Topical Collection "Histone Modification in Cancer"

Editor

Collection Editor
Dr. Sibaji Sarkar

Department of Medicine Cancer Center, Hematology-Oncology, Genome Science Institute, Boston University School of Medicine, Boston, USA
Website | E-Mail
Phone: (617) 638-5630
Fax: (617) 638-5630
Interests: epigenetics/genetics related to gene silencing; imprinting; cancer; progenitor cell formation; cancer progression and metastais; signaling regulating epigenetics events; combination therapy of cancers by HDAC inhibitors and other drugs; integrin signaling related to thrombosis; inhibition of apoptosis and motility in cancer cells; inhibition of syk tyrosine kinase and protease calpain related to platelet clot lysis

Topical Collection Information

Dear Colleagues,

Cancer involves genetic alterations, including mutations, chromosomal abnormalities, genomic instability, and dysregulation of cellular signaling. There are six well-defined events associated with cancer, known as the hallmarks of cancer, which include resisting cell death, sustaining proliferative signaling, evading growth suppressors, activating invasion and metastasis, enabling replicative immortality, and inducing angiogenesis. Recent research suggests that epigenetic regulation is possibly involved in the formation of cancer progenitor cells. In addition, epigenetic mechanisms may regulate many aspects of these six hallmarks of cancer. Epigenetic drugs are expected to reduce cancer relapse as a component of combination therapy, as they have the potential to kill cancer progenitor cells and drug resistant cancer cells. Epigenetic mechanisms are usually reversible and include histone modification and DNA methylation. Acetylation and deacetylation of histones provide an open or closed chromatin conformation, which facilitate or inhibit transcription, respectively. In contrast, methylation of the lysine and arginine residues of histones could be activating or inhibitory depending on where the methylation occurs. There are specific histone methylases which perform this function. In addition to methylation, several other modifications in histones regulate gene expression. Other modifications include phosphorylation, ubiquitination, and sumoylation. Histone modifications are also known to recruit DNA methylation enzymes at the site of methylation. Additionally, histone modifications are involved in creating an insulation zone around enhancer-promoter regions by recruiting CTCF, which plays an important role in tissue specific gene expression. Histone modifications also seem to play a significant role in development. Aberration of this process could be involved in carcinogenesis. The current Special Issue entitled, “Histone Modifications,” is designed to include articles that will address these issues.

Dr. Sibaji Sarkar
Collection Editor

Manuscript Submission Information

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Keywords

  • cancer
  • epigenetics
  • histone modification
  • genomics

Published Papers (19 papers)

