scholarly journals Epigenetic Factors that Control Pericentric Heterochromatin Organization in Mammals

Genes ◽  
2020 ◽  
Vol 11 (6) ◽  
pp. 595 ◽  
Author(s):  
Salvatore Fioriniello ◽  
Domenico Marano ◽  
Francesca Fiorillo ◽  
Maurizio D’Esposito ◽  
Floriana Della Ragione
Keyword(s):  
Cancer Progression ◽  
Histone Deacetylases ◽  
Molecular Mechanisms ◽  
Dna Methyltransferases ◽  
Pericentric Heterochromatin ◽  
Molecular Signature ◽  
Genome Integrity ◽  
Biological Phenomena ◽  
Species Specific ◽  
And Function

Pericentric heterochromatin (PCH) is a particular form of constitutive heterochromatin that is localized to both sides of centromeres and that forms silent compartments enriched in repressive marks. These genomic regions contain species-specific repetitive satellite DNA that differs in terms of nucleotide sequences and repeat lengths. In spite of this sequence diversity, PCH is involved in many biological phenomena that are conserved among species, including centromere function, the preservation of genome integrity, the suppression of spurious recombination during meiosis, and the organization of genomic silent compartments in the nucleus. PCH organization and maintenance of its repressive state is tightly regulated by a plethora of factors, including enzymes (e.g., DNA methyltransferases, histone deacetylases, and histone methyltransferases), DNA and histone methylation binding factors (e.g., MECP2 and HP1), chromatin remodeling proteins (e.g., ATRX and DAXX), and non-coding RNAs. This evidence helps us to understand how PCH organization is crucial for genome integrity. It then follows that alterations to the molecular signature of PCH might contribute to the onset of many genetic pathologies and to cancer progression. Here, we describe the most recent updates on the molecular mechanisms known to underlie PCH organization and function.

scholarly journals Molecular Targets of Epigallocatechin—Gallate (EGCG): A Special Focus on Signal Transduction and Cancer

Nutrients ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 1936 ◽  
Author(s):  
Aide Negri ◽  
Valeria Naponelli ◽  
Federica Rizzi ◽  
Saverio Bettuzzi
Keyword(s):  
Cell Proliferation ◽  
Green Tea ◽  
Histone Deacetylases ◽  
Molecular Mechanisms ◽  
Epigallocatechin Gallate ◽  
Dna Methyltransferases ◽  
Biologically Active ◽  
Special Focus ◽  
Dependent Inhibition

Green tea is a beverage that is widely consumed worldwide and is believed to exert effects on different diseases, including cancer. The major components of green tea are catechins, a family of polyphenols. Among them, epigallocatechin-gallate (EGCG) is the most abundant and biologically active. EGCG is widely studied for its anti-cancer properties. However, the cellular and molecular mechanisms explaining its action have not been completely understood, yet. EGCG is effective in vivo at micromolar concentrations, suggesting that its action is mediated by interaction with specific targets that are involved in the regulation of crucial steps of cell proliferation, survival, and metastatic spread. Recently, several proteins have been identified as EGCG direct interactors. Among them, the trans-membrane receptor 67LR has been identified as a high affinity EGCG receptor. 67LR is a master regulator of many pathways affecting cell proliferation or apoptosis, also regulating cancer stem cells (CSCs) activity. EGCG was also found to be interacting directly with Pin1, TGFR-II, and metalloproteinases (MMPs) (mainly MMP2 and MMP9), which respectively regulate EGCG-dependent inhibition of NF-kB, epithelial-mesenchimal transaction (EMT) and cellular invasion. EGCG interacts with DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), which modulates epigenetic changes. The bulk of this novel knowledge provides information about the mechanisms of action of EGCG and may explain its onco-suppressive function. The identification of crucial signalling pathways that are related to cancer onset and progression whose master regulators interacts with EGCG may disclose intriguing pharmacological targets, and eventually lead to novel combined treatments in which EGCG acts synergistically with known drugs.

scholarly journals Human Slug Is a Repressor That Localizes to Sites of Active Transcription

2000 ◽  
Vol 20 (14) ◽  
pp. 5087-5095 ◽  
Author(s):  
Kirugaval Hemavathy ◽  
Siradanahalli C. Guru ◽  
John Harris ◽  
J. Don Chen ◽  
Y. Tony Ip
Keyword(s):  
Dna Binding ◽  
Cell Fate ◽  
Histone Deacetylases ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Protein Localization ◽  
Zinc Fingers ◽  
Cell Movement ◽  
Left Right Asymmetry ◽  
And Function

