Search Results (4)

We have previously shown that the overexpression of acetyl-CoA carboxylase 1 (ACC1) was associated with the poor prognosis of cholangiocarcinoma (CCA) patients, and suppression of its expression in CCA cell lines deteriorated cell growth. The present study explored the mechanism by which ACC1 inhibition affects global protein acetylation, using genetic knockdown and pharmacological inhibition with an ACC1 inhibitor ND-646 as models. Both ACC1 knockdown and ACC1-inhibitor-treated cells displayed the hyperacetylation of proteins, accompanied by impaired growth and migration. The immunoprecipitation of hyperacetylated proteins using the anti-acetylated lysine antibody, followed by tandem mass spectrometry, identified three potential verification candidates, namely POTE ankyrin domain family member E, peroxisomal biogenesis factor 1, and heat shock protein 90 beta (HSP90B). HSP90 acetylation was the candidate selected for the verification of protein acetylation. To establish the effects of protein hyperacetylation, treatment with suberoylanilide hydroxamic acid (SAHA), a lysine deacetylase inhibitor, was conducted, and this served as an independent model. Decreased tumor growth but increased acetylated protein levels were observed in ACC1-KD xenograft tumors. Hyperacetylated-alleviated cell growth and migration were consistently observed in the SAHA-treated models. The molecular linkage between protein hyperacetylation and the AKT/GSK3β/Snail pathway was demonstrated. This study highlighted the importance of protein acetylation in CCA progression, suggesting that ACC1 and KDAC are potential targets for CCA treatment. Full article

The growing number of immunocompromised patients begs for efficient therapy strategies against invasive fungal infections. As conventional antifungal treatment is increasingly hampered by resistance to commonly used antifungals, development of novel therapy regimens is required. On the other hand, numerous fungal species are industrially exploited as cell factories of enzymes and chemicals or as producers of medically relevant pharmaceuticals. Consequently, there is immense interest in tapping the almost inexhaustible fungal portfolio of natural products for potential medical and industrial applications. Both the pathogenicity and production of those small metabolites are significantly dependent on the acetylation status of distinct regulatory proteins. Thus, classical lysine deacetylases (KDACs) are crucial virulence determinants and important regulators of natural products of fungi. In this review, we present an overview of the members of classical KDACs and their complexes in filamentous fungi. Further, we discuss the impact of the genetic manipulation of KDACs on the pathogenicity and production of bioactive molecules. Special consideration is given to inhibitors of these enzymes and their role as potential new antifungals and emerging tools for the discovery of novel pharmaceutical drugs and antibiotics in fungal producer strains. Full article

Parkinson’s disease (PD) is one of the most common neurodegenerative disorders. The neuropathological features of PD are selective and progressive loss of dopaminergic neurons in the substantia nigra pars compacta, deficiencies in striatal dopamine levels, and the presence of intracellular Lewy bodies. Interactions among aging and genetic and environmental factors are considered to underlie the common etiology of PD, which involves multiple changes in cellular processes. Recent studies suggest that changes in lysine acetylation and deacetylation of many proteins, including histones and nonhistone proteins, might be tightly associated with PD pathogenesis. Here, we summarize the changes in lysine acetylation of both histones and nonhistone proteins, as well as the related lysine acetyltransferases (KATs) and lysine deacetylases (KDACs), in PD patients and various PD models. We discuss the potential roles and underlying mechanisms of these changes in PD and highlight that restoring the balance of lysine acetylation/deacetylation of histones and nonhistone proteins is critical for PD treatment. Finally, we discuss the advantages and disadvantages of different KAT/KDAC inhibitors or activators in the treatment of PD models and emphasize that SIRT1 and SIRT3 activators and SIRT2 inhibitors are the most promising effective therapeutics for PD. Full article

Anti-microbial resistance (AMR) is currently one of the most serious threats to global human health and, appropriately, research to tackle AMR garnishes significant investment and extensive attention from the scientific community. However, most of this effort focuses on antibiotics, and research into anti-fungal resistance (AFR) is vastly under-represented in comparison. Given the growing number of vulnerable, immunocompromised individuals, as well as the positive impact global warming has on fungal growth, there is an immediate urgency to tackle fungal disease, and the disturbing rise in AFR. Chromatin structure and gene expression regulation play pivotal roles in the adaptation of fungal species to anti-fungal stress, suggesting a potential therapeutic avenue to tackle AFR. In this review we discuss both the genetic and epigenetic mechanisms by which chromatin structure can dictate AFR mechanisms and will present evidence of how pathogenic yeast, specifically from the Candida genus, modify chromatin structure to promote survival in the presence of anti-fungal drugs. We also discuss the mechanisms by which anti-chromatin therapy, specifically lysine deacetylase inhibitors, influence the acquisition and phenotypic expression of AFR in Candida spp. and their potential as effective adjuvants to mitigate against AFR. Full article