The epigenetic landscape of renal cancer

This is an accepted manuscript of an article published by Nature in Nature Reviews: Nephrology on 28/11/2016, available online: https://doi.org/10.1038/nrneph.2016.168 The accepted version of the publication may differ from the final published version.The majority of kidney cancers are associated with mutations in the von Hippel-Lindau gene and a small proportion are associated with infrequent mutations in other well characterized tumour-suppressor genes. In the past 15 years, efforts to uncover other key genes involved in renal cancer have identified many genes that are dysregulated or silenced via epigenetic mechanisms, mainly through methylation of promoter CpG islands or dysregulation of specific microRNAs. In addition, the advent of next-generation sequencing has led to the identification of several novel genes that are mutated in renal cancer, such as PBRM1, BAP1 and SETD2, which are all involved in histone modification and nucleosome and chromatin remodelling. In this Review, we discuss how altered DNA methylation, microRNA dysregulation and mutations in histone-modifying enzymes disrupt cellular pathways in renal cancers

Epigenetic modulators as therapeutic targets in prostate cancer

Prostate cancer is one of the most common non-cutaneous malignancies among men worldwide. Epigenetic aberrations, including changes in DNA methylation patterns and/or histone modifications, are key drivers of prostate carcinogenesis. These epigenetic defects might be due to deregulated function and/or expression of the epigenetic machinery, affecting the expression of several important genes. Remarkably, epigenetic modifications are reversible and numerous compounds that target the epigenetic enzymes and regulatory proteins were reported to be effective in cancer growth control. In fact, some of these drugs are already being tested in clinical trials. This review discusses the most important epigenetic alterations in prostate cancer, highlighting the role of epigenetic modulating compounds in pre-clinical and clinical trials as potential therapeutic agents for prostate cancer management.info:eu-repo/semantics/publishedVersio

Possible survival of simple amino acids to X-ray irradiation in ice: the case of glycine

International audienceContext. Glycine, the simplest of amino acids, has been found in several carbonaceous meteorites collected on Earth, though its presence in the interstellar medium (ISM) has never been confirmed as of today. It is now considered that its synthesis took place in the icy mantles of interstellar grains, but it remains unclear how glycine, once synthesized and trapped in interplanetary particles, survives during the transfer to the Earth.Aims. Assuming that glycine was effectively formed in the ice, we address the question of its resistance to a solar-like radiation field and look for the possible molecular remnants that would be useful tracers of its former existence.Methods. The search was conducted using an interdisciplinary approach that mixes, on the one hand, irradiations in ultra high vacuum at 30 K on the TEMPO beam line of the synchrotron SOLEIL, simultaneously with near-edge X-ray absorption spectroscopy (NEXAFS) measurements, and on the other hand, quantum calculations to determine the energetics of the fragmentations and the relative stability of the different byproducts. The last points were addressed by means of density functional theory (DFT) simulations followed by high-level post Hartree-Fock calculations when more accurate relative energies were necessary. The constraints of an icy environment deserved special attention and the ice was modeled by a polarizable continuum medium that relies on the dielectric constant of water ice at 10–50 K.Results. Destruction of glycine is observed in the first seconds of irradiation, and carbon dioxide (CO2) and methylamine (CH3NH2) are formed. Carbon monoxide (CO), methanimine (CH2NH) and hydrogen cyanide (HCN) are also produced in secondary reactions. The amino acid destruction is the same for pure glycine and glycine in ice, indicating that the OH radicals released by the water matrix is barely involved in the photolytic process; however, these radicals are involved in the production of the secondary byproducts through dehydrogenation reactions as shown by ab initio quantum chemical simulation presented in this article along with the experimental results.Conclusions. The experiments show that glycine is only partially destroyed. Its abundance is found to stay at a level of ~30% of the initial concentration, for an irradiation dose equivalent to three years of solar radiation (at a distance of one astronomical unit). This result supports the hypothesis that, if trapped in protected icy environments and/or in the interior of interplanetary particles and meteorites, glycine may partly resist the radiation field to which it is submitted and, accordingly, survives its journey to the Earth