2019

Jump to: 2018, 2017

Open AccessReview
Histone H3 Mutations: An Updated View of Their Role in Chromatin Deregulation and Cancer
Cancers 2019, 11(5), 660; https://doi.org/10.3390/cancers11050660
Received: 23 April 2019 / Revised: 3 May 2019 / Accepted: 6 May 2019 / Published: 13 May 2019
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Abstract
In this review, we describe the attributes of histone H3 mutants identified in cancer. H3 mutants were first identified in genes encoding H3.3, in pediatric high-grade glioma, and subsequently in chondrosarcomas and giant cell tumors of bone (GCTB) in adolescents. The most heavily [...] Read more.
In this review, we describe the attributes of histone H3 mutants identified in cancer. H3 mutants were first identified in genes encoding H3.3, in pediatric high-grade glioma, and subsequently in chondrosarcomas and giant cell tumors of bone (GCTB) in adolescents. The most heavily studied are the lysine to methionine mutants K27M and K36M, which perturb the target site for specific lysine methyltransferases and dominantly perturb methylation of corresponding lysines in other histone H3 proteins. We discuss recent progress in defining the consequences of these mutations on chromatin, including a newly emerging view of the central importance of the disruption of H3K36 modification in many distinct K to M histone mutant cancers. We also review new work exploring the role of H3.3 G34 mutants identified in pediatric glioma and GCTB. G34 is not itself post-translationally modified, but G34 mutation impinges on the modification of H3K36. Here, we ask if G34R mutation generates a new site for methylation on the histone tail. Finally, we consider evidence indicating that histone mutations might be more widespread in cancer than previously thought, and if the perceived bias towards mutation of H3.3 is real or reflects the biology of tumors in which the histone mutants were first identified. Full article
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Open AccessReview
Perturbing Enhancer Activity in Cancer Therapy
Cancers 2019, 11(5), 634; https://doi.org/10.3390/cancers11050634
Received: 28 March 2019 / Revised: 26 April 2019 / Accepted: 5 May 2019 / Published: 7 May 2019
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Abstract
Tight regulation of gene transcription is essential for normal development, tissue homeostasis, and disease-free survival. Enhancers are distal regulatory elements in the genome that provide specificity to gene expression programs and are frequently misregulated in cancer. Recent studies examined various enhancer-driven malignant dependencies [...] Read more.
Tight regulation of gene transcription is essential for normal development, tissue homeostasis, and disease-free survival. Enhancers are distal regulatory elements in the genome that provide specificity to gene expression programs and are frequently misregulated in cancer. Recent studies examined various enhancer-driven malignant dependencies and identified different approaches to specifically target these programs. In this review, we describe numerous features that make enhancers good transcriptional targets in cancer therapy and discuss different approaches to overcome enhancer perturbation. Interestingly, a number of approved therapeutic agents, such as cyclosporine, steroid hormones, and thiazolidinediones, actually function by affecting enhancer landscapes by directly targeting very specific transcription factor programs. More recently, a broader approach to targeting deregulated enhancer programs has been achieved via Bromodomain and Extraterminal (BET) inhibition or perturbation of transcription-related cyclin-dependent kinases (CDK). One challenge to enhancer-targeted therapy is proper patient stratification. We suggest that monitoring of enhancer RNA (eRNA) expression may serve as a unique biomarker of enhancer activity that can help to predict and monitor responsiveness to enhancer-targeted therapies. A more thorough investigation of cancer-specific enhancers and the underlying mechanisms of deregulation will pave the road for an effective utilization of enhancer modulators in a precision oncology approach to cancer treatment. Full article
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Open AccessArticle
Influence of the HDAC Inhibitor Valproic Acid on the Growth and Proliferation of Temsirolimus-Resistant Prostate Cancer Cells In Vitro
Cancers 2019, 11(4), 566; https://doi.org/10.3390/cancers11040566
Received: 1 April 2019 / Accepted: 16 April 2019 / Published: 19 April 2019
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Abstract
The mechanistic target of rapamycin (mTOR) is elevated in prostate cancer, making this protein attractive for tumor treatment. Unfortunately, resistance towards mTOR inhibitors develops and the tumor becomes reactivated. We determined whether epigenetic modulation by the histone deacetylase (HDAC) inhibitor, valproic acid (VPA), [...] Read more.
The mechanistic target of rapamycin (mTOR) is elevated in prostate cancer, making this protein attractive for tumor treatment. Unfortunately, resistance towards mTOR inhibitors develops and the tumor becomes reactivated. We determined whether epigenetic modulation by the histone deacetylase (HDAC) inhibitor, valproic acid (VPA), may counteract non-responsiveness to the mTOR inhibitor, temsirolimus, in prostate cancer (PCa) cells. Prostate cancer cells, sensitive (parental) and resistant to temsirolimus, were exposed to VPA, and tumor cell growth behavior compared. Temsirolimus resistance enhanced the number of tumor cells in the G2/M-phase, correlating with elevated cell proliferation and clonal growth. The cell cycling proteins cdk1 and cyclin B, along with Akt-mTOR signaling increased, whereas p19, p21 and p27 decreased, compared to the parental cells. VPA significantly reduced cell growth and up-regulated the acetylated histones H3 and H4. Cdk1 and cyclin B decreased, as did phosphorylated mTOR and the mTOR sub-complex Raptor. The mTOR sub-member Rictor and phosphorylated Akt increased under VPA. Knockdown of cdk1, cyclin B, or Raptor led to significant cell growth reduction. HDAC inhibition through VPA counteracts temsirolimus resistance, probably by down-regulating cdk1, cyclin B and Raptor. Enhanced Rictor and Akt, however, may represent an undesired feedback loop, which should be considered when designing future therapeutic regimens. Full article
