scholarly journals Polyamine analogues targeting epigenetic gene regulation

2009 ◽  
Vol 46 ◽  
pp. 95-110 ◽  
Author(s):  
Yi Huang ◽  
Laurence J. Marton ◽  
Patrick M. Woster ◽  
Robert A. Casero
Keyword(s):  
Transcriptional Activation ◽  
Histone Deacetylases ◽  
Significant Inhibition ◽  
Chromatin Remodelling ◽  
Polyamine Metabolism ◽  
Lysine Methylation ◽  
Protein Activity ◽  
Histone Lysine Methylation ◽  
Polyamine Analogues ◽  
Novel Approach

Over the past three decades the metabolism and functions of the polyamines have been actively pursued as targets for antineoplastic therapy. Interactions between cationic polyamines and negatively charged nucleic acids play a pivotal role in DNA stabilization and RNA processing that may affect gene expression, translation and protein activity. Our growing understanding of the unique roles that the polyamines play in chromatin regulation, and the discovery of novel proteins homologous with specific regulatory enzymes in polyamine metabolism, have led to our interest in exploring chromatin remodelling enzymes as potential therapeutic targets for specific polyamine analogues. One of our initial efforts focused on utilizing the strong affinity that the polyamines have for chromatin to create a backbone structure, which could be combined with active-site-directed inhibitor moieties of HDACs (histone deacetylases). Specific PAHAs (polyaminohydroxamic acids) and PABAs (polyaminobenzamides) polyamine analogues have demonstrated potent inhibition of the HDACs, re-expression of p21 and significant inhibition of tumour growth. A second means of targeting the chromatin-remodelling enzymes with polyamine analogues was facilitated by the recent identification of flavin-dependent LSD1 (lysine-specific demethylase 1). The existence of this enzyme demonstrated that histone lysine methylation is a dynamic process similar to other histone post-translational modifications. LSD1 specifically catalyses demethylation of mono- and di-methyl Lys4 of histone 3, key positive chromatin marks associated with transcriptional activation. Structural and catalytic similarities between LSD1 and polyamine oxidases facilitated the identification of biguanide, bisguanidine and oligoamine polyamine analogues that are potent inhibitors of LSD1. Cellular inhibition of LSD1 by these unique compounds led to the re-activation of multiple epigenetically silenced genes important in tumorigenesis. The use of these novel polyamine-based HDAC or LSD1 inhibitors represents a highly promising and novel approach to cancer prevention and therapy.

scholarly journals Divergent regulation of the key enzymes of polyamine metabolism by chiral α-methylated polyamine analogues

2009 ◽  
Vol 422 (2) ◽  
pp. 321-328 ◽  
Author(s):  
Mervi T. Hyvönen ◽  
Michael T. Howard ◽  
Christine B. Anderson ◽  
Nikolay Grigorenko ◽  
Alex R. Khomutov ◽  
...  
Keyword(s):  
Cellular Proliferation ◽  
Upstream Open Reading Frame ◽  
Polyamine Metabolism ◽  
Therapeutic Drug ◽  
Optical Isomers ◽  
Control Mechanisms ◽  
Reading Frame ◽  
Polyamine Analogues ◽  
Novel Approach ◽  
Polyamine Uptake

