1,721,211 research outputs found
Effects of HDAC inhibitors in human diseases.
No full textContains fulltext :
91753.pdf (Publisher’s version ) (Open Access)Radboud Universiteit Nijmegen, 07 november 2011Promotores : Stunnenberg, H.G., Altucci, L
Deregulation of cell death in cancer: Recent highlights
Full text linkThe aim of this Special Issue on the deregulation of cell death in cancer is to bring together recent perspectives on the relationship between tumorigenesis and programmed cell death (PCD) [...]
Comment on: LncRNA SBF2-AS1 promotes hepatocellular carcinoma metastasis by regulating EMT and predicts unfavorable prognosis
No full textThe last worldwide evaluation on HCC impact and alarm refer to 20121
with dramatic information in
term of incidence rate and survival outcome. Despite the fact that more than 6 years are passed, the HCC
represents, still nowadays, one of the main oncological diseases in terms of incidence and negative survival
rate with worrying incidence also in many industrialized countries2
. Scientific evidence highlights how
antioxidant3
as well as nutraceutical agents4
can reduce the risk to develop the HCC, but it is not enough in
order to fight its progression and metastasis5
. Several mechanisms of action and markers were discovered
for the HCC6
, laying the foundations of the future innovative therapies and diagnosis approaches. In this
scenario, we read with great interest the article of Zhang et al7
. They evaluated and disseminated the role
of the LncRNA SBF2-AS1 in HCC patients. Starting from patients’ data, they focus on the LncRNA SBF2-
AS1 levels via bioinformatics and qPCR approaches. The data outcome correlates with the SBF2-AS1 up
regulation in HCC. Moreover, the authors investigated the clinical features and prognosis in HCC patients
in correlation with the SBF2-AS1 levels. Vein invasion and TNM stage, together with the low survival rate
strongly correlate with the high levels of LncRNA SBF2-AS1. On the other hands, the suppression of SBF2-
AS1 directly reduces the HCC proliferation and invasion acting on EMT pathway. The Zhang et al7
paper is
oriented towards the new frontiers of precision medicine passing by the patients stratification8
. The final
goal of last decade oncology research aims to provide the right therapy to the right patient9,10.
Concerning the fact the LncRNAs associated with HCC molecular mechanisms is grooving11, the LncRNA
SBF2-AS1 should be considered pivotal for as possible new diagnostic marker and therapy in HCC patient.
Indeed SBF2-AS1 could represent a new source as druggable target able for innovative HCC treatment.
Future studies12 should try to elucidate the potential interplay of mechanism in HCC initiation, progression
and fate among the genetic and epigenetic mechanisms
Design of dual inhibitors of histone deacetylase 6 and heat shock protein 90
Full text linkHistone deacetylase 6 (HDAC6) and heat shock protein 90 (Hsp90) are widely investigated anticancer drug targets. Importantly, several lines of evidence indicate that their regulation and activity are intimately linked, and that their combined inhibition may lead to impressive therapeutic benefits. In this study, we developed and applied an integrated computational strategy to design dual inhibitors of HDAC6 and Hsp90. Although the two targets share very little homology, an integrated ligand-based and structure-based virtual screening approach indicated a subset of compounds possessing the key structural requirements for binding at both targets. In vitro tests demonstrated that some of the selected candidates are able to selectively inhibit HDAC6 over HDAC1, to increase the acetylation levels of tubulin on cell assays and to reduce cell proliferation. The discovered compounds represent valuable starting points for further hit optimization
SIRT1 Activation by Natural Phytochemicals: An Overview
No full textSirtuins are class III histone deacetylases, whose enzymatic activity is dependent on NAD+ as a cofactor. Sirtuins are reported to modulate numerous activities by controlling gene expression, DNA repair, metabolism, oxidative stress response, mitochondrial function, and biogenesis. Deregulation of their expression and/or action may lead to tissue-specific degenerative events involved in the development of several human pathologies, including cancer, neurodegeneration, and cardiovascular disease. The most studied member of this class of enzymes is sirtuin 1 (SIRT1), whose expression is associated with increasing insulin sensitivity. SIRT1 has been implicated in both tumorigenic and anticancer processes, and is reported to regulate essential metabolic pathways, suggesting that its activation might be beneficial against disorders of the metabolism. Via regulation of p53 deacetylation and modulation of autophagy, SIRT1 is implicated in cellular response to caloric restriction and lifespan extension. In recent years, scientific interest focusing on the identification of SIRT1 modulators has led to the discovery of novel small molecules targeting SIRT1 activity. This review will examine compounds of natural origin recently found to upregulate SIRT1 activity, such as polyphenolic products in fruits, vegetables, and plants including resveratrol, fisetin, quercetin, and curcumin. We will also discuss the potential therapeutic effects of these natural compounds in the prevention and treatment of human disorders, with particular emphasis on their metabolic impact
Design of selective nuclear receptor modulators: RAR and RXR as a case study
No full textRetinoic acid receptors (RARs) and retinoid X receptors (RXRs) are members of the nuclear receptor superfamily whose effects on cell growth and survival can be modulated therapeutically by small-molecule ligands. Although compounds that target these receptors are powerful anticancer drugs, their use is limited by toxicity. An improved understanding of the structural biology of RXRs and RARs and recent advances in the chemical synthesis of modified retinoid and rexinoid ligands should enable the rational design of more selective agents that might overcome such problems. Here, we review structural data for RXRs and RARs, discuss strategies in the design of selective RXR and RAR modulators, and consider lessons that can be learned for the design of selective nuclear-receptor modulators in general
Gene transactivation and transrepression in myc-driven cancers
No full textMYC is a proto-oncogene regulating a large number of genes involved in a plethora of cellular functions. Its deregulation results in activation of MYC gene expression and/or an increase in MYC protein stability. MYC overexpression is a hallmark of malignant growth, inducing self-renewal of stem cells and blocking senescence and cell differentiation. This review summarizes the latest advances in our understanding of MYC-mediated molecular mechanisms responsible for its oncogenic activity. Several recent findings indicate that MYC is a regulator of cancer genome and epigenome: MYC modulates expression of target genes in a site-specific manner, by recruiting chromatin remodeling co-factors at promoter regions, and at genome-wide level, by regulating the expression of several epigenetic modifiers that alter the entire chromatin structure. We also discuss novel emerging therapeutic strategies based on both direct modulation of MYC and its epigenetic cofactors
NAA60 (HAT4): the newly discovered bi-functional Golgi member of the acetyltransferase family
No full textChromatin structural organization, gene expression and proteostasis are intricately regulated in a wide range of biological processes, both physiological and pathological. Protein acetylation, a major post-translational modification, is tightly involved in interconnected biological networks, modulating the activation of gene transcription and protein action in cells. A very large number of studies describe the pivotal role of the so-called acetylome (accounting for more than 80% of the human proteome) in orchestrating different pathways in response to stimuli and triggering severe diseases, including cancer. NAA60/NatF (N-terminal acetyltransferase F), also named HAT4 (histone acetyltransferase type B protein 4), is a newly discovered acetyltransferase in humans modifying N-termini of transmembrane proteins starting with M–K/M-A/M-V/M-M residues and is also thought to modify lysine residues of histone H4. Because of its enzymatic features and unusual cell localization on the Golgi membrane, NAA60 is an intriguing acetyltransferase that warrants biochemical and clinical investigation. Although it is still poorly studied, this review summarizes current findings concerning the structural hallmarks and biological role of this novel targetable epigenetic enzyme
- …
