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Epigenetic Alterations in Age-Associated Diseases and Cancers
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Epigenetic Alterations in Age-Associated Diseases and Cancers

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 November 2020) | Viewed by 25744

Special Issue Editor

Prof. Dr. Agustin F. Fernandez

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Guest Editor
Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Health Research Institute of Asturias (ISPA), Institute of Oncology of Asturias (IUOPA), Avda. de Roma, s/n. Laboratorio de Epigenética del cáncer y nanomedicina, Ed. FINBA planta 0, 33011-Oviedo, Spain
Interests: epigenetics; epigenomics; aging; cancer; environmental epigenetics; nanomedicine; nanomaterials; rare diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The alterations of DNA methylation during aging, a process known as “epigenetic drift”, are well-documented. However, the alterations of other epigenetic marks such as the posttranslational histone modifications or the non-coding RNAs (ncRNAs) are not as well studied. Although the alterations of DNA methylation marks during aging are specific to each cell type, the histone marks associated with them appear to follow similar patterns in different tissues. That said, the association of these epigenetic alterations with functional changes are not yet well established.

Aging is a risk factor for many human diseases, including but not limited to neurological, cardiovascular, metabolic, and autoimmune conditions, as well as disorders such as infertility and even certain types of cancer. It is challenging to conduct in-depth study of the epigenetic alterations (i.e., DNA methylation, histone modifications, ncRNAs) associated specifically with human age-related diseases, and how internal factors (e.g., genotype) as well as external and stochastic factors are mediating these processes.

This Special Issue “Epigenetic Alterations in Age-Associated Diseases and Cancer” calls for original research and review articles that address current knowledge and progress being made in our understanding of the epigenetic alterations associated with age-related diseases, the possible functional effects that these alterations may trigger, and the role of the internal, external, and/or stochastic factors that may underlie these changes.

Prof. Dr. Agustin F. Fernandez
Guest Editor

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Keywords

  • epigenetics
  • epigenome
  • age-related diseases
  • aging
  • DNA methylation
  • histone modifications
  • ncRNAs
  • epigenetic drift
  • epigenetic clock

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Published Papers (6 papers)

