https://pubs.rsc.org/en/content/articlepdf/2019/NP/C8NP00092A

Marine natural products.

Epigenetic mechanisms, which involve DNA and histone modifications, result in the heritable silencing of genes without a change in their coding sequence. The study of human disease has focused on genetic mechanisms, but disruption of the balance of epigenetic networks can cause several major pathologies, including cancer, syndromes involving chromosomal instabilities, and mental retardation. The development of new diagnostic tools might reveal other diseases that are caused by epigenetic alterations. Great potential lies in the development of ‘epigenetic therapies’ — several inhibitors of enzymes controlling epigenetic modifications, specifically DNA methyltransferases and histone deacetylases, have shown promising anti-tumorigenic effects for some malignancies.

Epigenetics in human disease and prospects for epigenetic therapy

The initiation and progression of cancer is controlled by both genetic and epigenetic events. Unlike genetic alterations, which are almost impossible to reverse, epigenetic aberrations are potentially reversible, allowing the malignant cell population to revert to a more normal state. With the advent of numerous drugs that target specific enzymes involved in the epigenetic regulation of gene expression, the utilization of epigenetic targets is emerging as an effective and valuable approach to chemotherapy as well as chemoprevention of cancer.

Epigenetic therapy of cancer: past, present and future

DNA methylation is one of the most intensely studied epigenetic modifications in mammals. In normal cells, it assures the proper regulation of gene expression and stable gene silencing. DNA methylation is associated with histone modifications and the interplay of these epigenetic modifications is crucial to regulate the functioning of the genome by changing chromatin architecture. The covalent addition of a methyl group occurs generally in cytosine within CpG dinucleotides which are concentrated in large clusters called CpG islands. DNA methyltransferases are responsible for establishing and maintenance of methylation pattern. It is commonly known that inactivation of certain tumor-suppressor genes occurs as a consequence of hypermethylation within the promoter regions and a numerous studies have demonstrated a broad range of genes silenced by DNA methylation in different cancer types. On the other hand, global hypomethylation, inducing genomic instability, also contributes to cell transformation. Apart from DNA methylation alterations in promoter regions and repetitive DNA sequences, this phenomenon is associated also with regulation of expression of noncoding RNAs such as microRNAs that may play role in tumor suppression. DNA methylation seems to be promising in putative translational use in patients and hypermethylated promoters may serve as biomarkers. Moreover, unlike genetic alterations, DNA methylation is reversible what makes it extremely interesting for therapy approaches. The importance of DNA methylation alterations in tumorigenesis encourages us to decode the human epigenome. Different DNA methylome mapping techniques are indispensable to realize this project in the future.

DNA methylation and cancer.

Natural products to drugs: natural product derived compounds in clinical trials

Four novel bisulfide bromotyrosine derivatives, psammaplins E (9), F (10), G (11), and H (12), and two new bromotyrosine derivatives, psammaplins I (13) and J (14), were isolated from the sponge Pseudoceratina purpurea, along with known psammaplins A (4), B (6), C (7), and D (8) and bisaprasin (5). The structures of psammaplins E (9) and F (10), which each contain an oxalyl group rarely found in marine organisms, were determined by spectroscopic analysis. Compounds 4, 5, and 10 are potent histone deacetylase inhibitors and also show mild cytotoxicity. Furthermore, compounds 4, 5, and 11 are potent DNA methyltransferase inhibitors. The biogenetic pathway previously proposed for the psammaplins class is also revisited.

Kenneth W Bair

Papers

Psammaplins from the Sponge Pseudoceratina purpurea: Inhibition of Both Histone Deacetylase and DNA Methyltransferase