ABSTRACT Snail/Slug family proteins have been identified in diverse species of both vertebrates and invertebrates. The proteins contain four to six zinc fingers and function as DNA-binding transcriptional regulators. Various members of the family have been demonstrated to regulate cell movement, neural cell fate, left-right asymmetry, cell cycle, and apoptosis. However, the molecular mechanisms of how these regulators function and the target genes involved are largely unknown. In this report, we demonstrate that human Slug (hSlug) is a repressor and modulates both activator-dependent and basal transcription. The repression depends on the C-terminal DNA-binding zinc fingers and on a separable repression domain located in the N terminus. This domain may recruit histone deacetylases to modify the chromatin and effect repression. Protein localization study demonstrates that hSlug is present in discrete foci in the nucleus. This subnuclear pattern does not colocalize with the PML foci or the coiled bodies. Instead, the hSlug foci overlap extensively with areas of the SC-35 staining, some of which have been suggested to be sites of active splicing or transcription. These results lead us to postulate that hSlug localizes to target promoters, where activation occurs, to repress basal and activator-mediated transcription.

scholarly journals The Role of Glucocorticoid Receptor Signaling in Bladder Cancer Progression

Cancers ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 484 ◽  
Author(s):  
Hiroki Ide ◽  
Satoshi Inoue ◽  
Hiroshi Miyamoto
Keyword(s):  
Bladder Cancer ◽  
Glucocorticoid Receptor ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Receptor Expression ◽  
Receptor Signaling ◽  
Castration Resistant Prostate Cancer ◽  
And Function

Previous preclinical studies have indicated that the activation of glucocorticoid receptor signaling results in inhibition of the growth of various types of tumors. Indeed, several glucocorticoids, such as dexamethasone and prednisone, have been prescribed for the treatment of, for example, hematological malignancies and castration-resistant prostate cancer. By contrast, the role of glucocorticoid-mediated glucocorticoid receptor signaling in the progression of bladder cancer remains far from being fully understood. Nonetheless, emerging evidence implies its unique functions in urothelial cancer cells. Moreover, the levels of glucocorticoid receptor expression have been documented to significantly associate with the prognosis of patients with bladder cancer. This review summarizes the available data suggesting the involvement of glucocorticoid-mediated glucocorticoid receptor signaling in urothelial tumor outgrowth and highlights the potential underlying molecular mechanisms. The molecules/pathways that contribute to modulating glucocorticoid receptor activity and function in bladder cancer cells are also discussed.

scholarly journals Chromatin Regulator SPEN/SHARP in X Inactivation and Disease

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1665
Author(s):  
Benedetto Daniele Giaimo ◽  
Teresa Robert-Finestra ◽  
Franz Oswald ◽  
Joost Gribnau ◽  
Tilman Borggrefe
Keyword(s):  
X Chromosome ◽  
Histone Deacetylases ◽  
Molecular Mechanisms ◽  
Dna Methyltransferases ◽  
Heterochromatin Formation ◽  
Non Coding Rna ◽  
Chromatin Regulator ◽  
Specificity Factor ◽  
The Right ◽  
Long Non Coding Rna

Enzymes, such as histone methyltransferases and demethylases, histone acetyltransferases and deacetylases, and DNA methyltransferases are known as epigenetic modifiers that are often implicated in tumorigenesis and disease. One of the best-studied chromatin-based mechanism is X chromosome inactivation (XCI), a process that establishes facultative heterochromatin on only one X chromosome in females and establishes the right dosage of gene expression. The specificity factor for this process is the long non-coding RNA Xinactivespecifictranscript (Xist), which is upregulated from one X chromosome in female cells. Subsequently, Xist is bound by the corepressor SHARP/SPEN, recruiting and/or activating histone deacetylases (HDACs), leading to the loss of active chromatin marks such as H3K27ac. In addition, polycomb complexes PRC1 and PRC2 establish wide-spread accumulation of H3K27me3 and H2AK119ub1 chromatin marks. The lack of active marks and establishment of repressive marks set the stage for DNA methyltransferases (DNMTs) to stably silence the X chromosome. Here, we will review the recent advances in understanding the molecular mechanisms of how heterochromatin formation is established and put this into the context of carcinogenesis and disease.