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Open AccessArticle
Contingencies of UTX/KDM6A Action in Urothelial Carcinoma
Cancers 2019, 11(4), 481; https://doi.org/10.3390/cancers11040481
Received: 28 February 2019 / Revised: 28 March 2019 / Accepted: 2 April 2019 / Published: 4 April 2019
Cited by 1 | PDF Full-text (5058 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The histone demethylase Ubiquitously Transcribed Tetratricopeptide Repeat Protein X-Linked (UTX/KDM6A) demethylates H3K27me2/3 at genes and enhancers and is often inactivated by mutations in urothelial carcinoma (UC). The consequences of its inactivation are however poorly understood. We have investigated the consequences of moderate UTX [...] Read more.
The histone demethylase Ubiquitously Transcribed Tetratricopeptide Repeat Protein X-Linked (UTX/KDM6A) demethylates H3K27me2/3 at genes and enhancers and is often inactivated by mutations in urothelial carcinoma (UC). The consequences of its inactivation are however poorly understood. We have investigated the consequences of moderate UTX overexpression across a range of UC cell lines with or without mutations in KDM6A or its interaction partners and in a normal control cell line. Effects on cell proliferation, especially long-term, varied dramatically between the cell lines, ranging from deleterious to beneficial. Similarly, effects on global gene expression determined by RNA-Seq were variable with few overlapping up- or downregulated genes between the cell lines. Our data indicate that UTX does not act in a uniform fashion in UC. Rather, its effect depends on several contingencies including, prominently, the status of KMT2C and KMT2D which interact with UTX in the COMPASS complex. In particular, we provide evidence that these factors determine the amount of nuclear UTX. Full article
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Open AccessReview
HDAC Inhibitors Exert Anti-Myeloma Effects through Multiple Modes of Action
Cancers 2019, 11(4), 475; https://doi.org/10.3390/cancers11040475
Received: 25 January 2019 / Revised: 20 March 2019 / Accepted: 25 March 2019 / Published: 4 April 2019
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Abstract
HDACs are critical regulators of gene expression that function through histone modification. Non-histone proteins and histones are targeted by these proteins and the inhibition of HDACs results in various biological effects. Moreover, the aberrant expression and function of these proteins is thought to [...] Read more.
HDACs are critical regulators of gene expression that function through histone modification. Non-histone proteins and histones are targeted by these proteins and the inhibition of HDACs results in various biological effects. Moreover, the aberrant expression and function of these proteins is thought to be related to the pathogenesis of multiple myeloma (MM) and several inhibitors have been introduced or clinically tested. Panobinostat, a pan-HDAC inhibitor, in combination with a proteasome inhibitor and dexamethasone has improved survival in relapsing/refractory MM patients. We revealed that panobinostat inhibits MM cell growth by degrading the protein PPP3CA, a catalytic subunit of calcineurin. This degradation was suggested to be mediated by suppression of the chaperone function of HSP90 due to HDAC6 inhibition. Cytotoxicity due to the epigenetic regulation of tumor-associated genes by HDAC inhibitors has also been reported. In addition, HDAC6 inhibition enhances tumor immunity and has been suggested to strengthen the cytotoxic effects of therapeutic antibodies against myeloma. Furthermore, therapeutic strategies to enhance the anti-myeloma effects of HDAC inhibitors through the addition of other agents has been intensely evaluated. Thus, the treatment of patients with MM using HDAC inhibitors is promising as these drugs exert their effects through multiple modes of action. Full article
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Open AccessReview
Expanding the Role of the Histone Lysine-Specific Demethylase LSD1 in Cancer
Cancers 2019, 11(3), 324; https://doi.org/10.3390/cancers11030324
Received: 31 January 2019 / Revised: 25 February 2019 / Accepted: 4 March 2019 / Published: 7 March 2019
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Abstract
Studies of alterations in histone methylation in cancer have led to the identification of histone methyltransferases and demethylases as novel targets for therapy. Lysine-specific demethylase 1 (LSD1, also known as KDM1A), demethylates H3K4me1/2, or H3K9me1/2 in a context-dependent manner. In addition to the [...] Read more.
Studies of alterations in histone methylation in cancer have led to the identification of histone methyltransferases and demethylases as novel targets for therapy. Lysine-specific demethylase 1 (LSD1, also known as KDM1A), demethylates H3K4me1/2, or H3K9me1/2 in a context-dependent manner. In addition to the well-studied role of LSD1 in the epigenetic regulation of histone methylation changes, LSD1 regulates the methylation dynamic of several non-histone proteins and participates in the assembly of different long noncoding RNA (lncRNA_ complexes. LSD1 is highly expressed in various cancers, playing a pivotal role in different cancer-related processes. Here, we summarized recent findings on the role of LSD1 in the regulation of different biological processes in cancer cells through dynamic methylation of non-histone proteins and physical association with dedicated lncRNA. Full article
