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Sahoo K, Lingasamy P, Khatun M, Sudhakaran SL, Salumets A, Sundararajan V, Modhukur V. Artificial Intelligence in cancer epigenomics: a review on advances in pan-cancer detection and precision medicine. Epigenetics Chromatin 2025; 18:35. [PMID: 40517231 DOI: 10.1186/s13072-025-00595-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2025] [Accepted: 05/19/2025] [Indexed: 06/16/2025] Open
Abstract
DNA methylation is a fundamental epigenetic modification that regulates gene expression and maintains genomic stability. Consequently, DNA methylation remains a key biomarker in cancer research, playing a vital role in diagnosis, prognosis, and tailored treatment strategies. Aberrant methylation patterns enable early cancer detection and therapeutic stratification; however, their complex patterns necessitates advanced analytical tools. Recent advances in artificial intelligence (AI) and machine learning (ML), including deep learning networks and graph-based models, have revolutionized cancer epigenomics by enabling rapid, high-resolution analysis of DNA methylation profiles. Moreover, these technologies are accelerating the development of Multi-Cancer Early Detection (MCED) tests, such as GRAIL's Galleri and CancerSEEK, which improve diagnostic accuracy across diverse cancer types. In this review, we explore the synergy between AI and DNA methylation profiling to advance precision oncology. We first examine the role of DNA methylation as a biomarker in cancer, followed by an overview of DNA profiling technologies. We then assess how AI-driven approaches transform clinical practice by enabling early detection and accurate classification. Despite their promise, challenges remain, including limited sensitivity for early-stage cancers, the black-box nature of many AI algorithms, and the need for validation across diverse populations to ensure equitable implementation. Future directions include integrating multi-omics data, developing explainable AI frameworks, and addressing ethical concerns, such as data privacy and algorithmic bias. By overcoming these gaps, AI-powered epigenetic diagnostics can enable earlier detection, more effective treatments, and improved patient outcomes, globally. In summary, this review synthesizes current advancements in the field and envisions a future where AI and epigenomics converge to redefine cancer diagnostics and therapy.
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Affiliation(s)
- Karishma Sahoo
- Integrative Multiomics Lab, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, 632014, Tamil Nadu, India
| | - Prakash Lingasamy
- Department of Obstetrics and Gynecology, Institute of Clinical Medicine, University of Tartu, L. Puusepa 8, 50406, Tartu, Estonia
- Celvia CC AS, 50411, Tartu, Estonia
| | - Masuma Khatun
- Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 8, 00290, Helsinki, Finland
| | - Sajitha Lulu Sudhakaran
- Integrative Multiomics Lab, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, 632014, Tamil Nadu, India
| | - Andres Salumets
- Department of Obstetrics and Gynecology, Institute of Clinical Medicine, University of Tartu, L. Puusepa 8, 50406, Tartu, Estonia.
- Celvia CC AS, 50411, Tartu, Estonia.
- Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute, and Karolinska University Hospital, 14183, Huddinge, Sweden.
| | - Vino Sundararajan
- Integrative Multiomics Lab, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, 632014, Tamil Nadu, India
| | - Vijayachitra Modhukur
- Department of Obstetrics and Gynecology, Institute of Clinical Medicine, University of Tartu, L. Puusepa 8, 50406, Tartu, Estonia.
- Celvia CC AS, 50411, Tartu, Estonia.
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Meevassana J, Vongsuly CW, Nakbua T, Kamolratanakul S, Thitiwanichpiwong P, Bin-Alee F, Keelawat S, Kitkumthorn N. Selected Alu methylation levels in the gastric carcinogenesis cascade. PeerJ 2025; 13:e19485. [PMID: 40416611 PMCID: PMC12101442 DOI: 10.7717/peerj.19485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Accepted: 04/27/2025] [Indexed: 05/27/2025] Open
Abstract
Background Genome-wide hypomethylation, a common epigenetic change that occurs during cancer development, primarily affects repetitive elements, such as Alu repeats. Consequently, Alu repeats can be used as a surrogate marker of genomic hypomethylation. Methods In this study, we aimed to investigate the correlation between Alu methylation levels and the multistage course of gastric carcinogenesis. Results We found that the Alu methylation levels in gastric cancer tissue decreased compared with those in normal gastric tissue, with the change in methylation levels and pattern being most significant between chronic gastritis and intestinal metaplasia. Moreover, Alu methylation levels were not associated with Helicobacter pylori or Epstein-Barr virus infection. Conclusions Finally, our sensitivity and specificity analyses suggested that Alu methylation level can be used to distinguish gastric cancer tissue from normal tissue. Thus, Alu methylation level shows promise as biomarker for gastric cancer diagnosis.