The natural polyamines are ubiquitous multifunctional organic cations which play important roles in regulating cellular proliferation and survival. Here we present a novel approach to investigating polyamine functions by using optical isomers of MeSpd (α-methylspermidine) and Me2Spm (α,ω-bismethylspermine), metabolically stable functional mimetics of natural polyamines. We studied the ability of MeSpd and Me2Spm to alter the normal polyamine regulation pathways at the level of polyamine uptake and the major control mechanisms known to affect the key polyamine metabolic enzymes. These include: (i) ODC (ornithine decarboxylase), which catalyses the rate-limiting step of polyamine synthesis; (ii) ODC antizyme, an inhibitor of ODC and polyamine uptake; (iii) SSAT (spermidine/spermine N1-acetyltransferase), the major polyamine catabolic enzyme; and (iv) AdoMetDC (S-adenosyl-L-methionine decarboxylase), which is required for the conversion of putrescine into spermidine, and spermidine into spermine. We show that the stereoisomers differ in their cellular uptake and ability to downregulate ODC and AdoMetDC, and to induce SSAT. These effects are mediated by the ability of the enantiomers to induce +1 ribosomal frameshifting on ODC antizyme mRNA, to suppress the translation of AdoMetDC uORF (upstream open reading frame) and to regulate the alternative splicing of SSAT pre-mRNA. The unique effects of chiral polyamine analogues on polyamine metabolism may offer novel possibilities for studying the physiological functions, control mechanisms, and targets of the natural polyamines, as well as advance therapeutic drug development in cancer and other human health-related issues.

Copper-dependent ATP7B up-regulation drives the resistance of TMEM16A-overexpressing head-and-neck cancer models to platinum toxicity

2019 ◽  
Vol 476 (24) ◽  
pp. 3705-3719 ◽  
Author(s):  
Avani Vyas ◽  
Umamaheswar Duvvuri ◽  
Kirill Kiselyov
Keyword(s):  
Oxidative Stress ◽  
Head And Neck ◽  
Transcriptional Activation ◽  
Platinum Resistance ◽  
Mrna Levels ◽  
Strong Positive Correlation ◽  
Platinum Compounds ◽  
Copper Chelation ◽  
Novel Approach ◽  
Cancer Models

Platinum-containing drugs such as cisplatin and carboplatin are routinely used for the treatment of many solid tumors including squamous cell carcinoma of the head and neck (SCCHN). However, SCCHN resistance to platinum compounds is well documented. The resistance to platinum has been linked to the activity of divalent transporter ATP7B, which pumps platinum from the cytoplasm into lysosomes, decreasing its concentration in the cytoplasm. Several cancer models show increased expression of ATP7B; however, the reason for such an increase is not known. Here we show a strong positive correlation between mRNA levels of TMEM16A and ATP7B in human SCCHN tumors. TMEM16A overexpression and depletion in SCCHN cell lines caused parallel changes in the ATP7B mRNA levels. The ATP7B increase in TMEM16A-overexpressing cells was reversed by suppression of NADPH oxidase 2 (NOX2), by the antioxidant N-Acetyl-Cysteine (NAC) and by copper chelation using cuprizone and bathocuproine sulphonate (BCS). Pretreatment with either chelator significantly increased cisplatin's sensitivity, particularly in the context of TMEM16A overexpression. We propose that increased oxidative stress in TMEM16A-overexpressing cells liberates the chelated copper in the cytoplasm, leading to the transcriptional activation of ATP7B expression. This, in turn, decreases the efficacy of platinum compounds by promoting their vesicular sequestration. We think that such a new explanation of the mechanism of SCCHN tumors’ platinum resistance identifies novel approach to treating these tumors.

scholarly journals Histone Deacetylase Enzymes as Potential Drug Targets in Cancer and Parasitic Diseases

2006 ◽  
Vol 2006 ◽  
pp. 1-10 ◽  
Author(s):  
Mehdi Ouaissi ◽  
Ali Ouaissi
Keyword(s):  
Transcriptional Activation ◽  
Histone Deacetylases ◽  
Drug Targets ◽  
Large Family ◽  
Current Data ◽  
Functional Study ◽  
Parasitic Diseases ◽  
Antitumor Effects ◽  
Protozoan Infections