scholarly journals Humanized H19/Igf2 locus reveals diverged imprinting mechanism between mouse and human and reflects Silver–Russell syndrome phenotypes

2016 ◽  
Vol 113 (39) ◽  
pp. 10938-10943 ◽  
Author(s):  
Stella K. Hur ◽  
Andrea Freschi ◽  
Folami Ideraabdullah ◽  
Joanne L. Thorvaldsen ◽  
Lacey J. Luense ◽  
...  
Keyword(s):  
Genomic Imprinting ◽  
Posttranslational Modifications ◽  
Molecular Mechanisms ◽  
Germ Line ◽  
Regulatory Elements ◽  
Allele Specific ◽  
Species Specific ◽  
And Function ◽  
Maternal Imprinting ◽  
Silver Russell Syndrome

Genomic imprinting affects a subset of genes in mammals, such that they are expressed in a monoallelic, parent-of-origin–specific manner. These genes are regulated by imprinting control regions (ICRs), cis-regulatory elements that exhibit allele-specific differential DNA methylation. Although genomic imprinting is conserved in mammals, ICRs are genetically divergent across species. This raises the fundamental question of whether the ICR plays a species-specific role in regulating imprinting at a given locus. We addressed this question at the H19/insulin-like growth factor 2 (Igf2) imprinted locus, the misregulation of which is associated with the human imprinting disorders Beckwith–Wiedemann syndrome (BWS) and Silver–Russell syndrome (SRS). We generated a knock-in mouse in which the endogenous H19/Igf2 ICR (mIC1) is replaced by the orthologous human ICR (hIC1) sequence, designated H19hIC1. We show that hIC1 can functionally replace mIC1 on the maternal allele. In contrast, paternally transmitted hIC1 leads to growth restriction, abnormal hIC1 methylation, and loss of H19 and Igf2 imprinted expression. Imprint establishment at hIC1 is impaired in the male germ line, which is associated with an abnormal composition of histone posttranslational modifications compared with mIC1. Overall, this study reveals evolutionarily divergent paternal imprinting at IC1 between mice and humans. The conserved maternal imprinting mechanism and function at IC1 demonstrates the possibility of modeling maternal transmission of hIC1 mutations associated with BWS in mice. In addition, we propose that further analyses in the paternal knock-in H19+/hIC1 mice will elucidate the molecular mechanisms that may underlie SRS.

scholarly journals Evolution Shapes the Gene Expression Response to Oxidative Stress

2019 ◽  
Vol 20 (12) ◽  
pp. 3040 ◽  
Author(s):  
Rima Siauciunaite ◽  
Nicholas S. Foulkes ◽  
Viola Calabrò ◽  
Daniela Vallone
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Molecular Mechanisms ◽  
Survival Strategies ◽  
Cell Physiology ◽  
Gene Expression Response ◽  
Low Levels ◽  
Expression Response ◽  
Species Specific ◽  
And Function

Reactive oxygen species (ROS) play a key role in cell physiology and function. ROS represents a potential source of damage for many macromolecules including DNA. It is thought that daily changes in oxidative stress levels were an important early factor driving evolution of the circadian clock which enables organisms to predict changes in ROS levels before they actually occur and thereby optimally coordinate survival strategies. It is clear that ROS, at relatively low levels, can serve as an important signaling molecule and also serves as a key regulator of gene expression. Therefore, the mechanisms that have evolved to survive or harness these effects of ROS are ancient evolutionary adaptations that are tightly interconnected with most aspects of cellular physiology. Our understanding of these mechanisms has been mainly based on studies using a relatively small group of genetic models. However, we know comparatively little about how these mechanisms are conserved or have adapted during evolution under different environmental conditions. In this review, we describe recent work that has revealed significant species-specific differences in the gene expression response to ROS by exploring diverse organisms. This evidence supports the notion that during evolution, rather than being highly conserved, there is inherent plasticity in the molecular mechanisms responding to oxidative stress.

scholarly journals Sirtuin 1 (SIRT1) and steroid hormone receptor activity in cancer

