The epigenomics of cancer.

This article reviews the mechanisms of gene silencing in cancer and clinical applications of this phenomenon. The silencing of genes, especially tumor-suppressor genes, is a key event in the development of cancer. The silencing can be effected by a disabling mutation or by a shutting down of the promoter region, the site at which transcription of the gene begins.

Gene Silencing in Cancer in Association with Promoter Hypermethylation

Transcriptional regulation in eukaryotes occurs within a chromatin setting, and is strongly influenced by the post-translational modification of histones, the building blocks of chromatin, such as methylation, phosphorylation and acetylation. Acetylation is probably the best understood of these modifications: hyperacetylation leads to an increase in the expression of particular genes, and hypoacetylation has the opposite effect. Many studies have identified several large, multisubunit enzyme complexes that are responsible for the targeted deacetylation of histones. The aim of this review is to give a comprehensive overview of the structure, function and tissue distribution of members of the classical histone deacetylase (HDAC) family, in order to gain insight into the regulation of gene expression through HDAC activity. SAGE (serial analysis of gene expression) data show that HDACs are generally expressed in almost all tissues investigated. Surprisingly, no major differences were observed between the expression pattern in normal and malignant tissues. However, significant variation in HDAC expression was observed within tissue types. HDAC inhibitors have been shown to induce specific changes in gene expression and to influence a variety of other processes, including growth arrest, differentiation, cytotoxicity and induction of apoptosis. This challenging field has generated many fascinating results which will ultimately lead to a better understanding of the mechanism of gene transcription as a whole.

/pdf/histone-deacetylases-hdacs-characterization-of-the-classical-170nc52558.pdf

Histone deacetylases (HDACs): characterization of the classical HDAC family

Histone deacetylases (HDACs) are enzymes involved in the remodelling of chromatin, and have a key role in the epigenetic regulation of gene expression. In addition, the activity of non-histone proteins can be regulated through HDAC-mediated hypo-acetylation. In recent years, inhibition of HDACs has emerged as a potential strategy to reverse aberrant epigenetic changes associated with cancer, and several classes of HDAC inhibitors have been found to have potent and specific anticancer activities in preclinical studies. However, such studies have also indicated that the effects of HDAC inhibitors could be considerably broader and more complicated than originally understood. Here we summarize recent advances in the understanding of the molecular events that underlie the anticancer effects of HDAC inhibitors, and discuss how such information could be used in optimizing the development and application of these agents in the clinic, either as monotherapies or in combination with other anticancer drugs.

http://dipbsf.uninsubria.it/monti/BFPN%202009/HDACi2.pdf

Anticancer activities of histone deacetylase inhibitors.

NF‐κB is responsible for upregulating gene products that control cell survival. In this study, we demonstrate that SIRT1, a nicotinamide adenosine dinucleotide‐dependent histone deacetylase, regulates the transcriptional activity of NF‐κB. SIRT1, the mammalian ortholog of the yeast SIR2 (Silencing Information Regulator) and a member of the Sirtuin family, has been implicated in modulating transcriptional silencing and cell survival. SIRT1 physically interacts with the RelA/p65 subunit of NF‐κB and inhibits transcription by deacetylating RelA/p65 at lysine 310. Treatment of cells with resveratrol, a small‐molecule agonist of Sirtuin activity, potentiates chromatin‐associated SIRT1 protein on the cIAP‐2 promoter region, an effect that correlates with a loss of NF‐κB‐regulated gene expression and sensitization of cells to TNFα‐induced apoptosis. While SIRT1 is capable of protecting cells from p53‐induced apoptosis, our work provides evidence that SIRT1 activity augments apoptosis in response to TNFα by the ability of the deacetylase to inhibit the transactivation potential of the RelA/p65 protein.

/pdf/modulation-of-nf-kb-dependent-transcription-and-cell-4tfbiib05o.pdf

Modulation of NF-κB-dependent transcription and cell survival by the SIRT1 deacetylase

Together, histone acetyltransferases and histone deacetylases (HDACs) determine the acetylation status of histones. This acetylation affects the regulation of gene expression, and inhibitors of HDACs have been found to cause growth arrest, differentiation and/or apoptosis of many tumours cells by altering the transcription of a small number of genes. HDAC inhibitors are proving to be an exciting therapeutic approach to cancer, but how do they exert this effect?

