Inhibition of p300 lysine acetyltransferase activity by luteolin reduces tumor growth in head and neck squamous cell carcinoma (HNSCC) xenograft mouse model.

Chromatin acetylation is attributed with distinct functional relevance with respect to gene expression in normal and diseased conditions thereby leading to a topical interest in the concept of epigenetic modulators and therapy. We report here the identification and characterization of the acetylation inhibitory potential of an important dietary flavonoid, luteolin. Luteolin was found to inhibit p300 acetyltransferase with competitive binding to the acetyl CoA binding site. Luteolin treatment in a xenografted tumor model of head and neck squamous cell carcinoma (HNSCC), led to a dramatic reduction in tumor growth within 4 weeks corresponding to a decrease in histone acetylation. Cells treated with luteolin exhibit cell cycle arrest and decreased cell migration. Luteolin treatment led to an alteration in gene expression and miRNA profile including up-regulation of p53 induced miR-195/215, let7C; potentially translating into a tumor suppressor function. It also led to down-regulation of oncomiRNAs such as miR-135a, thereby reflecting global changes in the microRNA network. Furthermore, a direct correlation between the inhibition of histone acetylation and gene expression was established using chromatin immunoprecipitation on promoters of differentially expressed genes. A network of dysregulated genes and miRNAs was mapped along with the gene ontology categories, and the effects of luteolin were observed to be potentially at multiple levels: at the level of gene expression, miRNA expression and miRNA processing.

Multifunctional carbon nanospheres with magnetic and luminescent probes: probable brain theranostic agents.

Multi-functional carbon nanospheres with magnetic Prussian blue nanoparticles and luminescent lanthanide ions have been prepared. The negatively charged surface of the glucose derived carbon sphere facilitates the nucleation of Prussian blue nanoparticles on its surface. The luminescent lanthanide probes were attached to the surface of the carbon sphere through a benzene tricarboxylic acid linker. These multifunctional hybrid organic-inorganic composites are superparamagnetic and show enhanced luminescent properties. Their ability to cross the blood-brain barrier (enter the brain cell nucleus with no animal toxicity) in a mouse model indicate that these nanocomposites are promising theranostic agents for the treatment of brain diseases.

Inhibition of acetyltransferase alters different histone modifications: probed by small molecule inhibitor plumbagin.

Histone modifications; acetylation, methylation (both Lysine and Arginine) etc., at different positions regulates the chromatin fluidity and function in a combinatorial manner, which could be referred as an epigenetic language. In the context of transcription, histone acetylation, methylation and phosphorylation at specific sites, especially at the N-terminal tails of histones play very important roles in activation and/or repression. While acetylation of histones is generally important for transcriptional activation, methylation and phosphorylation could also be involved in repression, depending on the context. Here, we have investigated the crosstalk of histone modifications on a gross scale over histone H3, using a small molecule inhibitor of lysine acetyltransferase KAT3B/p300, Plumbagin, to analyze the histone modification profile upon inhibition of acetylation. In addition to the inhibition of acetylation, there was a concomitant decrease of transcriptional activation mark, H3 lysine 4 trimethylation (H3K4me3) in the cellular context. The histone H3 Serine 10 Phosphorylation (H3S10p) also decreased upon inhibition of acetylation. However, there were no changes observed with transcriptional repressive marks like H3 Lysine 9 di/trimethylation (H3K9me2/me3) suggesting that transcriptional activation marks were selectively targeted. These data suggest that Plumbagin induces a distinct modification profile involving transcriptional activation marks H3K4me3 and H3S10 phosphorylation in the context of histone acetylation brought about by KAT3B/ p300.

ATP driven clathrin dependent entry of carbon nanospheres prefer cells with glucose receptors.

BACKGROUND: Intrinsically fluorescent glucose derived carbon nanospheres (CSP) efficiently enter mammalian cells and also cross the blood brain barrier (BBB). However, the mechanistic details of CSP entry inside mammalian cells and its specificity are not known. RESULTS: In this report, the biochemical and cellular mechanism of CSP entry into the living cell have been investigated. By employing confocal imaging we show that CSP entry into the mammalian cells is an ATP-dependent clathrin mediated endocytosis process. Zeta potential studies suggest that it has a strong preference for cells which possess high levels of glucose transporters such as the glial cells, thereby enabling it to target individual organs/tissues such as the brain with increased specificity. CONCLUSION: The endocytosis of Glucose derived CSP into mammalian cells is an ATP dependent process mediated by clathrin coated pits. CSPs utilize the surface functional groups to target cells containing glucose transporters on its membrane thereby implicating a potential application for specific targeting of the brain or cancer cells.

Reversible acetylation of chromatin: implication in regulation of gene expression, disease and therapeutics.

The eukaryotic genome is a highly dynamic nucleoprotein complex that is comprised of DNA, histones, nonhistone proteins and RNA, and is termed as chromatin. The dynamic of the chromatin is responsible for the regulation of all the DNA-templated phenomena in the cell. Several factors, including the nonhistone chromatin components, ATP-dependent remodeling factors and the chromatin-modifying enzymes, mediate the combinatorial post-translational modifications that control the chromatin fluidity and, thereby, the cellular functions. Among these modifications, reversible acetylation plays a central role in the highly orchestrated network. The enzymes responsible for the reversible acetylation, the histone acetyltransferases (HATs) and histone deacetylases (HDACs), not only act on histone substrates but also on nonhistone proteins. Dysfunction of the HATs/HDACs is associated with various diseases like cancer, diabetes, asthma, cardiac hypertrophy, retroviral pathogenesis and neurodegenerative disorders. Therefore, modulation of these enzymes is being considered as an important therapeutic strategy. Although substantial progress has been made in the area of HDAC inhibitors, we have focused this review on the HATs and their small-molecule modulators in the context of disease and therapeutics. Recent discoveries from different groups have established the involvement of HAT function in various diseases. Furthermore, several new classes of HAT modulators have been identified and their biological activities have also been reported. The scaffold of these small molecules can be used for the design and synthesis of better and efficient modulators with superior therapeutic efficacy.