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Affiliation(s)
- Jiraroch Meevassana
- Center of Excellence in Burn and Wound Care, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Chawisa Wanda Vongsuly
- Center of Excellence in Burn and Wound Care, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Tanchanok Nakbua
- Center of Excellence in Burn and Wound Care, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Supitcha Kamolratanakul
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | | | - Fardeela Bin-Alee
- Faculty of Medicine, Princess of Naradhiwas University, Narathiwat, Thailand
| | - Somboon Keelawat
- Department of Pathology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Nakarin Kitkumthorn
- Department of Oral Biology, Faculty of Dentistry, Mahidol University, Bangkok, Thailand
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Arbet J, Yamaguchi TN, Shiah YJ, Hugh-White R, Wiggins A, Oh J, Gebo T, Foucal A, Lesurf R, Jung CH, Dang RMA, Agrawal R, Livingstone J, Salcedo A, Yao CQ, Espiritu SMG, Houlahan KE, Yousif F, Heisler LE, Papenfuss AT, Fraser M, Pope B, Kishan A, Berlin A, Chua MLK, Corcoran NM, van der Kwast T, Hovens CM, Bristow RG, Boutros PC. The Landscape of Prostate Tumour Methylation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.07.637178. [PMID: 39990314 PMCID: PMC11844408 DOI: 10.1101/2025.02.07.637178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/25/2025]
Abstract
Prostate cancer is characterized by profound clinical and molecular heterogeneity. While its genomic heterogeneity is well-characterized, its epigenomic heterogeneity remains less understood. We therefore created a compendium of 3,001 multi-ancestry prostate methylomes spanning normal tissue through localized disease of all grades to poly-metastatic disease. A subset of 884 samples had multi-omic DNA and/or RNA characterization. We identify four epigenomic subtypes that risk-stratify patients and reflect distinct evolutionary trajectories. We demonstrate extensive regulatory interplay between DNA ploidy and DNA methylation, with transcriptional consequences that vary across genes and disease stages. We define the epigenetic dysregulation signatures of the 15 most important clinico-molecular features, creating predictive models for each. For example, we identify specific epigenetic features that predict patient outcome and that are synergistic with clinico-genomic prognostic features. These results define a complex interplay between tumour genetics and epigenetics that converges to modify gene-expression programs and clinical presentation.
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Carollo PS, Barra V. Induction of DNA Demethylation: Strategies and Consequences. EPIGENOMES 2025; 9:11. [PMID: 40265378 PMCID: PMC12015805 DOI: 10.3390/epigenomes9020011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2025] [Revised: 03/28/2025] [Accepted: 04/10/2025] [Indexed: 04/24/2025] Open
Abstract
DNA methylation is an important epigenetic modification with a plethora of effects on cells, ranging from the regulation of gene transcription to shaping chromatin structure. Notably, DNA methylation occurs thanks to the activity of DNA methyltransferases (DNMTs), which covalently add a methyl group to the cytosine in position 5' in CpG dinucleotides. Different strategies have been developed to study the effects of DNA methylation in cells, involving either DNMTs inhibition (passive DNA demethylation) or the use of Ten-eleven translocation protein (TET) family enzymes, which directly demethylate DNA (active DNA demethylation). In this manuscript, we will briefly cover the most commonly used strategies in the last two decades to achieve DNA demethylation, along with their effects on cells. We will also discuss some of the newest inducible ways to inhibit DNMTs without remarkable side effects, as well as the effect of non-coding RNAs on DNA methylation. Lastly, we will briefly examine the use of DNA methylation inhibition in biomedical research.
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Affiliation(s)
| | - Viviana Barra
- Department of Biological Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90128 Palermo, Italy
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Zhang S, Jin J, Xu B, Zheng Q, Mou H. The relationship between epigenetic biomarkers and the risk of diabetes and cancer: a machine learning modeling approach. Front Public Health 2025; 13:1509458. [PMID: 40190762 PMCID: PMC11968389 DOI: 10.3389/fpubh.2025.1509458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 02/24/2025] [Indexed: 04/09/2025] Open
Abstract
Introduction Epigenetic biomarkers are molecular indicators of epigenetic changes, and some studies have suggested that these biomarkers have predictive power for disease risk. This study aims to analyze the relationship between 30 epigenetic biomarkers and the risk of diabetes and cancer using machine learning modeling. Methods The data for this study were sourced from the NHANES database, which includes DNA methylation arrays and epigenetic biomarker datasets. Nine machine learning algorithms were used to build models: AdaBoost, GBM, KNN, lightGBM, MLP, RF, SVM, XGBoost, and logistics. Model stability was evaluated using metrics such as Accuracy, MCC, and Sensitivity. The performance and decision-making ability of the models were displayed using ROC curves and DCA curves, while SHAP values were used to visualize the importance of each epigenetic biomarker. Results Epigenetic age acceleration was strongly associated with cancer risk but had a weaker relationship with diabetes. In the diabetes model, the top three contributing features were logA1Mort, family income-to-poverty ratio, and marital status. In the cancer model, the top three contributing features were gender, non-Hispanic White ethnicity, and PACKYRSMort. Conclusion Our study identified the relationship between epigenetic biomarkers and the risk of diabetes and cancer, and used machine learning techniques to analyze the contributions of various epigenetic biomarkers to disease risk.
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Affiliation(s)
- Shiqi Zhang
- Department of Oncology, Shulan (Hangzhou) Hospital, Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, Zhejiang, China
- Graduate School, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Jianan Jin
- Graduate School, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Benfeng Xu
- Graduate School, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Qi Zheng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Haibo Mou
- Department of Oncology, Shulan (Hangzhou) Hospital, Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, Zhejiang, China
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Wang TW, Nakanishi M. Immune surveillance of senescence: potential application to age-related diseases. Trends Cell Biol 2025; 35:248-257. [PMID: 39025762 DOI: 10.1016/j.tcb.2024.06.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 06/18/2024] [Accepted: 06/20/2024] [Indexed: 07/20/2024]
Abstract
Several lines of evidence suggest that the age-dependent accumulation of senescent cells leads to chronic tissue microinflammation, which in turn contributes to age-related pathologies. In general, senescent cells can be eliminated by the host's innate and adaptive immune surveillance system, including macrophages, NK cells, and T cells. Impaired immune surveillance leads to the accumulation of senescent cells and accelerates the aging process. Recently, senescent cells, like cancer cells, have been shown to express certain types of immune checkpoint proteins as well as non-classical immune-tolerant MHC variants, leading to immune escape from surveillance systems. Thus, immune checkpoint blockade (ICB) may be a promising strategy to enhance immune surveillance of senescence, leading to the amelioration of some age-related diseases and tissue dysfunction.