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Open AccessReview
Inhibition of BET Proteins and Histone Deacetylase (HDACs): Crossing Roads in Cancer Therapy
Cancers 2019, 11(3), 304; https://doi.org/10.3390/cancers11030304
Received: 24 January 2019 / Revised: 18 February 2019 / Accepted: 26 February 2019 / Published: 5 March 2019
Cited by 1 | PDF Full-text (1891 KB) | HTML Full-text | XML Full-text
Abstract
Histone DeACetylases (HDACs) are enzymes that remove acetyl groups from histones and other proteins, regulating the expression of target genes. Pharmacological inhibition of these enzymes re-shapes chromatin acetylation status, confusing boundaries between transcriptionally active and quiescent chromatin. This results in reinducing expression of [...] Read more.
Histone DeACetylases (HDACs) are enzymes that remove acetyl groups from histones and other proteins, regulating the expression of target genes. Pharmacological inhibition of these enzymes re-shapes chromatin acetylation status, confusing boundaries between transcriptionally active and quiescent chromatin. This results in reinducing expression of silent genes while repressing highly transcribed genes. Bromodomain and Extraterminal domain (BET) proteins are readers of acetylated chromatin status and accumulate on transcriptionally active regulatory elements where they serve as scaffold for the building of transcription-promoting complexes. The expression of many well-known oncogenes relies on BET proteins function, indicating BET inhibition as a strategy to counteract their activity. BETi and HDACi share many common targets and affect similar cellular processes to the point that combined inhibition of both these classes of proteins is regarded as a strategy to improve the effectiveness of these drugs in cancer. In this work, we aim to discuss the molecular basis of the interplay between HDAC and BET proteins, pointing at chromatin acetylation as a crucial node of their functional interaction. We will also describe the state of the art of their dual inhibition in cancer therapy. Finally, starting from their mechanism of action we will provide a speculative perspective on how these drugs may be employed in combination with standard therapies to improve effectiveness and/or overcome resistance. Full article
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Open AccessReview
Histone Deacetylase Inhibitors and Phenotypical Transformation of Cancer Cells
Cancers 2019, 11(2), 148; https://doi.org/10.3390/cancers11020148
Received: 23 December 2018 / Revised: 18 January 2019 / Accepted: 22 January 2019 / Published: 27 January 2019
Cited by 4 | PDF Full-text (6116 KB) | HTML Full-text | XML Full-text
Abstract
Histone deacetylase inhibitors (HDIs) are a group of potent epigenetic drugs which have been investigated for their therapeutic potential in various clinical disorders, including hematological malignancies and solid tumors. Currently, several HDIs are already in clinical use and many more are on clinical [...] Read more.
Histone deacetylase inhibitors (HDIs) are a group of potent epigenetic drugs which have been investigated for their therapeutic potential in various clinical disorders, including hematological malignancies and solid tumors. Currently, several HDIs are already in clinical use and many more are on clinical trials. HDIs have shown efficacy to inhibit initiation and progression of cancer cells. Nevertheless, both pro-invasive and anti-invasive activities of HDIs have been reported, questioning their impact in carcinogenesis. The aim of this review is to compile and discuss the most recent findings on the effect of HDIs on the epithelial-mesenchymal transition (EMT) process in human cancers. We have summarized the impact of HDIs on epithelial (E-cadherin, β-catenin) and mesenchymal (N-cadherin, vimentin) markers, EMT activators (TWIST, SNAIL, SLUG, SMAD, ZEB), as well as morphology, migration and invasion potential of cancer cells. We further discuss the use of HDIs as monotherapy or in combination with existing or novel anti-neoplastic drugs in relation to changes in EMT. Full article
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Open AccessReview
Reading Cancer: Chromatin Readers as Druggable Targets for Cancer Treatment
Received: 13 December 2018 / Revised: 30 December 2018 / Accepted: 3 January 2019 / Published: 9 January 2019
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Abstract
The epigenetic machinery deputed to control histone post-translational modifications is frequently dysregulated in cancer cells. With epigenetics being naturally reversible, it represents a good target for therapies directed to restore normal gene expression. Since the discovery of Bromodomain and Extra Terminal (BET) inhibitors, [...] Read more.
The epigenetic machinery deputed to control histone post-translational modifications is frequently dysregulated in cancer cells. With epigenetics being naturally reversible, it represents a good target for therapies directed to restore normal gene expression. Since the discovery of Bromodomain and Extra Terminal (BET) inhibitors, a great effort has been spent investigating the effects of chromatin readers’ inhibition, specifically the class of proteins assigned to bind acetylated and methylated residues. So far, focused studies have been produced on epigenetic regulation, dissecting a specific class of epigenetic-related proteins or investigating epigenetic therapy in a specific tumor type. In this review, recent steps toward drug discovery on the different classes of chromatin readers have been outlined, highlighting the pros and cons of current therapeutic approaches. Full article
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2018

