No abstract

Histone deacetylase (HDAC)6 is a member of the class IIb HDAC family. This enzyme is zinc-dependent and mainly localized in the cytoplasm. HDAC6 is a unique isoenzyme with two functional catalytic domains and specific physiological roles. Indeed, HDAC6 deacetylates various substrates including α-tubulin and HSP90α, and is involved in protein trafficking and degradation, cell shape and migration. Consequently, deregulation of HDAC6 activity was associated to a variety of diseases including cancer, neurodegenerative diseases and pathological autoimmune response. Therefore, HDAC6 represents an interesting potential therapeutic target. In this review, we discuss structural features of this histone deacetylase, regulation of its expression and activity, biological functions, implication in human disease initiation and progression. Finally will describe novel and selective HDAC6 inhibitors.

Arsenic ranks as the number one toxic environmental contaminant. In humans, arsenic exposure is associated with various forms of cancer, cardiovascular and skin diseases, neuropathies of the central nervous system, and genotoxic and immunotoxic effects. Although a well recognized human carcinogen, arsenic itself is not a potent mutagen and has been thought to act through epigenetic mechanisms that modify DNA methylation patterns, perhaps in conjunction with DNA-damaging agents. To develop preliminary support for a more thorough examination of this hypothesis, we have measured the effect of submicromolar and low-micromolar concentrations of arsenite on the methylation status of DNA and the biochemical reactions that regulate it. We find that arsenic causes the depletion of S-adenosylmethionine, the main cellular methyl donor, and represses the expression of the DNA methyltransferase genes DNMT1 and DNMT3A. Possibly as a consequence of these two complementary mechanisms, long-term exposure to arsenic results in DNA hypomethylation.

DNA methyltransferases (DNMTs) are important enzymes involved in epigenetic control of gene expression and represent valuable targets in cancer chemotherapy. A number of nucleoside DNMT inhibitors (DNMTi) have been studied in cancer, including in cancer stem cells, and two of them (azacytidine and decitabine) have been approved for treatment of myelodysplastic syndromes. However, only a few non-nucleoside DNMTi have been identified so far, and even fewer have been validated in cancer. Through a process of hit-to-lead optimization, we report here the discovery of compound 5 as a potent non-nucleoside DNMTi that is also selective toward other AdoMet-dependent protein methyltransferases. Compound 5 was potent at single-digit micromolar concentrations against a panel of cancer cells and was less toxic in peripheral blood mononuclear cells than two other compounds tested. In mouse medulloblastoma stem cells, 5 inhibited cell growth, whereas related compound 2 showed high cell differentiation. To the best of our knowledge, 2 and 5 are the first non-nucleoside DNMTi tested in a cancer stem cell line.