2011 ◽  
Vol 213 (1) ◽  
pp. 37-48 ◽  
Author(s):  
R L Moore ◽  
Y Dai ◽  
D V Faller
Keyword(s):  
Cancer Progression ◽  
Hormone Receptor ◽  
Histone Deacetylases ◽  
Molecular Mechanisms ◽  
Hormone Receptors ◽  
Steroid Hormone ◽  
Steroid Hormone Receptors ◽  
Sirtuin 1 ◽  
Steroid Hormone Receptor ◽  
Class Iii

Sirtuins, which are class III NAD-dependent histone deacetylases that regulate a number of physiological processes, play important roles in the regulation of metabolism, aging, oncogenesis, and cancer progression. Recently, a role for the sirtuins in the regulation of steroid hormone receptor signaling is emerging. In this mini-review, we will summarize current research into the regulation of estrogen, androgen, progesterone, mineralocorticoid, and glucocorticoid signaling by sirtuins in cancer. Sirtuins can regulate steroid hormone signaling through a variety of molecular mechanisms, including acting as co-regulatory transcription factors, deacetylating histones in the promoters of genes with nuclear receptor-binding sites, directly deacetylating steroid hormone nuclear receptors, and regulating pathways that modify steroid hormone receptors through phosphorylation. Furthermore, disruption of sirtuin activity may be an important step in the development of steroid hormone-refractory cancers.

scholarly journals Transcription Factors: The Fulcrum Between Cell Development and Carcinogenesis

2021 ◽  
Vol 11 ◽  
Author(s):  
Zeyaul Islam ◽  
Ameena Mohamed Ali ◽  
Adviti Naik ◽  
Mohamed Eldaw ◽  
Julie Decock ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Fate ◽  
Cancer Progression ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Tumor Development ◽  
Treatment Resistance ◽  
Cell Development ◽  
Fate Decision ◽  
And Function

Higher eukaryotic development is a complex and tightly regulated process, whereby transcription factors (TFs) play a key role in controlling the gene regulatory networks. Dysregulation of these regulatory networks has also been associated with carcinogenesis. Transcription factors are key enablers of cancer stemness, which support the maintenance and function of cancer stem cells that are believed to act as seeds for cancer initiation, progression and metastasis, and treatment resistance. One key area of research is to understand how these factors interact and collaborate to define cellular fate during embryogenesis as well as during tumor development. This review focuses on understanding the role of TFs in cell development and cancer. The molecular mechanisms of cell fate decision are of key importance in efforts towards developing better protocols for directed differentiation of cells in research and medicine. We also discuss the dysregulation of TFs and their role in cancer progression and metastasis, exploring TF networks as direct or indirect targets for therapeutic intervention, as well as specific TFs’ potential as biomarkers for predicting and monitoring treatment responses.

A Mucin-Specific Protease Enables Molecular and Functional Analysis of Human Cancer-Associated Mucins

2018 ◽  
Author(s):  
Stacy A. Malaker ◽  
Kayvon Pedram ◽  
Michael J. Ferracane ◽  
Elliot C. Woods ◽  
Jessica Kramer ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Molecular Mechanisms ◽  
Cultured Cells ◽  
High Resolution Mass Spectrometry ◽  
Human Cancer ◽  
Glycosylation Sites ◽  
Bacterial Protease ◽  
Specific Protease ◽  
To Come ◽  
And Function

<div> <div> <div> <p>Mucins are a class of highly O-glycosylated proteins that are ubiquitously expressed on cellular surfaces and are important for human health, especially in the context of carcinomas. However, the molecular mechanisms by which aberrant mucin structures lead to tumor progression and immune evasion have been slow to come to light, in part because methods for selective mucin degradation are lacking. Here we employ high resolution mass spectrometry, polymer synthesis, and computational peptide docking to demonstrate that a bacterial protease, called StcE, cleaves mucin domains by recognizing a discrete peptide-, glycan-, and secondary structure- based motif. We exploited StcE’s unique properties to map glycosylation sites and structures of purified and recombinant human mucins by mass spectrometry. As well, we found that StcE will digest cancer-associated mucins from cultured cells and from ovarian cancer patient-derived ascites fluid. Finally, using StcE we discovered that Siglec-7, a glyco-immune checkpoint receptor, specifically binds sialomucins as biological ligands, whereas the related Siglec-9 receptor does not. Mucin-specific proteolysis, as exemplified by StcE, is therefore a powerful tool for the study of glycoprotein structure and function and for deorphanizing mucin-binding receptors. </p> </div> </div> </div>

Sign in / Sign up

Export Citation Format

Share Document