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Affiliation(s)
- Teh-Wei Wang
- Division of Cancer Cell Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
| | - Makoto Nakanishi
- Division of Cancer Cell Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
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Martino S, Gargano S, Carollo PS, Di Leonardo A, Barra V. DNMT1 prolonged absence is a tunable cellular stress that triggers cell proliferation arrest to protect from major DNA methylation loss. Cell Mol Life Sci 2024; 82:7. [PMID: 39694934 DOI: 10.1007/s00018-024-05547-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 11/16/2024] [Accepted: 12/11/2024] [Indexed: 12/20/2024]
Abstract
Methylation of cytosine in CpG dinucleotides is an epigenetic modification carried out by DNA-methyltransferases (DNMTs) that contributes to chromatin condensation and structure and, thus, to gene transcription regulation and chromosome stability. DNMT1 maintains the DNA methylation pattern of the genome at each cell cycle by copying it to the newly synthesized DNA strand during the S-phase. DNMT1 pharmacological inhibition as well as genetic knockout and knockdown, leads to passive DNA methylation loss. However, these strategies have been associated with different cell fates, even in the same cell background, suggesting that they can question the interpretation of the obtained results. Using a cell system in which endogenous DNMT1 is fused with an inducible degron and can be rapidly degraded, we found that in non-tumoral RPE-1 cells, DNMT1 loss progressively induced cell proliferation slowing-down and cell cycle arrest at the G1/S transition. The latter is due to p21 activation, which is partly mediated by p53 and leads to a global reduction in DNA methylation. DNMT1 restoration rescues cell proliferation, indicating that its deregulation is sensed as tunable cellular stress.
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Affiliation(s)
- Salvatore Martino
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90128, Palermo, Italy
| | - Serena Gargano
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90128, Palermo, Italy
| | - Pietro Salvatore Carollo
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90128, Palermo, Italy
| | - Aldo Di Leonardo
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90128, Palermo, Italy
- Centro Di Oncobiologia Sperimentale (C.O.B.S.), Viale Delle Scienze, 90128, Palermo, Italy
| | - Viviana Barra
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90128, Palermo, Italy.
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Balamurli G, Liew AQX, Tee WW, Pervaiz S. Interplay between epigenetics, senescence and cellular redox metabolism in cancer and its therapeutic implications. Redox Biol 2024; 78:103441. [PMID: 39612910 PMCID: PMC11629570 DOI: 10.1016/j.redox.2024.103441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 11/20/2024] [Accepted: 11/22/2024] [Indexed: 12/01/2024] Open
Abstract
There is accumulating evidence indicating a close crosstalk between key molecular events regulating cell growth and proliferation, which could profoundly impact carcinogenesis and its progression. Here we focus on reviewing observations highlighting the interplay between epigenetic modifications, irreversible cell cycle arrest or senescence, and cellular redox metabolism. Epigenetic alterations, such as DNA methylation and histone modifications, dynamically influence tumour transcriptome, thereby impacting tumour phenotype, survival, growth and spread. Interestingly, the acquisition of senescent phenotype can be triggered by epigenetic changes, acting as a double-edged sword via its ability to suppress tumorigenesis or by facilitating an inflammatory milieu conducive for cancer progression. Concurrently, an aberrant redox metabolism, which is a function of the balance between reactive oxygen species (ROS) generation and intracellular anti-oxidant defences, influences signalling cascades and genomic stability in cancer cells by serving as a critical link between epigenetics and senescence. Recognizing this intricate interconnection offers a nuanced perspective for therapeutic intervention by simultaneously targeting specific epigenetic modifications, modulating senescence dynamics, and restoring redox homeostasis.
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Affiliation(s)
- Geoffrey Balamurli
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore; NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, NUS, Singapore; Chromatin Dynamics and Disease Epigenetics Lab, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), Singapore
| | - Angeline Qiu Xia Liew
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore; Integrative Science and Engineering Programme (ISEP), NUS Graduate School (NUSGS), NUS, Singapore
| | - Wee Wei Tee
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore; NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, NUS, Singapore; Chromatin Dynamics and Disease Epigenetics Lab, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), Singapore
| | - Shazib Pervaiz
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore; NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, NUS, Singapore; Integrative Science and Engineering Programme (ISEP), NUS Graduate School (NUSGS), NUS, Singapore; NUS Medicine Healthy Longevity Program, NUS, Singapore; National University Cancer Institute, National University Health System, Singapore.
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Hatawsh A, Al-Haddad RH, Okafor UG, Diab LM, Dekanoidze N, Abdulwahab AA, Mohammed OA, Doghish AS, Moussa R, Elimam H. Mitoepigenetics pathways and natural compounds: a dual approach to combatting hepatocellular carcinoma. Med Oncol 2024; 41:302. [PMID: 39465473 DOI: 10.1007/s12032-024-02538-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 10/07/2024] [Indexed: 10/29/2024]
Abstract
Hepatocellular carcinoma (HCC) is a leading liver cancer that significantly impacts global life expectancy and remains challenging to treat due to often late diagnoses. Despite advances in treatment, the prognosis is still poor, especially in advanced stages. Studies have pointed out that investigations into the molecular mechanisms underlying HCC, including mitochondrial dysfunction and epigenetic regulators, are potentially important targets for diagnosis and therapy. Mitoepigenetics, or the epigenetic modifications of mitochondrial DNA, have drawn wide attention for their role in HCC progression. Besides, molecular biomarkers such as mitochondrial DNA alterations and non-coding RNAs showed early diagnosis and prognosis potential. Additionally, natural compounds like alkaloids, resveratrol, curcumin, and flavonoids show promise in HCC show promise in modulating mitochondrial and epigenetic pathways involved in cancer-related processes. This review discusses how mitochondrial dysfunction and epigenetic modifications, especially mitoepigenetics, influence HCC and delves into the potential of natural products as new adjuvant treatments against HCC.
