HIV "shock and kill" therapy: In need of revision.

Protein lysine methylation is a crucial post-translational modification that regulates the functions of both histone and non-histone proteins. Deregulation of the enzymes or ‘writers’ of protein lysine methylation, lysine methyltransferases (KMTs), is implicated in the cause of many diseases, including cancer, mental health disorders and developmental disorders. Over the past decade, significant advances have been made in developing drugs to target KMTs that are involved in histone methylation and epigenetic regulation. The first of these inhibitors, tazemetostat, was recently approved for the treatment of epithelioid sarcoma and follicular lymphoma, and several more are in clinical and preclinical evaluation. Beyond chromatin, the many KMTs that regulate protein synthesis and other fundamental biological processes are emerging as promising new targets for drug development to treat diverse diseases. Protein lysine methylation is an important post-translational modification of histone and non-histone proteins. In this Review, Gozani and colleagues discuss the role of protein lysine methyltransferases, the ‘writers’ of protein lysine methylation, in a range of diseases, and the progress and potential of targeting these enzymes therapeutically. They also consider the biology of lysine methyltransferases beyond epigenetic regulation as emerging targets for drug discovery.

Epigenetics and beyond: targeting writers of protein lysine methylation to treat disease.

In recent years, lipid metabolism has garnered significant attention as it provides the necessary building blocks required to sustain tumor growth and serves as an alternative fuel source for ATP generation. Fatty acid synthase (FASN) functions as a central regulator of lipid metabolism and plays a critical role in the growth and survival of tumors with lipogenic phenotypes. Accumulating evidence has shown that it is capable of rewiring tumor cells for greater energy flexibility to attain their high energy requirements. This multi-enzyme protein is capable of modulating the function of subcellular organelles for optimal function under different conditions. Apart from lipid metabolism, FASN has functional roles in other cellular processes such as glycolysis and amino acid metabolism. These pivotal roles of FASN in lipid metabolism make it an attractive target in the clinic with several new inhibitors currently being tested in early clinical trials. This article aims to present the current evidence on the emergence of FASN as a target in human malignancies.

Fatty Acid Synthase: An Emerging Target in Cancer

Histone deacetylase inhibitors (HDIs) are a group of potent epigenetic drugs which have been investigated for their therapeutic potential in various clinical disorders, including hematological malignancies and solid tumors. Currently, several HDIs are already in clinical use and many more are on clinical trials. HDIs have shown efficacy to inhibit initiation and progression of cancer cells. Nevertheless, both pro-invasive and anti-invasive activities of HDIs have been reported, questioning their impact in carcinogenesis. The aim of this review is to compile and discuss the most recent findings on the effect of HDIs on the epithelial-mesenchymal transition (EMT) process in human cancers. We have summarized the impact of HDIs on epithelial (E-cadherin, β-catenin) and mesenchymal (N-cadherin, vimentin) markers, EMT activators (TWIST, SNAIL, SLUG, SMAD, ZEB), as well as morphology, migration and invasion potential of cancer cells. We further discuss the use of HDIs as monotherapy or in combination with existing or novel anti-neoplastic drugs in relation to changes in EMT.

https://www.mdpi.com/2072-6694/11/2/148/pdf

Histone Deacetylase Inhibitors and Phenotypical Transformation of Cancer Cells

http://diposit.ub.edu/dspace/bitstream/2445/171626/1/DNA%20Repair%20.pdf

Scales and mechanisms of somatic mutation rate variation across the human genome

Mutations in, and the altered expression of, epigenetic modifiers are pervasive in human tumours, making epigenetic factors attractive antitumour targets. The open-versus-closed chromatin state within the cells-of-origin of cancer correlates with the uneven distribution of mutations. However, the long-term effect of targeting epigenetic modifiers on mutability in patients with cancer is unclear. Here, we increased chromatin accessibility by deleting the histone H3 lysine 9 (H3K9) methyltransferase G9a in murine epidermis and show that this does not alter the single nucleotide variant burden or global genomic distribution in chemical mutagen-induced squamous tumours. G9a-depleted tumours develop after a prolonged latency compared with their wild-type counterparts, but are more aggressive and have an expanded cancer progenitor pool, pronounced genomic instability and frequent loss-of-function p53 mutations. Thus, we call for caution when assessing long-term therapeutic benefits of chromatin modifier inhibitors, which may promote more aggressive disease.

/pdf/loss-of-g9a-preserves-mutation-patterns-but-increases-1izfiyqax8.pdf

Uxue Urdiroz-Urricelqui

Papers

Loss of G9a preserves mutation patterns but increases chromatin accessibility, genomic instability and aggressiveness in skin tumours.

The role of lipids in cancer progression and metastasis.

Lipid metabolism in metastasis and therapy

Repression of endogenous retroviruses prevents antiviral immune response and is required for mammary gland development