The elucidation of the mechanisms of transcriptional activation and repression in eukaryotic cells has shed light on the important role of acetylation-deacetylation of histones mediated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. Another group belonging to the large family of sirtuins (silent information regulators (SIRs)) has an (nicotinamide adenine dinucleotide)NAD+-dependent HDAC activity. Several inhibitors of HDACs (HDIs) have been shown to exert antitumor effects. Interestingly, some of the HDIs exerted a broad spectrum of antiprotozoal activity. The purpose of this review is to analyze some of the current data related to the deacetylase enzymes as a possible target for drug development in cancer and parasitic diseases with special reference to protozoan infections. Given the structural differences among members of this family of enzymes, development of specific inhibitors will not only allow selective therapeutic intervention, but may also provide a powerful tool for functional study of these enzymes.

scholarly journals Dynamic Patterns of Histone Lysine Methylation in the Developing Retina

2010 ◽  
Vol 51 (12) ◽  
pp. 6784 ◽  
Author(s):  
Rajesh C. Rao ◽  
Kissaou T. Tchedre ◽  
Muhammad Taimur A. Malik ◽  
Natasha Coleman ◽  
Yuan Fang ◽  
...  
Keyword(s):  
Lysine Methylation ◽  
Histone Lysine Methylation ◽  
Histone Lysine ◽  
Dynamic Patterns

scholarly journals Multifunctional Inhibitor Mixture for Reducing Bacteria Growth and Corrosion on Marine Grade Steel

2021 ◽  
Author(s):  
Rainier Catubig ◽  
Agnes Michalczyk ◽  
Wayne Neil ◽  
Grant McAdam ◽  
John Forsyth ◽  
...  
Keyword(s):  
High Strength ◽  
Exposure Period ◽  
Significant Inhibition ◽  
Microbiologically Influenced Corrosion ◽  
Attractive Alternative ◽  
Bacteria Growth ◽  
Novel Approach ◽  
Inhibitor System ◽  
Strong Candidate ◽  
Low Sensitivity

<p><a></a>High strength steel in marine environments suffers from severe corrosion susceptibility and the presence of bacteria can exacerbate the effect, accelerating degradation via microbiologically influenced corrosion (MIC). Here we propose a novel approach to MIC inhibition by designing a system capable of limiting the effects of both bacteria growth and corrosion. The combination of a newly synthesised compound, cetrimonium 4-hydroxycinnamate, with lanthanum 4-hydroxycinnamate was the only system tested to date that could both inhibit abiotic corrosion in artificial seawater and minimise bacteria consortium densities over an exposure period of 24 hours. </p> <p>The electrochemical data for the La+Cet mixture demonstrated the significant inhibition of both abiotic corrosion to a level similar to La(4OHCin)<sub>3</sub>, as well as the ability to reduce bacteria densities of single strains and a consortium. This is unlike the La+CetNal mixture which accelerated abiotic corrosion and the La+IMI which had an insignificant effect on microbial densities (Catubig et al. 2020). </p> <p>A compatible mixture of ionic inhibitors was achieved by using the same cinnamate anion. </p> <p>This mixture of Cet-4OHCin and La(4OHCin)<sub>3</sub> demonstrated significant abiotic corrosion inhibition and bacteria density reductions, making it a strong candidate as an MIC inhibitor system for 80HLES. </p> <p>The Cet-4OHCin compound and its mixture with La(4OHCin)<sub>3</sub> retained relatively low sensitivity towards skin and intestinal cells, making it a safer and more attractive alternative than other more hazardous corrosion inhibitor materials. </p>

The Indexing Potential of Histone Lysine Methylation

2008 ◽  
pp. 22-47 ◽  
Author(s):  
Gunnar Schotta ◽  
Monika Lachner ◽  
Antoine H. F. M. Peters ◽  
Thomas Jenuwein
Keyword(s):  
Lysine Methylation ◽  
Histone Lysine Methylation ◽  
Histone Lysine

scholarly journals Protein lysine 43 methylation by EZH1 promotes AML1-ETO transcriptional repression in leukemia