Histone deacetylases and cancer: causes and therapies.

Objective. To evaluate the cardiovascular fitness of a group of patients with severe osteoarthritis (OA).



Methods. Thirty-seven patients with end-stage OA were evaluated just before hip or knee replacement surgery. Severity of arthritis was evaluated using standardized techniques. Patients and age- and sex-matched controls underwent a single, maximal, symptomlimited, cardiopulmonary exercise test using arm or leg ergometry and a metabolic cart to measure expired respiratory gases.



Results. Severe musculoskeletal disability and deformity was confirmed in the OA patient group. During exercise testing, OA patients were able to perform physiologically maximal cardiopulmonary exercise. Arthritis patients were noted to be severely deconditioned, with reduced peak oxygen consumption (OA hips mean ± SD 14.9 ± 4.2 versus control hips 19.0 ± 4.6, P 0.05) was also noted.



Conclusion. Patients with end-stage lower extremity OA are severely deconditioned. This may place them at incremental risk for the development of coronary heart disease.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.1780380613

Cardiovascular fitness and health in patients with end-stage osteoarthritis.

Histone deacetylase (HDAC) inhibitors represent a new class of targeted anticancer agents. A number of structural classes of HDAC inhibitors have been developed of which several are in clinical trials, including phenylbutyrate (PB) and related compounds; the hydroxamic acids, suberoylanilide hydroxamic acid (SAHA) and depsipeptide (FK-228); and the benzamides, MS-275 and C1-994. This review will focus on our studies with the hydroxamic acid HDAC inhibitors, of which SAHA is the lead agent. X-ray crystallographic studies with a HDAC homologue (HDLP) demonstrated that the hydroxamic acid group, most of the aliphatic chain and part of the phenyl amino group of SAHA inserts into the pocket-like catalytic site of the enzyme, at the base of which is a zinc molecule. SAHA inhibits the activity of class I and II HDACs and is selective in altering gene expression. SAHA is synergistic in its anticancer activity with radiation, kinase inhibitors, cytotoxic agents and differentiating agents. In phase I clinical trial with orally administered SAHA the agent caused accumulation of acetylated histones in peripheral mononuclear cells and tumour cells, has excellent bioavailability and has shown antitumour activity in patients with haematologic and solid tumours.

Histone deacetylase inhibitors: development as cancer therapy.

Since the discovery of quasars, it has been recognized that these objects must have either an extraordinary intrinsic brightness or a nonlinear redshift. The most widely accepted current belief incorporates a linear (Hubble) redshift-distance relation and time evolution within a Big Bang model. We reconsider the possibility of a nonlinear (de Sitter) redshift-distance relation and find quasar intrinsic brightness to be not at all extraordinary. Given a de Sitter law, intrinsic brightness is found to be independent of redshift over five orders of magnitude.

Low Correlation between Redshift and Intrinsic Brightness for Quasars and Galaxies in a De Sitter Universe

A fibre-optic time-of-flight instrument based on a modified Fizeau apparatus has been developed to measure the speed of light emanating from astronomical objects. The instrument is optimized for low photon flux sources. Lightspeed measurements from 11 nearby stars are reported, with a mean value of (2.98 ? 0.03) ? 108 m?s?1. These are the first direct photon velocity measurements for sources outside the solar system.

https://iopscience.iop.org/article/10.1088/0957-0233/14/10/311/pdf

Thomas E. Miller

Papers

Histone deacetylases and cancer: causes and therapies.

Cardiovascular fitness and health in patients with end-stage osteoarthritis.

Histone deacetylase inhibitors: development as cancer therapy.

Low Correlation between Redshift and Intrinsic Brightness for Quasars and Galaxies in a De Sitter Universe

A telescopic instrument for direct astronomical lightspeed measurements