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Research

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12 pages, 2287 KiB  
Article
Epigenetic Regulation of Gfi1 in Endocrine-Related Cancers: A Role Regulating Tumor Growth
by Nadia Ashour, Javier C. Angulo, Ana González-Corpas, María J. Orea, María V. T. Lobo, Ramón Colomer, Begoña Colás, Manel Esteller and Santiago Ropero
Int. J. Mol. Sci. 2020, 21(13), 4687; https://doi.org/10.3390/ijms21134687 - 30 Jun 2020
Cited by 5 | Viewed by 2617
Abstract
Prostate and breast cancer constitute the most common cancers among men and women worldwide. The aging population is one of the main risk factors for prostate and breast cancer development and accumulating studies link aging with epigenetic changes. Growth factor independence-1 (Gfi1) is [...] Read more.
Prostate and breast cancer constitute the most common cancers among men and women worldwide. The aging population is one of the main risk factors for prostate and breast cancer development and accumulating studies link aging with epigenetic changes. Growth factor independence-1 (Gfi1) is a transcriptional repressor with an important role in human malignancies, including leukemia, colorectal carcinoma, and lung cancer, but its role in prostate and breast cancer is unknown. We have found that Gfi1 epigenetic silencing is a common event in prostate and breast cancer. Gfi1 re-expression in prostate and breast cancer cell lines displaying Gfi1 epigenetic silencing decreases cell proliferation, reduced colony formation density, and tumor growth in nude mice xenografts. In addition, we found that Gfi1 repress alpha 1-anti-trypsin (AAT) and alpha 1-anti-chymotrypsin (ACT) expression, two genes with important functions in cancer development, suggesting that Gfi1 silencing promotes tumor growth by increasing AAT and ACT expression in our system. Finally, Gfi1 epigenetic silencing could be a promising biomarker for prostate cancer progression because it is associated with shorter disease-free survival. In conclusion, our findings strongly indicate that Gfi1 epigenetic silencing in prostate and breast cancer could be a crucial step in the development of these two-well characterized endocrine related tumors. Full article
(This article belongs to the Special Issue Epigenetic Alterations in Age-Associated Diseases and Cancers)
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22 pages, 1693 KiB  
Article
Promoter Methylation of Selected Genes in Non-Small-Cell Lung Cancer Patients and Cell Lines
by Victoria Sarne, Samuel Huter, Sandrina Braunmueller, Lisa Rakob, Nico Jacobi, Melitta Kitzwögerer, Christoph Wiesner, Peter Obrist and Rita Seeboeck
Int. J. Mol. Sci. 2020, 21(13), 4595; https://doi.org/10.3390/ijms21134595 - 28 Jun 2020
Cited by 10 | Viewed by 3471
Abstract
Specific gene promoter DNA methylation is becoming a powerful epigenetic biomarker in cancer diagnostics. Five genes (CDH1, CDKN2Ap16, RASSF1A, TERT, and WT1) were selected based on their frequently published potential as epigenetic markers. Diagnostic promoter methylation assays [...] Read more.
Specific gene promoter DNA methylation is becoming a powerful epigenetic biomarker in cancer diagnostics. Five genes (CDH1, CDKN2Ap16, RASSF1A, TERT, and WT1) were selected based on their frequently published potential as epigenetic markers. Diagnostic promoter methylation assays were generated based on bisulfite-converted DNA pyrosequencing. The methylation patterns of 144 non-small-cell lung cancer (NSCLC) and 7 healthy control formalin-fixed paraffin-embedded (FFPE) samples were analyzed to evaluate the applicability of the putative diagnostic markers. Statistically significant changes in methylation levels are shown for TERT and WT1. Furthermore, 12 NSCLC and two benign lung cell lines were characterized for promoter methylation. The in vitro tests involved a comparison of promoter methylation in 2D and 3D cultures, as well as therapeutic tests investigating the impact of CDH1/CDKN2Ap16/RASSF1A/TERT/WT1 promoter methylation on sensitivity to tyrosine kinase inhibitor (TKI) and DNA methyl-transferase inhibitor (DNMTI) treatments. We conclude that the selected markers have potential and putative impacts as diagnostic or even predictive marker genes, although a closer examination of the resulting protein expression and pathway regulation is needed. Full article
(This article belongs to the Special Issue Epigenetic Alterations in Age-Associated Diseases and Cancers)
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14 pages, 2532 KiB  
Article
SMARCB1 Acts as a Quiescent Gatekeeper for Cell Cycle and Immune Response in Human Cells
by Sung Kyung Choi, Myoung Jun Kim and Jueng Soo You
Int. J. Mol. Sci. 2020, 21(11), 3969; https://doi.org/10.3390/ijms21113969 - 1 Jun 2020
Cited by 8 | Viewed by 2878
Abstract
Switch/sucrose non-fermentable (SWI/SNF)-related matrix-associated actin-dependent regulator of chromatin (SMARC) subfamily B member 1 (SMARCB1) is a core subunit of the switch/sucrose non-fermentable (SWI/SNF) complex, one of the adenosine triphosphate (ATP)-dependent chromatin remodeler complexes. The unique role of SMARCB1 has been reported in various [...] Read more.
Switch/sucrose non-fermentable (SWI/SNF)-related matrix-associated actin-dependent regulator of chromatin (SMARC) subfamily B member 1 (SMARCB1) is a core subunit of the switch/sucrose non-fermentable (SWI/SNF) complex, one of the adenosine triphosphate (ATP)-dependent chromatin remodeler complexes. The unique role of SMARCB1 has been reported in various cellular contexts. Here, we focused on the general role of the ubiquitous expression of SMARCB1 in a normal cell state. We selected ARPE19 (human primary retinal pigment epithelium) and IMR90 (from human fetal lung fibroblasts) cell lines as they have completely different contexts. Furthermore, although these cell lines have been immortalized, they are relatively close to normal human cells. The loss of SMARCB1 in ARPE19 and IMR90 cells reduced cell cycle progression via the upregulation of P21. Transcriptome analysis followed by SMARCB1 knockdown in both cell lines revealed that SMARCB1 was not only involved in cell maintenance but also conferred immunomodulation. Of note, SMARCB1 bound to interleukin (IL) 6 promoter in a steady state and dissociated in an active immune response state, suggesting that SMARCB1 was a direct repressor of IL6, which was further confirmed via loss- and gain-of-function studies. Taken together, we demonstrated that SMARCB1 is a critical gatekeeper molecule of the cell cycle and immune response. Full article
(This article belongs to the Special Issue Epigenetic Alterations in Age-Associated Diseases and Cancers)
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15 pages, 2279 KiB  
Article
Methylation Density Pattern of KEAP1 Gene in Lung Cancer Cell Lines Detected by Quantitative Methylation Specific PCR and Pyrosequencing
by Federico Pio Fabrizio, Angelo Sparaneo, Flavia Centra, Domenico Trombetta, Clelia Tiziana Storlazzi, Paolo Graziano, Evaristo Maiello, Vito Michele Fazio and Lucia Anna Muscarella
Int. J. Mol. Sci. 2019, 20(11), 2697; https://doi.org/10.3390/ijms20112697 - 31 May 2019
Cited by 17 | Viewed by 4089
Abstract
Background. The KEAP1/NRF2 pathway is the key regulator of antioxidants and cellular stress responses, and is implicated in neoplastic progression and resistance of tumors to treatment. KEAP1 silencing by promoter methylation is widely reported in solid tumors as part of the complex regulation [...] Read more.
Background. The KEAP1/NRF2 pathway is the key regulator of antioxidants and cellular stress responses, and is implicated in neoplastic progression and resistance of tumors to treatment. KEAP1 silencing by promoter methylation is widely reported in solid tumors as part of the complex regulation of the KEAP1/NRF2 axis, but its prognostic role remains to be addressed in lung cancer. Methods. We performed a detailed methylation density map of 13 CpGs located into the KEAP1 promoter region by analyzing a set of 25 cell lines from different histologies of lung cancer. The methylation status was assessed using quantitative methylation specific PCR (QMSP) and pyrosequencing, and the performance of the two assays was compared. Results. Hypermethylation at the promoter region of the KEAP1 was detected in one third of cell lines and its effect on the modulation KEAP1 mRNA levels was also confirmed by in vitro 5-Azacytidine treatment on lung carcinoid, small lung cancer and adenocarcinoma cell lines. QMSP and pyrosequencing showed a high rate of concordant results, even if pyrosequencing revealed two different promoter CpGs sub-islands (P1a and P1b) with a different methylation density pattern. Conclusions. Our results confirm the effect of methylation on KEAP1 transcription control across multiple histologies of lung cancer and suggest pyrosequencing as the best approach to investigate the pattern of CpGs methylation in the promoter region of KEAP1. The validation of this approach on lung cancer patient cohorts is mandatory to clarify the prognostic value of the epigenetic deregulation of KEAP1 in lung tumors. Full article
(This article belongs to the Special Issue Epigenetic Alterations in Age-Associated Diseases and Cancers)
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13 pages, 1124 KiB  
Article
Chromosome Conformation Capture Reveals Two Elements That Interact with the PTBP3 (ROD1) Transcription Start Site
by Marta Kubiak, Anna Jurek, Katarzyna Kamińska, Janusz Kowalewski, Sui Huang and Marzena Anna Lewandowska
Int. J. Mol. Sci. 2019, 20(2), 242; https://doi.org/10.3390/ijms20020242 - 9 Jan 2019
Cited by 3 | Viewed by 3709
Abstract
The long-range control of gene expression is facilitated by chromatin looping and can be detected using chromosome conformation capture—3C. Here we focus on the chromatin architecture of the PTBP3 (Polypyrimidine tract binding protein 3) locus to evaluate its potential role in regulating expression [...] Read more.
The long-range control of gene expression is facilitated by chromatin looping and can be detected using chromosome conformation capture—3C. Here we focus on the chromatin architecture of the PTBP3 (Polypyrimidine tract binding protein 3) locus to evaluate its potential role in regulating expression of the gene. PTBP3 expression in prostate cancer cell lines is found significantly higher compared to skin fibroblasts using real-time PCR (p < 0.05) and digital droplet PCR (p < 0.01). Exploration of the chromatin spatial architecture of a nearly 200-kb fragment of chromosome 9 encompassing the PTBP3 gene identified two elements located 63 kb upstream and 48 kb downstream of PTBP3, which looped specifically to the PTBP3 promoter. These elements contain histone acetylation patterns characteristic of open chromatin regions with active enhancers. Our results reveal for the first time that long-range chromatin interactions between the −63 kb and +48 kb loci and the PTBP3 promoter regulate the expression of this gene in prostate cancer cells. These interactions support an open chromatin form for the PTBP3 locus in cancer cells and the three-dimensional structural model proposed in this paper. Full article
(This article belongs to the Special Issue Epigenetic Alterations in Age-Associated Diseases and Cancers)
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Review

