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Cancers
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Histone Modification in Cancer
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Histone Modification in Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Pathophysiology".

Deadline for manuscript submissions: closed (28 December 2023) | Viewed by 156035

Special Issue Editor

Dr. Sibaji Sarkar

E-Mail Website
Collection Editor
Division of Biotechnology, Quincy College, Quincy, MA 02169, USA
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
Special Issues, Collections and Topics in MDPI journals

Special Issue 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 submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue 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 semimonthly 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 2900 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 (25 papers)

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Research

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14 pages, 5547 KiB  
Article
Epigenome Mapping Identifies Tumor-Specific Gene Expression in Primary Rectal Cancer
by Hannah Flebbe, Feda H. Hamdan, Vijayalakshmi Kari, Julia Kitz, Jochen Gaedcke, B. Michael Ghadimi, Steven A. Johnsen and Marian Grade
Cancers 2019, 11(8), 1142; https://doi.org/10.3390/cancers11081142 - 09 Aug 2019
Cited by 11 | Viewed by 3925
Abstract
Epigenetic alterations play a central role in cancer development and progression. The acetylation of histone 3 at lysine 27 (H3K27ac) specifically marks active genes. While chromatin immunoprecipitation (ChIP) followed by next-generation sequencing (ChIP-seq) analyses are commonly performed in cell lines, only limited data [...] Read more.
Epigenetic alterations play a central role in cancer development and progression. The acetylation of histone 3 at lysine 27 (H3K27ac) specifically marks active genes. While chromatin immunoprecipitation (ChIP) followed by next-generation sequencing (ChIP-seq) analyses are commonly performed in cell lines, only limited data are available from primary tumors. We therefore examined whether cancer-specific alterations in H3K27ac occupancy can be identified in primary rectal cancer. Tissue samples from primary rectal cancer and matched mucosa were obtained. ChIP-seq for H3K27ac was performed and differentially occupied regions were identified. The expression of selected genes displaying differential occupancy between tumor and mucosa were examined in gene expression data from an independent patient cohort. Differential expression of four proteins was further examined by immunohistochemistry. ChIP-seq for H3K27ac in primary rectal cancer and matched mucosa was successfully performed and revealed differential binding on 44 regions. This led to the identification of genes with increased H3K27ac, i.e., RIPK2, FOXQ1, KRT23, and EPHX4, which were also highly upregulated in primary rectal cancer in an independent dataset. The increased expression of these four proteins was confirmed by immunohistochemistry. This study demonstrates the feasibility of ChIP-seq-based epigenome mapping of primary rectal cancer and confirms the value of H3K27ac occupancy to predict gene expression differences. Full article
(This article belongs to the Special Issue Histone Modification in Cancer)
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16 pages, 8901 KiB  
Article
Targeting of Histone Demethylases KDM5A and KDM6B Inhibits the Proliferation of Temozolomide-Resistant Glioblastoma Cells
by Massimo Romani, Antonio Daga, Alessandra Forlani, Maria Pia Pistillo and Barbara Banelli
Cancers 2019, 11(6), 878; https://doi.org/10.3390/cancers11060878 - 24 Jun 2019
Cited by 38 | Viewed by 4837
Abstract
Lysine histone demethylases (KDMs) are considered potential therapeutic targets in several tumors, including glioblastoma (GB). In particular, KDM5A is involved in the acquisition of temozolomide (TMZ) resistance in adult GB cells and UDX/KDM6B regulates H3K27 methylation, which is involved in the pediatric diffuse [...] Read more.