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Affiliation(s)
- Abdulrahman Hatawsh
- Biotechnology School, Nile University, 26th of July Corridor, Sheikh Zayed City, Giza, 12588, Egypt
| | - Roya Hadi Al-Haddad
- Research and Technology Center of Environment, Water and Renewable Energy, Scientific Research Commission, Baghdad, Iraq
| | | | - Lamis M Diab
- Department of Medical Biochemistry, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | | | | | - Osama A Mohammed
- Department of Pharmacology, College of Medicine, University of Bisha, 61922, Bisha, Saudi Arabia
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo, 11829, Egypt.
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo, 11231, Egypt.
| | - Rewan Moussa
- Faculty of Medicine, Helwan University, Helwan, Cairo, 11795, Egypt
| | - Hanan Elimam
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Sādāt, 32897, Egypt.
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Halter K, Chen J, Priklopil T, Monfort A, Wutz A. Cdk8 and Hira mutations trigger X chromosome elimination in naive female hybrid mouse embryonic stem cells. Chromosome Res 2024; 32:12. [PMID: 39390295 PMCID: PMC11467062 DOI: 10.1007/s10577-024-09756-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 09/11/2024] [Accepted: 09/18/2024] [Indexed: 10/12/2024]
Abstract
Mouse embryonic stem cells (ESCs) possess a pluripotent developmental potential and a stable karyotype. An exception is the frequent loss of one X chromosome in female ESCs derived from inbred mice. In contrast, female ESCs from crosses between different Mus musculus subspecies often maintain two X chromosomes and can model X chromosome inactivation. Here we report that combined mutations of Hira and Cdk8 induce rapid loss of one X chromosome in a Mus musculus castaneus hybrid female ESC line that originally maintains two X chromosomes. We show that MEK1 inhibition, which is used for culturing naive pluripotent ESCs is sufficient to induce X chromosome loss. In conventional ESC media, Hira and Cdk8 mutant ESCs maintain both X chromosomes. Induction of X chromosome loss by switching to naive culture media allows us to perform kinetic measurements for calculating the chromosome loss rate. Our analysis shows that X chromosome loss is not explained by selection of XO cells, but likely driven by a process of chromosome elimination. We show that elimination of the X chromosome occurs with a rate of 0.3% per cell per division, which exceeds reported autosomal loss rates by 3 orders of magnitude. We show that chromosomes 8 and 11 are stably maintained. Notably, Xist expression from one of the two X chromosomes rescues X chromosomal instability in ΔHiraΔCdk8 ESCs. Our study defines mutations of Hira and Cdk8 as molecular drivers for X chromosome elimination in naive female ESCs and describes a cell system for elucidating the underlying mechanism.
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Affiliation(s)
- Kevin Halter
- Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology, ETH Hönggerberg, Zurich, Switzerland
| | - Jingyi Chen
- Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology, ETH Hönggerberg, Zurich, Switzerland
| | - Tadeas Priklopil
- Department of Biology and Department of Environmental Systems Science, ETH Zurich, Zurich, Switzerland
| | - Asun Monfort
- Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology, ETH Hönggerberg, Zurich, Switzerland
| | - Anton Wutz
- Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology, ETH Hönggerberg, Zurich, Switzerland.
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Zhao Y, Wan K, Wang J, Wang S, Chang Y, Du Z, Zhang L, Dong L, Zhou D, Zhang W, Wang S, Yang Q. DNA methylation and gene expression profiling reveal potential association of retinol metabolism related genes with hepatocellular carcinoma development. PeerJ 2024; 12:e17916. [PMID: 39193514 PMCID: PMC11348899 DOI: 10.7717/peerj.17916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 07/23/2024] [Indexed: 08/29/2024] Open
Abstract
Background Aberrant DNA methylation patterns play a critical role in the development of hepatocellular carcinoma (HCC). However, the molecular mechanisms associated with these aberrantly methylated genes remain unclear. This study aimed to comprehensively investigate the methylation-driven gene expression alterations in HCC using a multi-omics dataset. Methods Whole genome bisulfite sequencing (WGBS) and RNA sequencing (RNA-seq) techniques were used to assess the methylation and gene expression profiles of HCC tissues (HCCs) and normal adjacent tissues (NATs). The candidate genes' potential function was further investigated using single-cell RNA sequencing (scRNA seq) data. Results We observed widespread hypomethylation in HCCs compared to NATs. Methylation levels in distinct genomic regions exhibited significant differences between HCCs and NATs. We identified 247,632 differentially methylated regions (DMRs) and 4,926 differentially expressed genes (DEGs) between HCCs and NATs. Integrated analysis of DNA methylation and RNA-seq data identified 987 methylation-driven candidate genes, with 970 showing upregulation and 17 showing downregulation. Four genes involved in the retinol metabolic pathway, namely ADH1A, CYP2A6, CYP2C8, and CYP2C19, were identified as hyper-downregulated genes. Their expression levels could stratify HCCs into three subgroups with distinct survival outcomes, immune cell infiltration, and tumor microenvironments. Validation of these findings in an independent dataset yielded similar outcomes, confirming the high concordance and potential prognostic value of these genes. ScRNA seq data revealed the low expression of these genes in immune cells, emphasizing their role in promoting malignant cell proliferation and migration. In conclusion, this study provides insights into the molecular characteristics of HCC, revealing the involvement of retinol metabolism-related genes in the development and progression of HCC. These findings have implications for HCC diagnosis, prognosis prediction, and the development of therapeutic targets.
