for such effects. There is now evidence that intracellular signals activated by environmental events can directly modify the epigenetic state of the genome, including CpG methylation, histone modifications and microRNAs. ⋯ This epigenetic plasticity mediates neuronal differentiation and phenotypic plasticity, including that associated with learning and memory. Altered epigenetic states are also associated with the risk for and expression of mental disorders. In a broader context, these studies define a biological basis for the interplay between environmental signals and the genome in the regulation of individual differences in behavior, cognition and physiology, as well as the risk for psychopathology.