Lysine histone demethylases (KDMs) are considered potential therapeutic targets in several tumors, including glioblastoma (GB). In particular, KDM5A is involved in the acquisition of temozolomide (TMZ) resistance in adult GB cells and UDX/KDM6B regulates H3K27 methylation, which is involved in the pediatric diffuse intrinsic pontine glioma (DIPG). Synthetic inhibitors of KDM5A (JIB 04 and CPI-455) efficiently block the proliferation of native and TMZ-resistant cells and the KDM6B inhibitor GSK J4 improves survival in a model of DIPG. The aim of our work was to determine if GSK J4 could be effective against GB cells that have acquired TMZ resistance and if it could synergize with TMZ or JIB 04 to increase the clinical utility of these molecules. Standard functional and pharmacological analytical procedures were utilized to determine the efficacy of the molecules under study when used alone or in combination against native GB cells and in a model of drug resistance. The results of this study indicated that although GSK J4 is active against native and TMZ-resistant cells, it does so at a lower efficacy than JIB 04. Drug combination studies revealed that GSK J4, differently from JIB 04, does not synergize with TMZ. Interestingly, GSK J4 and JIB 04 strongly synergize and are a potent combination against TMZ-resistant cells. Further studies in animal models will be necessary to determine if this combination of molecules might foster the development of novel therapeutic approaches for glioblastoma. Full article
(This article belongs to the Special Issue Histone Modification in Cancer)
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14 pages, 2642 KiB  
Article
Pulmonary Carcinoid Surface Receptor Modulation Using Histone Deacetylase Inhibitors
by Rachael E. Guenter, Tolulope Aweda, Danilea M. Carmona Matos, Jason Whitt, Alexander W. Chang, Eric Y. Cheng, X. Margaret Liu, Herbert Chen, Suzanne E. Lapi and Renata Jaskula-Sztul
Cancers 2019, 11(6), 767; https://doi.org/10.3390/cancers11060767 - 03 Jun 2019
Cited by 18 | Viewed by 3423
Abstract
Pulmonary carcinoids are a type of neuroendocrine tumor (NET) accounting for 1–2% of lung cancer cases. Currently, Positron Emission Tomography (PET)/CT based on the radiolabeled sugar analogue [18F]-FDG is used to diagnose and stage pulmonary carcinoids, but is suboptimal due to [...] Read more.
Pulmonary carcinoids are a type of neuroendocrine tumor (NET) accounting for 1–2% of lung cancer cases. Currently, Positron Emission Tomography (PET)/CT based on the radiolabeled sugar analogue [18F]-FDG is used to diagnose and stage pulmonary carcinoids, but is suboptimal due to low metabolic activity in these tumors. A new technique for pulmonary carcinoid imaging, using PET/CT with radiolabeled somatostatin analogs that specifically target somatostatin receptor subtype 2 (SSTR2), is becoming more standard, as many tumors overexpress SSTR2. However, pulmonary carcinoid patients with diminished SSTR2 expression are not eligible for this imaging or any type of SSTR2-specific treatment. We have found that histone deacetylase (HDAC) inhibitors can upregulate the expression of SSTR2 in pulmonary carcinoid cell lines. In this study, we used a non-cytotoxic dose of HDAC inhibitors to induce pulmonary carcinoid SSTR2 expression in which we confirmed in vitro and in vivo. A non-cytotoxic dose of the HDAC inhibitors: thailandepsin A (TDP-A), romidepsin (FK228), suberoylanilide hydroxamic acid (SAHA), AB3, and valproic acid (VPA) were administered to promote SSTR2 expression in pulmonary carcinoid cell lines and xenografts. This SSTR2 upregulation technique using HDAC inhibitors could enhance radiolabeled somatostatin analog-based imaging and the development of potential targeted treatments for pulmonary carcinoid patients with marginal or diminished SSTR2 expression. Full article
(This article belongs to the Special Issue Histone Modification in Cancer)
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23 pages, 3176 KiB  
Communication
Profiling of Epigenetic Features in Clinical Samples Reveals Novel Widespread Changes in Cancer
by Roberta Noberini, Camilla Restellini, Evelyn Oliva Savoia, Francesco Raimondi, Lavinia Ghiani, Maria Giovanna Jodice, Giovanni Bertalot, Giuseppina Bonizzi, Maria Capra, Fausto Antonio Maffini, Marta Tagliabue, Mohssen Ansarin, Michela Lupia, Marco Giordano, Daniela Osti, Giuliana Pelicci, Susanna Chiocca and Tiziana Bonaldi
Cancers 2019, 11(5), 723; https://doi.org/10.3390/cancers11050723 - 24 May 2019
Cited by 18 | Viewed by 4888
Abstract
Aberrations in histone post-translational modifications (PTMs), as well as in the histone modifying enzymes (HMEs) that catalyze their deposition and removal, have been reported in many tumors and many epigenetic inhibitors are currently under investigation for cancer treatment. Therefore, profiling epigenetic features in [...] Read more.