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Affiliation(s)
- Yanteng Zhao
- Department of Transfusion, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Kangkang Wan
- Wuhan Ammunition Life-tech Company, Ltd., CN, Wuhan, Hubei Province, China
| | - Jing Wang
- Department of Transfusion, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Shuya Wang
- Department of Transfusion, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Yanli Chang
- Department of Transfusion, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Zhuanyun Du
- Department of Transfusion, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Lianglu Zhang
- Wuhan Ammunition Life-tech Company, Ltd., CN, Wuhan, Hubei Province, China
| | - Lanlan Dong
- Wuhan Ammunition Life-tech Company, Ltd., CN, Wuhan, Hubei Province, China
| | - Dihan Zhou
- Wuhan Ammunition Life-tech Company, Ltd., CN, Wuhan, Hubei Province, China
| | - Wei Zhang
- Wuhan Ammunition Life-tech Company, Ltd., CN, Wuhan, Hubei Province, China
| | - Shaochi Wang
- Center for Translational Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Qiankun Yang
- Department of Transfusion, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
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Newsham I, Sendera M, Jammula SG, Samarajiwa SA. Early detection and diagnosis of cancer with interpretable machine learning to uncover cancer-specific DNA methylation patterns. Biol Methods Protoc 2024; 9:bpae028. [PMID: 38903861 PMCID: PMC11186673 DOI: 10.1093/biomethods/bpae028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 03/30/2024] [Accepted: 04/29/2024] [Indexed: 06/22/2024] Open
Abstract
Cancer, a collection of more than two hundred different diseases, remains a leading cause of morbidity and mortality worldwide. Usually detected at the advanced stages of disease, metastatic cancer accounts for 90% of cancer-associated deaths. Therefore, the early detection of cancer, combined with current therapies, would have a significant impact on survival and treatment of various cancer types. Epigenetic changes such as DNA methylation are some of the early events underlying carcinogenesis. Here, we report on an interpretable machine learning model that can classify 13 cancer types as well as non-cancer tissue samples using only DNA methylome data, with 98.2% accuracy. We utilize the features identified by this model to develop EMethylNET, a robust model consisting of an XGBoost model that provides information to a deep neural network that can generalize to independent data sets. We also demonstrate that the methylation-associated genomic loci detected by the classifier are associated with genes, pathways and networks involved in cancer, providing insights into the epigenomic regulation of carcinogenesis.
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Affiliation(s)
- Izzy Newsham
- MRC Cancer Unit, University of Cambridge, Cambridge, CB2 0XZ, United Kingdom
- MRC Biostatistics Unit, University of Cambridge, Cambridge, CB2 0SR, United Kingdom
| | - Marcin Sendera
- MRC Cancer Unit, University of Cambridge, Cambridge, CB2 0XZ, United Kingdom
- Jagiellonian University, Faculty of Mathematics and Computer Science, 30-348 Kraków, Poland
| | - Sri Ganesh Jammula
- CRUK Cambridge Institute, University of Cambridge, Cambridge, CB2 0RE, United Kingdom
- MedGenome labs, Bengaluru, 560099, India
| | - Shamith A Samarajiwa
- MRC Cancer Unit, University of Cambridge, Cambridge, CB2 0XZ, United Kingdom
- Imperial College London, Hammersmith Campus, London, W12 0NN, United Kingdom
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13
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Lim GM, Maharajan N, Cho GW. How calorie restriction slows aging: an epigenetic perspective. J Mol Med (Berl) 2024; 102:629-640. [PMID: 38456926 DOI: 10.1007/s00109-024-02430-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 01/14/2024] [Accepted: 02/07/2024] [Indexed: 03/09/2024]
Abstract
Genomic instability and epigenetic alterations are some of the prominent factors affecting aging. Age-related heterochromatin loss and decreased whole-genome DNA methylation are associated with abnormal gene expression, leading to diseases and genomic instability. Modulation of these epigenetic changes is crucial for preserving genomic integrity and controlling cellular identity is important for slowing the aging process. Numerous studies have shown that caloric restriction is the gold standard for promoting longevity and healthy aging in various species ranging from rodents to primates. It can be inferred that delaying of aging through the main effector such as calorie restriction is involved in cellular identity and epigenetic modification. Thus, an understanding of aging through calorie restriction may seek a more in-depth understanding. In this review, we discuss how caloric restriction promotes longevity and healthy aging through genomic stability and epigenetic alterations. We have also highlighted how the effectors of caloric restriction are involved in modulating the chromatin-based barriers.
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Affiliation(s)
- Gyeong Min Lim
- Department of Biological Science, College of Natural Science, Chosun University, 309 Pilmun-Daero, Dong-Gu, Gwangju, 61452, Republic of Korea
- BK21 FOUR Education Research Group for Age-Associated Disorder Control Technology, Department of Integrative Biological Science, Chosun University, Gwangju, 61452, Republic of Korea
| | - Nagarajan Maharajan
- The Department of Obstetrics & Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Gwang-Won Cho
- Department of Biological Science, College of Natural Science, Chosun University, 309 Pilmun-Daero, Dong-Gu, Gwangju, 61452, Republic of Korea.
- BK21 FOUR Education Research Group for Age-Associated Disorder Control Technology, Department of Integrative Biological Science, Chosun University, Gwangju, 61452, Republic of Korea.
- The Basic Science Institute of Chosun University, Chosun University, Gwangju, 61452, Republic of Korea.