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31 pages, 1056 KiB  
Review
Senescence in the Development and Response to Cancer with Immunotherapy: A Double-Edged Sword
by Anthony M. Battram, Mireia Bachiller and Beatriz Martín-Antonio
Int. J. Mol. Sci. 2020, 21(12), 4346; https://doi.org/10.3390/ijms21124346 - 18 Jun 2020
Cited by 40 | Viewed by 8353
Abstract
Cellular senescence was first described as a physiological tumor cell suppressor mechanism that leads to cell growth arrest with production of the senescence-associated secretory phenotype known as SASP. The main role of SASP in physiological conditions is to attract immune cells to clear [...] Read more.
Cellular senescence was first described as a physiological tumor cell suppressor mechanism that leads to cell growth arrest with production of the senescence-associated secretory phenotype known as SASP. The main role of SASP in physiological conditions is to attract immune cells to clear senescent cells avoiding tumor development. However, senescence can be damage-associated and, depending on the nature of these stimuli, additional types of senescence have been described. In the context of cancer, damage-associated senescence has been described as a consequence of chemotherapy treatments that were initially thought of as a tumor suppressor mechanism. However, in certain contexts, senescence after chemotherapy can promote cancer progression, especially when immune cells become senescent and cannot clear senescent tumor cells. Moreover, aging itself leads to continuous inflammaging and immunosenescence which are responsible for rewiring immune cells to become defective in their functionality. Here, we define different types of senescence, pathways that activate them, and functions of SASP in these events. Additionally, we describe the role of senescence in cancer and its treatments, including how aging and chemotherapy contribute to senescence in tumor cells, before focusing on immune cell senescence and its role in cancer. Finally, we discuss potential therapeutic interventions to reverse cell senescence. Full article
(This article belongs to the Special Issue Epigenetic Alterations in Age-Associated Diseases and Cancers)
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