Jump to: 2019, 2017

Open AccessReview
The Role of DNA/Histone Modifying Enzymes and Chromatin Remodeling Complexes in Testicular Germ Cell Tumors
Received: 22 November 2018 / Revised: 10 December 2018 / Accepted: 18 December 2018 / Published: 20 December 2018
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Abstract
It is well established that cancer cells exhibit alterations in chromatin structure and accessibility. Indeed, the dysregulation of many protein-coding players with enzymatic activity (DNA and histone-modifying enzymes) and chromatin remodelers have been depicted in various tumor models in recent years. Still, little [...] Read more.
It is well established that cancer cells exhibit alterations in chromatin structure and accessibility. Indeed, the dysregulation of many protein-coding players with enzymatic activity (DNA and histone-modifying enzymes) and chromatin remodelers have been depicted in various tumor models in recent years. Still, little attention has been directed towards testicular germ cell tumors (TGCTs)—representing the most common neoplasm among young adult Caucasian men—with most studies focusing on exploring the role of DNA methyltransferases (DNMTs) and DNA demethylases (TETs). TGCTs represent a complex tumor model, associated with developmental and embryogenesis-related phenomena, and display seldom (cyto)genetic aberrations, leaving room for Epigenetics to explain such morphological and clinical diversity. Herein, we have summarized the major findings that were reported in literature regarding the dysregulation of DNA/histone-modifying enzymes and chromatin remodelers in TGCTs. Additionally, we performed in silico analysis of The Cancer Genome Atlas database to find the most relevant of those players in TGCTs. We concluded that several DNA/histone-modifying enzymes and chromatin remodelers may serve as biomarkers for subtyping, dictating prognosis and survival, and, possibly, for serving as targets of directed, less toxic therapies. Full article
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Open AccessReview
Breaking down the Contradictory Roles of Histone Deacetylase SIRT1 in Human Breast Cancer
Cancers 2018, 10(11), 409; https://doi.org/10.3390/cancers10110409
Received: 21 September 2018 / Revised: 23 October 2018 / Accepted: 26 October 2018 / Published: 30 October 2018
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Abstract
Breast cancer (BC) is the most common type of cancer in women worldwide; it is a multifactorial genetic disease. Acetylation and deacetylation are major post-translational protein modifications that regulate gene expression and the activity of a myriad of oncoproteins. Aberrant deacetylase activity can [...] Read more.
Breast cancer (BC) is the most common type of cancer in women worldwide; it is a multifactorial genetic disease. Acetylation and deacetylation are major post-translational protein modifications that regulate gene expression and the activity of a myriad of oncoproteins. Aberrant deacetylase activity can promote or suppress tumorigenesis and cancer metastasis in different types of human cancers, including breast cancer. Sirtuin-1 (SIRT1) is a class-III histone deacetylase (HDAC) that deacetylates both histone and non-histone targets. The often-described ‘regulator of regulators’ is deeply implicated in apoptosis, gene regulation, genome maintenance, DNA repair, aging, and cancer development. However, despite the accumulated studies over the past decade, the role of SIRT1 in human breast cancer remains a subject of debate and controversy. The ambiguity surrounding the implications of SIRT1 in breast tumorigenesis stems from the discrepancy between studies, which have shown both tumor-suppressive and promoting functions of SIRT1. Furthermore, studies have shown that SIRT1 deficiency promotes or suppresses tumors in breast cancer, making it an attractive therapeutic target in cancer treatment. This review provides a comprehensive examination of the various implications of SIRT1 in breast cancer development and metastasis. We will also discuss the mechanisms underlying the conflicting roles of SIRT1, as well as its selective modulators, in breast carcinogenesis. Full article
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Open AccessBrief Report
Selective Inhibition of Histone Deacetylation in Melanoma Increases Targeted Gene Delivery by a Bacteriophage Viral Vector
Cancers 2018, 10(4), 125; https://doi.org/10.3390/cancers10040125
Received: 2 April 2018 / Revised: 16 April 2018 / Accepted: 19 April 2018 / Published: 21 April 2018
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Abstract
The previously developed adeno-associated virus/phage (AAVP) vector, a hybrid between M13 bacteriophage (phage) viruses that infect bacteria only and human Adeno-Associated Virus (AAV), is a promising tool in targeted gene therapy against cancer. AAVP can be administered systemically and made tissue specific through [...] Read more.
