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

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the collection website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cancer
  • epigenetics
  • histone modification
  • genomics

Published Papers (8 papers)

2018

Jump to: 2017

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
PDF Full-text (2093 KB) | HTML Full-text | XML Full-text | Supplementary Files
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
Figures

Figure 1

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
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
Figures

Figure 1

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 3 | 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
Figures

Figure 1

2017

Jump to: 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 1 | 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
Figures

Figure 1

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
PDF Full-text (1021 KB) | HTML Full-text | XML Full-text
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
Figures

Figure 1

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 4 | 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
Figures

Figure 1

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 6 | 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
Figures

Figure 1

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
Cited by 4 | PDF Full-text (526 KB) | HTML Full-text | XML Full-text
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
Figures

Figure 1

Back to Top