Aberrations in histone post-translational modifications (PTMs), as well as in the histone modifying enzymes (HMEs) that catalyze their deposition and removal, have been reported in many tumors and many epigenetic inhibitors are currently under investigation for cancer treatment. Therefore, profiling epigenetic features in cancer could have important implications for the discovery of both biomarkers for patient stratification and novel epigenetic targets. In this study, we employed mass spectrometry-based approaches to comprehensively profile histone H3 PTMs in a panel of normal and tumoral tissues for different cancer types, identifying various changes, some of which appear to be a consequence of the increased proliferation rate of tumors, while others are cell-cycle independent. Histone PTM changes found in tumors partially correlate with alterations of the gene expression profiles of HMEs obtained from publicly available data and are generally lost in culture conditions. Through this analysis, we identified tumor- and subtype-specific histone PTM changes, but also widespread changes in the levels of histone H3 K9me3 and K14ac marks. In particular, H3K14ac showed a cell-cycle independent decrease in all the seven tumor/tumor subtype models tested and could represent a novel epigenetic hallmark of cancer. Full article
(This article belongs to the Special Issue Histone Modification in Cancer)
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18 pages, 4638 KiB  
Article
Mutant p53, Stabilized by Its Interplay with HSP90, Activates a Positive Feed-Back Loop Between NRF2 and p62 that Induces Chemo-Resistance to Apigenin in Pancreatic Cancer Cells
by Maria Saveria Gilardini Montani, Nives Cecere, Marisa Granato, Maria Anele Romeo, Luca Falcinelli, Umberto Ciciarelli, Gabriella D’Orazi, Alberto Faggioni and Mara Cirone
Cancers 2019, 11(5), 703; https://doi.org/10.3390/cancers11050703 - 22 May 2019
Cited by 51 | Viewed by 4586
Abstract
Pancreatic cancer is one of the most aggressive cancers whose prognosis is worsened by the poor response to the current chemotherapies. In this study, we investigated the cytotoxic effect of Apigenin, against two pancreatic cell lines, namely Panc1 and PaCa44, harboring different p53 [...] Read more.