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Liping Dou ◽  
Fei Yan ◽  
Jiuxia Pang ◽  
Dehua Zheng ◽  
Dandan Li ◽  
...  
Keyword(s):  
Dna Sequences ◽  
Transcriptional Repression ◽  
Lysine Methylation ◽  
Post Translational Modification ◽  
Histone Lysine Methylation ◽  
Histone Lysine ◽  
Histone Lysine Methyltransferase ◽  
Lysine Methyltransferase

Abstract The oncogenic fusion protein AML1-ETO retains the ability of AML1 to interact with the enhancer core DNA sequences, but blocks AML1-dependent transcription. Previous studies have shown that post-translational modification of AML1-ETO may play a role in its regulation. Here we report that AML1-ETO-positive patients, with high histone lysine methyltransferase Enhancer of zeste homolog 1 (EZH1) expression, show a worse overall survival than those with lower EZH1 expression. EZH1 knockdown impairs survival and proliferation of AML1-ETO-expressing cells in vitro and in vivo. We find that EZH1 WD domain binds to the AML1-ETO NHR1 domain and methylates AML1-ETO at lysine 43 (Lys43). This requires the EZH1 SET domain, which augments AML1-ETO-dependent repression of tumor suppressor genes. Loss of Lys43 methylation by point mutation or domain deletion impairs AML1-ETO-repressive activity. These findings highlight the role of EZH1 in non-histone lysine methylation, indicating that cooperation between AML1-ETO and EZH1 and AML1-ETO site-specific lysine methylation promote AML1-ETO transcriptional repression in leukemia.

Histone lysine methylation exhibits a distinct distribution during spermatogenesis in pigs

2015 ◽  
Vol 84 (9) ◽  
pp. 1455-1462 ◽  
Author(s):  
Junhui An ◽  
Jinzhou Qin ◽  
Yi Wan ◽  
Yaqing Zhang ◽  
Yuan Hu ◽  
...  
Keyword(s):  
Lysine Methylation ◽  
Histone Lysine Methylation ◽  
Histone Lysine ◽  
Distinct Distribution

Ankyrin repeats-containing cofactors interact with ADA3 and modulate its co-activator function

2008 ◽  
Vol 413 (2) ◽  
pp. 349-357 ◽  
Author(s):  
Chia-Wei Li ◽  
Gia Khanh Dinh ◽  
Aihua Zhang ◽  
J. Don Chen
Keyword(s):  
Nuclear Receptors ◽  
Transcriptional Activation ◽  
Histone Deacetylases ◽  
Binding Protein ◽  
Camp Response Element Binding ◽  
Transactivation Domain ◽  
Ankyrin Repeats ◽  
Camp Response Element ◽  
Element Binding Protein

ANCO (ankyrin repeats-containing cofactor)-1 and ANCO-2 are a family of unique transcriptional co-regulators with dual properties: they interact with both the co-activators and the co-repressors [Zhang, Yeung, Li, Tsai, Dinh, Wu, Li and Chen (2004) J. Biol. Chem. 279, 33799–33805]. Specifically, ANCO-1 is thought to recruit HDACs (histone deacetylases) to the p160 co-activator to repress transcriptional activation by nuclear receptors. In the present study, we provide new evidence to suggest further that ANCO-1 and ANCO-2 also interact with the co-activator ADA3 (alteration/deficiency in activation 3). The interaction occurs between the conserved C-terminal domain of ANCO-1 and the N-terminal transactivation domain of ADA3. Several subunits of the P/CAF {p300/CBP [CREB (cAMP-response-element-binding protein)-binding protein]-associated factor} complex, including ADA3, ADA2α/β and P/CAF, showed co-localization with ANCO-1 nuclear dots, indicating an in vivo association of ANCO-1 with the P/CAF complex. Furthermore, a transient reporter assay revealed that both ANCO-1 and ANCO-2 repress ADA3-mediated transcriptional co-activation on nuclear receptors, whereas ANCO-1 stimulated p53-mediated transactivation. These data suggest that ADA3 is a newly identified target of the ANCO proteins, which may modulate co-activator function in a transcription-factor-specific manner.

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