The previously developed adeno-associated virus/phage (AAVP) vector, a hybrid between M13 bacteriophage (phage) viruses that infect bacteria only and human Adeno-Associated Virus (AAV), is a promising tool in targeted gene therapy against cancer. AAVP can be administered systemically and made tissue specific through the use of ligand-directed targeting. Cancer cells and tumor-associated blood vessels overexpress the αν integrin receptors, which are involved in tumor angiogenesis and tumor invasion. AAVP is targeted to these integrins via a double cyclic RGD4C ligand displayed on the phage capsid. Nevertheless, there remain significant host-defense hurdles to the use of AAVP in targeted gene delivery and subsequently in gene therapy. We previously reported that histone deacetylation in cancer constitutes a barrier to AAVP. Herein, to improve AAVP-mediated gene delivery to cancer cells, we combined the vector with selective adjuvant chemicals that inhibit specific histone deacetylases (HDAC). We examined the effects of the HDAC inhibitor C1A that mainly targets HDAC6 and compared this to sodium butyrate, a pan-HDAC inhibitor with broad spectrum HDAC inhibition. We tested the effects on melanoma, known for HDAC6 up-regulation, and compared this side by side with a normal human kidney HEK293 cell line. Varying concentrations were tested to determine cytotoxic levels as well as effects on AAVP gene delivery. We report that the HDAC inhibitor C1A increased AAVP-mediated transgene expression by up to ~9-fold. These findings indicate that selective HDAC inhibition is a promising adjuvant treatment for increasing the therapeutic value of AAVP. Full article
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Open AccessReview
Post-Translational Modifications of H2A Histone Variants and Their Role in Cancer
Received: 15 January 2018 / Revised: 19 February 2018 / Accepted: 25 February 2018 / Published: 27 February 2018
Cited by 4 | PDF Full-text (1087 KB) | HTML Full-text | XML Full-text
Abstract
Histone variants are chromatin components that replace replication-coupled histones in a fraction of nucleosomes and confer particular characteristics to chromatin. H2A variants represent the most numerous and diverse group among histone protein families. In the nucleosomal structure, H2A-H2B dimers can be removed and [...] Read more.
Histone variants are chromatin components that replace replication-coupled histones in a fraction of nucleosomes and confer particular characteristics to chromatin. H2A variants represent the most numerous and diverse group among histone protein families. In the nucleosomal structure, H2A-H2B dimers can be removed and exchanged more easily than the stable H3-H4 core. The unstructured N-terminal histone tails of all histones, but also the C-terminal tails of H2A histones protrude out of the compact structure of the nucleosome core. These accessible tails are the preferential target sites for a large number of post-translational modifications (PTMs). While some PTMs are shared between replication-coupled H2A and H2A variants, many modifications are limited to a specific histone variant. The present review focuses on the H2A variants H2A.Z, H2A.X, and macroH2A, and summarizes their functions in chromatin and how these are linked to cancer development and progression. H2A.Z primarily acts as an oncogene and macroH2A and H2A.X as tumour suppressors. We further focus on the regulation by PTMs, which helps to understand a degree of context dependency. Full article
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Open AccessReview
Modification of Epigenetic Histone Acetylation in Hepatocellular Carcinoma
Received: 13 November 2017 / Revised: 19 December 2017 / Accepted: 30 December 2017 / Published: 3 January 2018
Cited by 11 | PDF Full-text (432 KB) | HTML Full-text | XML Full-text
Abstract
Cells respond to various environmental factors such as nutrients, food intake, and drugs or toxins by undergoing dynamic epigenetic changes. An imbalance in dynamic epigenetic changes is one of the major causes of disease, oncogenic activities, and immunosuppressive effects. The aryl hydrocarbon receptor [...] Read more.
Cells respond to various environmental factors such as nutrients, food intake, and drugs or toxins by undergoing dynamic epigenetic changes. An imbalance in dynamic epigenetic changes is one of the major causes of disease, oncogenic activities, and immunosuppressive effects. The aryl hydrocarbon receptor (AHR) is a unique cellular chemical sensor present in most organs, and its dysregulation has been demonstrated in multiple stages of tumor progression in humans and experimental models; however, the effects of the pathogenic mechanisms of AHR on epigenetic regulation remain unclear. Apart from proto-oncogene activation, epigenetic repressions of tumor suppressor genes are involved in tumor initiation, procession, and metastasis. Reverse epigenetic repression of the tumor suppressor genes by epigenetic enzyme activity inhibition and epigenetic enzyme level manipulation is a potential path for tumor therapy. Current evidence and our recent work on deacetylation of histones on tumor-suppressive genes suggest that histone deacetylase (HDAC) is involved in tumor formation and progression, and treating hepatocellular carcinoma with HDAC inhibitors can, at least partially, repress tumor proliferation and transformation by recusing the expression of tumor-suppressive genes such as TP53 and RB1. Full article
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2017