Pancreatic cancer is one of the most aggressive cancers whose prognosis is worsened by the poor response to the current chemotherapies. In this study, we investigated the cytotoxic effect of Apigenin, against two pancreatic cell lines, namely Panc1 and PaCa44, harboring different p53 mutations. Apigenin is a flavonoid widely distributed in nature that displays anti-inflammatory and anticancer properties against a variety of cancers. Here we observed that Apigenin exerted a stronger cytotoxic effect against Panc1 cell line in comparison to PaCa44. Searching for mechanisms responsible for such different effect, we found that the higher cytotoxicity of Apigenin correlated with induction of higher level of intracellular ROS, reduction of mutant (mut) p53 and HSP90 expression and mTORC1 inhibition. Interestingly, we found that mutp53 was stabilized by its interplay with HSP90 and activates a positive feed-back loop between NRF2 and p62, up-regulating the antioxidant response and reducing the cytotoxicity of Apigenin. These results suggest that targeting the molecules involved in the mTOR-HSP90-mutp53-p62-NRF2-antioxidant response axis could help to overcome the chemo-resistance of pancreatic cancer to Apigenin. Full article
(This article belongs to the Special Issue Histone Modification in Cancer)
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14 pages, 4375 KiB  
Article
Influence of the HDAC Inhibitor Valproic Acid on the Growth and Proliferation of Temsirolimus-Resistant Prostate Cancer Cells In Vitro
by Jasmina Makarević, Jochen Rutz, Eva Juengel, Sebastian Maxeiner, Igor Tsaur, Felix K.-H. Chun, Jürgen Bereiter-Hahn and Roman A. Blaheta
Cancers 2019, 11(4), 566; https://doi.org/10.3390/cancers11040566 - 19 Apr 2019
Cited by 15 | Viewed by 3665
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
(This article belongs to the Special Issue Histone Modification in Cancer)
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19 pages, 5058 KiB  
Article
Contingencies of UTX/KDM6A Action in Urothelial Carcinoma
by Alexander Lang, Merve Yilmaz, Christiane Hader, Sammy Murday, Xenia Kunz, Nicholas Wagner, Constanze Wiek, Patrick Petzsch, Karl Köhrer, Julian Koch, Michéle J. Hoffmann, Annemarie Greife and Wolfgang A. Schulz
Cancers 2019, 11(4), 481; https://doi.org/10.3390/cancers11040481 - 04 Apr 2019
Cited by 20 | Viewed by 4537
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
(This article belongs to the Special Issue Histone Modification in Cancer)
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1550 KiB  
Article
Stabilization of Nucleosomes by Histone Tails and by FACT Revealed by spFRET Microscopy
by Maria E. Valieva, Nadezhda S. Gerasimova, Kseniya S. Kudryashova, Anastasia L. Kozlova, Mikhail P. Kirpichnikov, Qi Hu, Maria Victoria Botuyan, Georges Mer, Alexey V. Feofanov and Vasily M. Studitsky
Cancers 2017, 9(1), 3; https://doi.org/10.3390/cancers9010003 - 06 Jan 2017
Cited by 29 | Viewed by 8384
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
(This article belongs to the Special Issue Histone Modification in Cancer)
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Review

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22 pages, 2437 KiB  
Review
Diverse Functions of KDM5 in Cancer: Transcriptional Repressor or Activator?
by Yasuyo Ohguchi and Hiroto Ohguchi
Cancers 2022, 14(13), 3270; https://doi.org/10.3390/cancers14133270 - 04 Jul 2022
Cited by 10 | Viewed by 3603
Abstract
Epigenetic modifications are crucial for chromatin remodeling and transcriptional regulation. Post-translational modifications of histones are epigenetic processes that are fine-tuned by writer and eraser enzymes, and the disorganization of these enzymes alters the cellular state, resulting in human diseases. The KDM5 family is [...] Read more.