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14
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Harachi M, Masui K, Shimizu E, Murakami K, Onizuka H, Muragaki Y, Kawamata T, Nakayama H, Miyata M, Komori T, Cavenee WK, Mischel PS, Kurata A, Shibata N. DNA hypomethylator phenotype reprograms glutamatergic network in receptor tyrosine kinase gene-mutated glioblastoma. Acta Neuropathol Commun 2024; 12:40. [PMID: 38481314 PMCID: PMC10935831 DOI: 10.1186/s40478-024-01750-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Accepted: 02/25/2024] [Indexed: 03/17/2024] Open
Abstract
DNA methylation is crucial for chromatin structure and gene expression and its aberrancies, including the global "hypomethylator phenotype", are associated with cancer. Here we show that an underlying mechanism for this phenotype in the large proportion of the highly lethal brain tumor glioblastoma (GBM) carrying receptor tyrosine kinase gene mutations, involves the mechanistic target of rapamycin complex 2 (mTORC2), that is critical for growth factor signaling. In this scenario, mTORC2 suppresses the expression of the de novo DNA methyltransferase (DNMT3A) thereby inducing genome-wide DNA hypomethylation. Mechanistically, mTORC2 facilitates a redistribution of EZH2 histone methyltransferase into the promoter region of DNMT3A, and epigenetically represses the expression of DNA methyltransferase. Integrated analyses in both orthotopic mouse models and clinical GBM samples indicate that the DNA hypomethylator phenotype consistently reprograms a glutamate metabolism network, eventually driving GBM cell invasion and survival. These results nominate mTORC2 as a novel regulator of DNA hypomethylation in cancer and an exploitable target against cancer-promoting epigenetics.
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Affiliation(s)
- Mio Harachi
- Department of Pathology, Tokyo Women's Medical University, Shinjuku, Tokyo, 162-8666, Japan
- Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, 230-0045, Japan
| | - Kenta Masui
- Department of Pathology, Tokyo Women's Medical University, Shinjuku, Tokyo, 162-8666, Japan.
| | - Erika Shimizu
- Department of Pathology, Tokyo Women's Medical University, Shinjuku, Tokyo, 162-8666, Japan
| | - Kumiko Murakami
- Department of Pathology, Tokyo Women's Medical University, Shinjuku, Tokyo, 162-8666, Japan
| | - Hiromi Onizuka
- Department of Pathology, Tokyo Women's Medical University, Shinjuku, Tokyo, 162-8666, Japan
| | - Yoshihiro Muragaki
- Department of Neurosurgery, Tokyo Women's Medical University, Shinjuku, Tokyo, 162-8666, Japan
- Center for Advanced Medical Engineering Research and Development, Kobe University, Kobe, Hyogo, 650-0047, Japan
| | - Takakazu Kawamata
- Department of Neurosurgery, Tokyo Women's Medical University, Shinjuku, Tokyo, 162-8666, Japan
| | - Hisako Nakayama
- Department of Physiology, Tokyo Women's Medical University, Shinjuku, Tokyo, 162-8666, Japan
| | - Mariko Miyata
- Department of Physiology, Tokyo Women's Medical University, Shinjuku, Tokyo, 162-8666, Japan
| | - Takashi Komori
- Department of Neuropathology, Tokyo Metropolitan Neurological Hospital, Musashinodai, Tokyo, 156-8506, Japan
| | - Webster K Cavenee
- Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA, 92093, USA
| | - Paul S Mischel
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Atsushi Kurata
- Department of Pathology, Tokyo Women's Medical University, Shinjuku, Tokyo, 162-8666, Japan
| | - Noriyuki Shibata
- Department of Pathology, Tokyo Women's Medical University, Shinjuku, Tokyo, 162-8666, Japan
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15
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Shim H, Jang K, Bang YH, Chu HBK, Kang J, Lee JY, Cho S, Lee HS, Jeon J, Hwang T, Joe S, Lim J, Choi JH, Joo EH, Park K, Moon JH, Han KY, Hong Y, Lee WY, Kim HC, Yun SH, Cho YB, Park YA, Huh JW, Shin JK, Pyo DH, Hong H, Lee HO, Park WY, Yang JO, Kim YJ. Comprehensive profiling of DNA methylation in Korean patients with colorectal cancer. BMB Rep 2024; 57:110-115. [PMID: 37605617 PMCID: PMC10910091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 06/27/2023] [Accepted: 08/21/2023] [Indexed: 08/23/2023] Open
Abstract
Alterations in DNA methylation play an important pathophysiological role in the development and progression of colorectal cancer. We comprehensively profiled DNA methylation alterations in 165 Korean patients with colorectal cancer (CRC), and conducted an in-depth investigation of cancer-specific methylation patterns. Our analysis of the tumor samples revealed a significant presence of hypomethylated probes, primarily within the gene body regions; few hypermethylated sites were observed, which were mostly enriched in promoter-like and CpG island regions. The CpG Island Methylator PhenotypeHigh (CIMP-H) exhibited notable enrichment of microsatellite instability-high (MSI-H). Additionally, our findings indicated a significant correlation between methylation of the MLH1 gene and MSI-H status. Furthermore, we found that the CIMP-H had a higher tendency to affect the right-side of the colon tissues and was slightly more prevalent among older patients. Through our methylome profile analysis, we successfully verified the thylation patterns and clinical characteristics of Korean patients with CRC. This valuable dataset lays a strong foundation for exploring novel molecular insights and potential therapeutic targets for the treatment of CRC. [BMB Reports 2024; 57(2): 110-115].