Jump to: 2019, 2018

Open AccessReview
Ubiquitin Specific Peptidase 22 Regulates Histone H2B Mono-Ubiquitination and Exhibits Both Oncogenic and Tumor Suppressor Roles in Cancer
Cancers 2017, 9(12), 167; https://doi.org/10.3390/cancers9120167
Received: 3 November 2017 / Revised: 3 December 2017 / Accepted: 4 December 2017 / Published: 6 December 2017
Cited by 3 | PDF Full-text (2496 KB) | HTML Full-text | XML Full-text
Abstract
Ubiquitin-Specific Peptidase 22 (USP22) is a ubiquitin hydrolase, notably catalyzing the removal of the mono-ubiquitin moiety from histone H2B (H2Bub1). Frequent overexpression of USP22 has been observed in various cancer types and is associated with poor patient prognosis. Multiple mechanisms have been identified [...] Read more.
Ubiquitin-Specific Peptidase 22 (USP22) is a ubiquitin hydrolase, notably catalyzing the removal of the mono-ubiquitin moiety from histone H2B (H2Bub1). Frequent overexpression of USP22 has been observed in various cancer types and is associated with poor patient prognosis. Multiple mechanisms have been identified to explain how USP22 overexpression contributes to cancer progression, and thus, USP22 has been proposed as a novel drug target in cancer. However, gene re-sequencing data from numerous cancer types show that USP22 expression is frequently diminished, suggesting it may also harbor tumor suppressor-like properties. This review will examine the current state of knowledge on USP22 expression in cancers, describe its impact on H2Bub1 abundance and present the mechanisms through which altered USP22 expression may contribute to oncogenesis, including an emerging role for USP22 in the maintenance of genome stability in cancer. Clarifying the impact aberrant USP22 expression and abnormal H2Bub1 levels have in oncogenesis is critical before precision medicine therapies can be developed that either directly target USP22 overexpression or exploit the loss of USP22 expression in cancer cells. Full article
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Open AccessFeature PaperPerspective
Genomic Destabilization Triggered by Replication Stress during Senescence
Cancers 2017, 9(11), 159; https://doi.org/10.3390/cancers9110159
Received: 25 September 2017 / Revised: 13 November 2017 / Accepted: 20 November 2017 / Published: 21 November 2017
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Abstract
Most cancers develop after middle age, and are often associated with multiple mutations and genomic instability, implying that genomic destabilization is critical for age-related tumor development. In this manuscript, we review current knowledge regarding (1) the senescent cellular background, which is associated with [...] Read more.
Most cancers develop after middle age, and are often associated with multiple mutations and genomic instability, implying that genomic destabilization is critical for age-related tumor development. In this manuscript, we review current knowledge regarding (1) the senescent cellular background, which is associated with a higher risk of genomic destabilization; and (2) the contributions of genomic destabilization to cancer development. Full article
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Open AccessReview
Circulating Nucleosomes and Nucleosome Modifications as Biomarkers in Cancer
Received: 14 November 2016 / Revised: 31 December 2016 / Accepted: 1 January 2017 / Published: 8 January 2017
Cited by 12 | PDF Full-text (1312 KB) | HTML Full-text | XML Full-text
Abstract
Traditionally the stratification of many cancers involves combining tumour and clinicopathological features (e.g., patient age; tumour size, grade, receptor status and location) to inform treatment options and predict recurrence risk and survival. However, current biomarkers often require invasive excision of the tumour for [...] Read more.
Traditionally the stratification of many cancers involves combining tumour and clinicopathological features (e.g., patient age; tumour size, grade, receptor status and location) to inform treatment options and predict recurrence risk and survival. However, current biomarkers often require invasive excision of the tumour for profiling, do not allow monitoring of the response to treatment and stratify patients into broad heterogeneous groups leading to inconsistent treatment responses. Here we explore and describe the benefits of using circulating biomarkers (nucleosomes and/or modifications to nucleosomes) as a non-invasive method for detecting cancer and monitoring response to treatment. Nucleosomes (DNA wound around eight core histone proteins) are responsible for compacting our genome and their composition and post-translational modifications are responsible for regulating gene expression. Here, we focus on breast and colorectal cancer as examples where utilizing circulating nucleosomes as biomarkers hold real potential as liquid biopsies. Utilizing circulating nucleosomes as biomarkers is an exciting new area of research that promises to allow both the early detection of cancer and monitoring of treatment response. Nucleosome-based biomarkers combine with current biomarkers, increasing both specificity and sensitivity of current tests and have the potential to provide individualised precision-medicine based treatments for patients. Full article