Epigenetic modifications are crucial for chromatin remodeling and transcriptional regulation. Post-translational modifications of histones are epigenetic processes that are fine-tuned by writer and eraser enzymes, and the disorganization of these enzymes alters the cellular state, resulting in human diseases. The KDM5 family is an enzymatic family that removes di- and tri-methyl groups (me2 and me3) from lysine 4 of histone H3 (H3K4), and its dysregulation has been implicated in cancer. Although H3K4me3 is an active chromatin marker, KDM5 proteins serve as not only transcriptional repressors but also transcriptional activators in a demethylase-dependent or -independent manner in different contexts. Notably, KDM5 proteins regulate the H3K4 methylation cycle required for active transcription. Here, we review the recent findings regarding the mechanisms of transcriptional regulation mediated by KDM5 in various contexts, with a focus on cancer, and further shed light on the potential of targeting KDM5 for cancer therapy. Full article
(This article belongs to the Special Issue Histone Modification in Cancer)
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24 pages, 1331 KiB  
Review
Histone H3 Mutations: An Updated View of Their Role in Chromatin Deregulation and Cancer
by Brandon R. Lowe, Lily A. Maxham, Joshua J. Hamey, Marc R. Wilkins and Janet F. Partridge
Cancers 2019, 11(5), 660; https://doi.org/10.3390/cancers11050660 - 13 May 2019
Cited by 82 | Viewed by 11516
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
(This article belongs to the Special Issue Histone Modification in Cancer)
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21 pages, 1338 KiB  
Review
Perturbing Enhancer Activity in Cancer Therapy
by Feda H. Hamdan and Steven A. Johnsen
Cancers 2019, 11(5), 634; https://doi.org/10.3390/cancers11050634 - 07 May 2019
Cited by 17 | Viewed by 5336
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
(This article belongs to the Special Issue Histone Modification in Cancer)
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15 pages, 1432 KiB  
Review
HDAC Inhibitors Exert Anti-Myeloma Effects through Multiple Modes of Action
by Yoichi Imai, Mitsuhito Hirano, Masayuki Kobayashi, Muneyoshi Futami and Arinobu Tojo
Cancers 2019, 11(4), 475; https://doi.org/10.3390/cancers11040475 - 04 Apr 2019
Cited by 43 | Viewed by 5358
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
(This article belongs to the Special Issue Histone Modification in Cancer)
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15 pages, 4296 KiB  
Review
Expanding the Role of the Histone Lysine-Specific Demethylase LSD1 in Cancer
by Barbara Majello, Francesca Gorini, Carmen Daniela Saccà and Stefano Amente
Cancers 2019, 11(3), 324; https://doi.org/10.3390/cancers11030324 - 07 Mar 2019
Cited by 95 | Viewed by 11005
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
(This article belongs to the Special Issue Histone Modification in Cancer)
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28 pages, 1891 KiB  
Review
Inhibition of BET Proteins and Histone Deacetylase (HDACs): Crossing Roads in Cancer Therapy
by Gloria Manzotti, Alessia Ciarrocchi and Valentina Sancisi
Cancers 2019, 11(3), 304; https://doi.org/10.3390/cancers11030304 - 05 Mar 2019
Cited by 52 | Viewed by 5721
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
(This article belongs to the Special Issue Histone Modification in Cancer)
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31 pages, 6116 KiB  
Review
Histone Deacetylase Inhibitors and Phenotypical Transformation of Cancer Cells
by Anna Wawruszak, Joanna Kalafut, Estera Okon, Jakub Czapinski, Marta Halasa, Alicja Przybyszewska, Paulina Miziak, Karolina Okla, Adolfo Rivero-Muller and Andrzej Stepulak
Cancers 2019, 11(2), 148; https://doi.org/10.3390/cancers11020148 - 27 Jan 2019
Cited by 70 | Viewed by 6147
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
(This article belongs to the Special Issue Histone Modification in Cancer)
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18 pages, 1196 KiB  
Review
Reading Cancer: Chromatin Readers as Druggable Targets for Cancer Treatment
by Catia Mio, Stefania Bulotta, Diego Russo and Giuseppe Damante
Cancers 2019, 11(1), 61; https://doi.org/10.3390/cancers11010061 - 09 Jan 2019
Cited by 29 | Viewed by 4412
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
(This article belongs to the Special Issue Histone Modification in Cancer)