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Affiliation(s)
- Hyeran Shim
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Kiwon Jang
- Korea Bioinformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
| | - Yeong Hak Bang
- Department of Digital Health, Samsung Advanced Institute for Health Science & Technology (SAIHST), Sungkyunkwan University, Seoul 06355, Korea
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
| | - Hoang Bao Khanh Chu
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Jisun Kang
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Jin-Young Lee
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Sheehyun Cho
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Hong Seok Lee
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Jongbum Jeon
- Korea Bioinformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
| | - Taeyeon Hwang
- Korea Bioinformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
| | - Soobok Joe
- Korea Bioinformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
| | - Jinyeong Lim
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 06355, Korea
| | - Ji-Hye Choi
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 06355, Korea
| | - Eun Hye Joo
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 06355, Korea
| | - Kyunghee Park
- Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea, Seoul 04779, Korea
| | - Ji Hwan Moon
- Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea, Seoul 04779, Korea
| | - Kyung Yeon Han
- Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea, Seoul 04779, Korea
| | - Yourae Hong
- Department of Oncology, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium, Seoul 04779, Korea
| | - Woo Yong Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
| | - Hee Cheol Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
| | - Seong Hyeon Yun
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
| | - Yong Beom Cho
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
| | - Yoon Ah Park
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
| | - Jung Wook Huh
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
| | - Jung Kyong Shin
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
| | - Dae Hee Pyo
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
| | - Hyekyung Hong
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
| | - Hae-Ock Lee
- Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
- Department of Biomedicine and Health Sciences, Graduate School, The Catholic University of Korea, Seoul 06591, Korea
| | - Woong-Yang Park
- Department of Digital Health, Samsung Advanced Institute for Health Science & Technology (SAIHST), Sungkyunkwan University, Seoul 06355, Korea
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 06355, Korea
- Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea, Seoul 04779, Korea
| | - Jin Ok Yang
- Korea Bioinformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
| | - Young-Joon Kim
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
- LepiDyne Co., Ltd., Seoul 04779, Korea
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16
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David L, Onaciu A, Toma V, Borșa RM, Moldovan C, Țigu AB, Cenariu D, Șimon I, Știufiuc GF, Carasevici E, Drăgoi B, Tomuleasa C, Știufiuc RI. Understanding DNA Epigenetics by Means of Raman/SERS Analysis for Cancer Detection. BIOSENSORS 2024; 14:41. [PMID: 38248418 PMCID: PMC10813173 DOI: 10.3390/bios14010041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 01/09/2024] [Accepted: 01/10/2024] [Indexed: 01/23/2024]
Abstract
This study delves into the intricate interaction between DNA and nanosystems, exploring its potential implications for biomedical applications. The focus lies in understanding the adsorption geometry of DNA when in proximity to plasmonic nanoparticles, utilizing ultrasensitive vibrational spectroscopy techniques. Employing a combined Raman-SERS analysis, we conducted an in-depth examination to clarify the molecular geometry of interactions between DNA and silver nanoparticles. Our findings also reveal distinctive spectral features regarding DNA samples due to their distinctive genome stability. To understand the subtle differences occurring between normal and cancerous DNA, their thermal stability was investigated by means of SERS measurement performed before and after a thermal treatment at 94 °C. It was proved that thermal treatment did not affect DNA integrity in the case of normal cells. On the other hand, due to epimutation pattern that characterizes cancerous DNA, variations between spectra recorded before and after heat treatment were observed, suggesting genome instability. These findings highlight the potential of DNA analysis using SERS for cancer detection. They demonstrate the applicability of this approach to overcoming challenges associated with low DNA concentrations (e.g., circulating tumor DNA) that occur in biofluids. In conclusion, this research contributes significant insights into the nanoscale behavior of DNA in the presence of nanosystems.
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Affiliation(s)
- Luca David
- Faculty of Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania;
| | - Anca Onaciu
- MedFuture—Research Center for Advanced Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (A.O.); (V.T.); (R.-M.B.); (C.M.); (A.-B.Ț.); (D.C.); (C.T.)
- Department of Pharmaceutical Physics & Biophysics, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania
| | - Valentin Toma
- MedFuture—Research Center for Advanced Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (A.O.); (V.T.); (R.-M.B.); (C.M.); (A.-B.Ț.); (D.C.); (C.T.)
| | - Rareș-Mario Borșa
- MedFuture—Research Center for Advanced Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (A.O.); (V.T.); (R.-M.B.); (C.M.); (A.-B.Ț.); (D.C.); (C.T.)
- Department of Maxillofacial Surgery and Implantology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania
| | - Cristian Moldovan
- MedFuture—Research Center for Advanced Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (A.O.); (V.T.); (R.-M.B.); (C.M.); (A.-B.Ț.); (D.C.); (C.T.)
- Department of Pharmaceutical Physics & Biophysics, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania
| | - Adrian-Bogdan Țigu
- MedFuture—Research Center for Advanced Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (A.O.); (V.T.); (R.-M.B.); (C.M.); (A.-B.Ț.); (D.C.); (C.T.)
| | - Diana Cenariu
- MedFuture—Research Center for Advanced Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (A.O.); (V.T.); (R.-M.B.); (C.M.); (A.-B.Ț.); (D.C.); (C.T.)
| | - Ioan Șimon
- Department of Surgery, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania;
| | | | - Eugen Carasevici
- Nanotechnology Laboratory, TRANSCEND Research Center, Regional Institute of Oncology, 700483 Iasi, Romania; (E.C.); (B.D.)
| | - Brîndușa Drăgoi
- Nanotechnology Laboratory, TRANSCEND Research Center, Regional Institute of Oncology, 700483 Iasi, Romania; (E.C.); (B.D.)
| | - Ciprian Tomuleasa
- MedFuture—Research Center for Advanced Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (A.O.); (V.T.); (R.-M.B.); (C.M.); (A.-B.Ț.); (D.C.); (C.T.)
