HDAOS

HDACs and HDAC Inhibitors in Cancer Development and Therapy

Over the last several decades, it has become clear that epigenetic abnormalities may be one of the hallmarks of cancer. Posttranslational modifications of histones, for example, may play a crucial role in cancer development and progression by modulating gene transcription, chromatin remodeling, and nuclear architecture. Histone acetylation, a well-studied posttranslational histone modification, is controlled by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). By removing acetyl groups, HDACs reverse chromatin acetylation and alter transcription of oncogenes and tumor suppressor genes. In addition, HDACs deacetylate numerous nonhistone cellular substrates that govern a wide array of biological processes including cancer initiation and progression. This review will discuss the role of HDACs in cancer and the therapeutic potential of HDAC inhibitors (HDACi) as emerging drugs in cancer treatment.

Classical HDACs in the regulation of neuroinflammation

Neuroinflammation is a key factor of the pathology of various neurological diseases (brain injury, depression, neurodegenerative diseases). It is a complex and orderly process that relies on various types of glial cells and peripheral immune cells. Inhibition of neuroinflammation can reduce the severity of neurological diseases. The initiation, progression, and termination of inflammation require gene activation, epigenetic modification, transcriptional translation, and post-translational regulation, all of which are tightly regulated by different enzymes. Epigenetics refers to the regulation of epigenetic gene expression by epigenetic changes (DNA methylation, histone modification, and non-coding RNAs such as miRNA) that are not dependent on changes in gene sequence and are heritable. Histone deacetylases (HDACs) are a group of important enzymes that regulate epigenetics. They can remove the acetyl group on the lysine ?-amino group of the target protein, thereby affecting gene transcription or altering protein activity. HDACs are involved in the regulation of immunity and inflammation. HDAC inhibitor (HDACi) has also become a new hotspot in the research of anti-inflammatory drugs. Therefore, the aim of the current review is to discuss and summarize the role and mechanism of different HDACs in neuroinflammation and the corresponding role of HDACi in neurological diseases, and to providing new ideas for future research on neuroinflammation-related diseases and drug development.

HDACs and the epigenetic plasticity of cancer cells: Target the complexity

Cancer cells must adapt to the hostile conditions of the microenvironment in terms of nutrition, space, and immune system attack. Mutations of DNA are the drivers of the tumorigenic process, but mutations must be able to hijack cellular functions to sustain the spread of mutant genomes. Transcriptional control is a key function in this context and is controlled by the rearrangement of the epigenome. Unlike genomic mutations, the epigenome of cancer cells can in principle be reversed. The discovery of the first epigenetic drugs triggered a contaminating enthusiasm. Unfortunately, the complexity of the epigenetic machinery has frustrated this enthusiasm. To develop efficient patient-oriented epigenetic therapies, we need to better understand the nature of this complexity. In this review, we will discuss recent advances in understanding the contribution of HDACs to the maintenance of the transformed state and the rational for their selective targeting.

Metabolism, HDACs, and HDAC Inhibitors: A Systems Biology Perspective

Histone deacetylases (HDACs) are epigenetic enzymes that play a central role in gene regulation and are sensitive to the metabolic state of the cell. The cross talk between metabolism and histone acetylation impacts numerous biological processes including development and immune function. HDAC inhibitors are being explored for treating cancers, viral infections, inflammation, neurodegenerative diseases, and metabolic disorders. However, how HDAC inhibitors impact cellular metabolism and how metabolism influences their potency is unclear. Discussed herein are recent applications and future potential of systems biology methods such as high throughput drug screens, cancer cell line profiling, single cell sequencing, proteomics, metabolomics, and computational modeling to uncover the interplay between metabolism, HDACs, and HDAC inhibitors. The synthesis of new systems technologies can ultimately help identify epigenomic and metabolic biomarkers for patient stratification and the design of effective therapeutics.

Targeting Class IIa HDACs: Insights from Phenotypes and Inhibitors

This review summarizes key literature defining the phenotypes of individual class IIa HDAC proteins and compounds that selectively target their enzymatic catalytic domain (CD). The focus is on the effects of class IIa HDACs in physiological and pathological conditions, both in vitro and in vivo, and on their mode of action in regulating genes, upstream proteins and signaling pathways. Phenotype studies further demonstrate either beneficial or detrimental effects of silencing selected class IIa HDACs or their enzymatic properties. We also summarize the knowledge gained from structure-activity relationships of CD inhibitors as well as molecular mechanisms underpinning isozyme selectivity where crystal structures or modelling studies are available. Given that the number of genes affected by silencing class IIa HDACs is much smaller than class I, the role of gene regulation of class IIa HDACs could be much more selective. Since class IIa HDACs have restricted tissue distributions and multiple functions independent of their CD, targeting the CD of class IIa HDACs could lead to more selective therapeutic agents with significantly fewer side-effects than other HDAC ligands.