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22 pages, 916 KiB  
Review
The Role of DNA/Histone Modifying Enzymes and Chromatin Remodeling Complexes in Testicular Germ Cell Tumors
by João Lobo, Rui Henrique and Carmen Jerónimo
Cancers 2019, 11(1), 6; https://doi.org/10.3390/cancers11010006 - 20 Dec 2018
Cited by 18 | Viewed by 3546
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
(This article belongs to the Special Issue Histone Modification in Cancer)
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15 pages, 926 KiB  
Review
Breaking down the Contradictory Roles of Histone Deacetylase SIRT1 in Human Breast Cancer
by Khaldoun Rifaï, Mouhamed Idrissou, Frédérique Penault-Llorca, Yves-Jean Bignon and Dominique Bernard-Gallon
Cancers 2018, 10(11), 409; https://doi.org/10.3390/cancers10110409 - 30 Oct 2018
Cited by 22 | Viewed by 4297
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
(This article belongs to the Special Issue Histone Modification in Cancer)
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25 pages, 1087 KiB  
Review
Post-Translational Modifications of H2A Histone Variants and Their Role in Cancer
by David Corujo and Marcus Buschbeck
Cancers 2018, 10(3), 59; https://doi.org/10.3390/cancers10030059 - 27 Feb 2018
Cited by 64 | Viewed by 10115
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
(This article belongs to the Special Issue Histone Modification in Cancer)
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13 pages, 432 KiB  
Review
Modification of Epigenetic Histone Acetylation in Hepatocellular Carcinoma
by Kwei-Yan Liu, Li-Ting Wang and Shih-Hsien Hsu
Cancers 2018, 10(1), 8; https://doi.org/10.3390/cancers10010008 - 03 Jan 2018
Cited by 35 | Viewed by 6345
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
(This article belongs to the Special Issue Histone Modification in Cancer)
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2496 KiB  
Review
Ubiquitin Specific Peptidase 22 Regulates Histone H2B Mono-Ubiquitination and Exhibits Both Oncogenic and Tumor Suppressor Roles in Cancer
by Lucile M-P. Jeusset and Kirk J. McManus
Cancers 2017, 9(12), 167; https://doi.org/10.3390/cancers9120167 - 06 Dec 2017
Cited by 44 | Viewed by 6974
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
(This article belongs to the Special Issue Histone Modification in Cancer)
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1312 KiB  
Review
Circulating Nucleosomes and Nucleosome Modifications as Biomarkers in Cancer
by Peter McAnena, James A. L. Brown and Michael J. Kerin
Cancers 2017, 9(1), 5; https://doi.org/10.3390/cancers9010005 - 08 Jan 2017
Cited by 81 | Viewed by 16189
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
(This article belongs to the Special Issue Histone Modification in Cancer)
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526 KiB  
Review
The Role of Histone Protein Modifications and Mutations in Histone Modifiers in Pediatric B-Cell Progenitor Acute Lymphoblastic Leukemia
by Szymon Janczar, Karolina Janczar, Agata Pastorczak, Hani Harb, Adam J. W. Paige, Beata Zalewska-Szewczyk, Marian Danilewicz and Wojciech Mlynarski
Cancers 2017, 9(1), 2; https://doi.org/10.3390/cancers9010002 - 03 Jan 2017
Cited by 18 | Viewed by 6515
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
(This article belongs to the Special Issue Histone Modification in Cancer)
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13 pages, 2093 KiB  
Brief Report
Selective Inhibition of Histone Deacetylation in Melanoma Increases Targeted Gene Delivery by a Bacteriophage Viral Vector
by Samuel Campbell, Keittisak Suwan, Sajee Waramit, Eric Ofori Aboagye and Amin Hajitou
Cancers 2018, 10(4), 125; https://doi.org/10.3390/cancers10040125 - 21 Apr 2018
Cited by 3 | Viewed by 4411
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
(This article belongs to the Special Issue Histone Modification in Cancer)
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1021 KiB  
Perspective
Genomic Destabilization Triggered by Replication Stress during Senescence
by Yusuke Minakawa, Atsuhiro Shimizu, Yusuke Matsuno and Ken-ichi Yoshioka
Cancers 2017, 9(11), 159; https://doi.org/10.3390/cancers9110159 - 21 Nov 2017
Cited by 3 | Viewed by 4272
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
(This article belongs to the Special Issue Histone Modification in Cancer)
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