Spectrum of microRNAs and their target genes in cancer: intervention in diagnosis and therapy.

Till date, several groups have studied the mechanism of microRNA (miRNA) biogenesis, processing, stability, silencing, and their dysregulation in cancer. The miRNA coding genes recurrently go through abnormal amplification, deletion, transcription, and epigenetic regulation in cancer. Some miRNAs function as tumor promoters while few others are tumor suppressors based on the transcriptional regulation of target genes. A review of miRNAs and their target genes in a wide range of cancers is attempted in this article, which may help in the development of new diagnostic tools and intervention therapies. The contribution of miRNAs for drug sensitivity or resistance in cancer therapy and opportunities of miRNAs in cancer prognosis or diagnosis and therapy is also presented in detail.

Insights into the function of HDAC3 and NCoR1/NCoR2 co-repressor complex in metabolic diseases.

Histone deacetylase 3 (HDAC3) and nuclear receptor co-repressor (NCoR1/2) are epigenetic regulators that play a key role in gene expression and metabolism. HDAC3 is a class I histone deacetylase that functions as a transcriptional co-repressor, modulating gene expression by removing acetyl groups from histones and non-histone proteins. NCoR1, on the other hand, is a transcriptional co-repressor that interacts with nuclear hormone receptors, including peroxisome proliferator-activated receptor gamma (PPARγ) and liver X receptor (LXR), to regulate metabolic gene expression. Recent research has revealed a functional link between HDAC3 and NCoR1 in the regulation of metabolic gene expression. Genetic deletion of HDAC3 in mouse models has been shown to improve glucose intolerance and insulin sensitivity in the liver, skeletal muscle, and adipose tissue. Similarly, genetic deletion of NCoR1 has improved insulin resistance and reduced adiposity in mouse models. Dysregulation of this interaction has been associated with the development of cardio-metabolic diseases such as cardiovascular diseases, obesity and type 2 diabetes, suggesting that targeting this pathway may hold promise for the development of novel therapeutic interventions. In this review, we summarize the current understanding of individual functions of HDAC3 and NCoR1/2 and the co-repressor complex formation (HDAC3/NCoR1/2) in different metabolic tissues. Further studies are needed to thoroughly understand the mechanisms through which HDAC3, and NCoR1/2 govern metabolic processes and the implications for treating metabolic diseases.

Histone deacetylase (HDACs) inhibitors: Clinical applications.

Histone Deacetylases (HDACs) deacetylate lysine residues in histone and non-histone proteins. HDACs have been implicated in several diseases, including cancer, neurodegeneration, and cardiovascular disease. HDACs play an essential role in gene transcription, cell survival, growth, and proliferation, with histone hypoacetylation as one of the critical downstream signatures. HDAC inhibitors (HDACi) regulate gene expression epigenetically by restoring acetylation levels. Contrarily, only few HDACi have received FDA approval, and the majority are presently undergoing clinical trials to ascertain their effectiveness in the prevention and treatment of disease. In this book chapter, we give a detailed list of HDAC classes, and their functions in advancing diseases like cancer, cardiovascular, and neurodegeneration. Furthermore we touch upon novel and promising HDACi therapy approaches in the relevance of the current clinical scenario.

The lipid droplet-associated protein ABHD5 protects the heart through proteolysis of HDAC4.

Catecholamines stimulate the first step of lipolysis by PKA-dependent release of the lipid droplet-associated protein ABHD5 from perilipin to co-activate the lipase ATGL. Here, we unmask a yet unrecognized proteolytic and cardioprotective function of ABHD5. ABHD5 acts in vivo and in vitro as a serine protease cleaving HDAC4. Through the production of an N-terminal polypeptide of HDAC4 (HDAC4-NT), ABHD5 inhibits MEF2-dependent gene expression and thereby controls glucose handling. ABHD5-deficiency leads to neutral lipid storage disease in mice. Cardiac-specific gene therapy of HDAC4-NT does not protect from intra-cardiomyocyte lipid accumulation but strikingly from heart failure, thereby challenging the concept of lipotoxicity-induced heart failure. ABHD5 levels are reduced in failing human hearts and murine transgenic ABHD5 expression protects from pressure-overload induced heart failure. These findings represent a conceptual advance by connecting lipid with glucose metabolism through HDAC4 proteolysis and enable new translational approaches to treat cardiometabolic disease.