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Open AccessArticle
Stabilization of Nucleosomes by Histone Tails and by FACT Revealed by spFRET Microscopy
Received: 10 November 2016 / Revised: 19 December 2016 / Accepted: 22 December 2016 / Published: 6 January 2017
Cited by 10 | PDF Full-text (1550 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
A correct chromatin structure is important for cell viability and is tightly regulated by numerous factors. Human protein complex FACT (facilitates chromatin transcription) is an essential factor involved in chromatin transcription and cancer development. Here FACT-dependent changes in the structure of single nucleosomes [...] Read more.
A correct chromatin structure is important for cell viability and is tightly regulated by numerous factors. Human protein complex FACT (facilitates chromatin transcription) is an essential factor involved in chromatin transcription and cancer development. Here FACT-dependent changes in the structure of single nucleosomes were studied with single-particle Förster resonance energy transfer (spFRET) microscopy using nucleosomes labeled with a donor-acceptor pair of fluorophores, which were attached to the adjacent gyres of DNA near the contact between H2A-H2B dimers. Human FACT and its version without the C-terminal domain (CTD) and the high mobility group (HMG) domain of the structure-specific recognition protein 1 (SSRP1) subunit did not change the structure of the nucleosomes, while FACT without the acidic C-terminal domains of the suppressor of Ty 16 (Spt16) and the SSRP1 subunits caused nucleosome aggregation. Proteolytic removal of histone tails significantly disturbed the nucleosome structure, inducing partial unwrapping of nucleosomal DNA. Human FACT reduced DNA unwrapping and stabilized the structure of tailless nucleosomes. CTD and/or HMG domains of SSRP1 are required for this FACT activity. In contrast, previously it has been shown that yeast FACT unfolds (reorganizes) nucleosomes using the CTD domain of SSRP1-like Pol I-binding protein 3 subunit (Pob3). Thus, yeast and human FACT complexes likely utilize the same domains for nucleosome reorganization and stabilization, respectively, and these processes are mechanistically similar. Full article
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Open AccessReview
The Role of Histone Protein Modifications and Mutations in Histone Modifiers in Pediatric B-Cell Progenitor Acute Lymphoblastic Leukemia
Received: 26 October 2016 / Revised: 14 December 2016 / Accepted: 23 December 2016 / Published: 3 January 2017
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Abstract
While cancer has been long recognized as a disease of the genome, the importance of epigenetic mechanisms in neoplasia was acknowledged more recently. The most active epigenetic marks are DNA methylation and histone protein modifications and they are involved in basic biological phenomena [...] Read more.
While cancer has been long recognized as a disease of the genome, the importance of epigenetic mechanisms in neoplasia was acknowledged more recently. The most active epigenetic marks are DNA methylation and histone protein modifications and they are involved in basic biological phenomena in every cell. Their role in tumorigenesis is stressed by recent unbiased large-scale studies providing evidence that several epigenetic modifiers are recurrently mutated or frequently dysregulated in multiple cancers. The interest in epigenetic marks is especially due to the fact that they are potentially reversible and thus druggable. In B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) there is a relative paucity of reports on the role of histone protein modifications (acetylation, methylation, phosphorylation) as compared to acute myeloid leukemia, T-cell ALL, or other hematologic cancers, and in this setting chromatin modifications are relatively less well studied and reviewed than DNA methylation. In this paper, we discuss the biomarker associations and evidence for a driver role of dysregulated global and loci-specific histone marks, as well as mutations in epigenetic modifiers in BCP-ALL. Examples of chromatin modifiers recurrently mutated/disrupted in BCP-ALL and associated with disease outcomes include MLL1, CREBBP, NSD2, and SETD2. Altered histone marks and histone modifiers and readers may play a particular role in disease chemoresistance and relapse. We also suggest that epigenetic regulation of B-cell differentiation may have parallel roles in leukemogenesis. Full article
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