- Department of Hematology, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania
- Department of Hematology, “Ion Chiricuta” Clinical Cancer Center, 400015 Cluj-Napoca, Romania
| | - Rareș-Ionuț Știufiuc
- MedFuture—Research Center for Advanced Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (A.O.); (V.T.); (R.-M.B.); (C.M.); (A.-B.Ț.); (D.C.); (C.T.)
- Department of Pharmaceutical Physics & Biophysics, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania
- Nanotechnology Laboratory, TRANSCEND Research Center, Regional Institute of Oncology, 700483 Iasi, Romania; (E.C.); (B.D.)
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17
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Łuczkowska K, Kulig P, Baumert B, Machaliński B. Vitamin D and K Supplementation Is Associated with Changes in the Methylation Profile of U266-Multiple Myeloma Cells, Influencing the Proliferative Potential and Resistance to Bortezomib. Nutrients 2023; 16:142. [PMID: 38201971 PMCID: PMC10780809 DOI: 10.3390/nu16010142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 12/28/2023] [Accepted: 12/28/2023] [Indexed: 01/12/2024] Open
Abstract
Multiple myeloma (MM) is a plasma cell malignancy that, despite recent advances in therapy, continues to pose a major challenge to hematologists. Currently, different classes of drugs are applied to treat MM, among others, proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies. Most of them participate in an interplay with the immune system, hijacking its effector functions and redirecting them to anti-MM activity. Therefore, adjuvant therapies boosting the immune system may be potentially beneficial in MM therapy. Vitamin D (VD) and vitamin K (VK) have multiple so called "non-classical" actions. They exhibit various anti-inflammatory and anti-cancer properties. In this paper, we investigated the influence of VD and VK on epigenetic alterations associated with the proliferative potential of MM cells and the development of BTZ resistance. Our results showed that the development of BTZ resistance is associated with a global decrease in DNA methylation. On the contrary, both control MM cells and BTZ-resistant MM cells exposed to VD alone and to the combination of VD and VK exhibit a global increase in methylation. In conclusion, VD and VK in vitro have the potential to induce epigenetic changes that reduce the proliferative potential of plasma cells and may at least partially prevent the development of resistance to BTZ. However, further ex vivo and in vivo studies are needed to confirm the results and introduce new supplementation recommendations as part of adjuvant therapy.
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Affiliation(s)
- Karolina Łuczkowska
- Department of General Pathology, Pomeranian Medical University, 70-111 Szczecin, Poland; (P.K.); (B.M.)
| | - Piotr Kulig
- Department of General Pathology, Pomeranian Medical University, 70-111 Szczecin, Poland; (P.K.); (B.M.)
| | - Bartłomiej Baumert
- Department of Hematology and Transplantology, Pomeranian Medical University, 71-252 Szczecin, Poland
| | - Bogusław Machaliński
- Department of General Pathology, Pomeranian Medical University, 70-111 Szczecin, Poland; (P.K.); (B.M.)
- Department of Hematology and Transplantology, Pomeranian Medical University, 71-252 Szczecin, Poland
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18
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Bao-Caamano A, Costa-Fraga N, Cayrefourcq L, Rodriguez-Casanova A, Muinelo-Romay L, López-López R, Alix-Panabières C, Díaz-Lagares A. Epigenomic reprogramming of therapy-resistant circulating tumor cells in colon cancer. Front Cell Dev Biol 2023; 11:1291179. [PMID: 38188020 PMCID: PMC10771310 DOI: 10.3389/fcell.2023.1291179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 11/28/2023] [Indexed: 01/09/2024] Open
Abstract
Therapy resistance is a major challenge in colorectal cancer management. Epigenetic changes, such as DNA methylation, in tumor cells are involved in the development of acquired resistance during treatment. Here, we characterized the DNA methylation landscape of colon circulating tumor cells (CTCs) during cancer progression and therapy resistance development. To this aim, we used nine permanent CTC lines that were derived from peripheral blood samples of a patient with metastatic colon cancer collected before treatment initiation (CTC-MCC-41) and during treatment and cancer progression (CTC-MCC-41.4 and CTC-MCC-41.5 [A-G]). We analyzed the DNA methylome of these nine CTC lines using EPIC arrays and also assessed the association between DNA methylation and gene expression profiles. We confirmed DNA methylation and gene expression results by pyrosequencing and RT-qPCR, respectively. The global DNA methylation profiles were different in the pre-treatment CTC line and in CTC lines derived during therapy resistance development. These resistant CTC lines were characterized by a more hypomethylated profile compared with the pre-treatment CTC line. Most of the observed DNA methylation differences were localized at CpG-poor regions and some in CpG islands, shore regions and promoters. We identified a distinctive DNA methylation signature that clearly differentiated the pre-treatment CTC line from the others. Of note, the genes involved in this signature were associated with cancer-relevant pathways, including PI3K/AKT, MAPK, Wnt signaling and metabolism. We identified several epigenetically deregulated genes associated with therapy resistance in CTCs, such as AP2M1. Our results bring new knowledge on the epigenomic landscape of therapy-resistant CTCs, providing novel mechanisms of resistance as well as potential biomarkers and therapeutic targets for advanced CRC management.
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Affiliation(s)
- Aida Bao-Caamano
- Epigenomics Unit, Cancer Epigenomics, Translational Medical Oncology Group (ONCOMET), Health Research Institute of Santiago de Compostela (IDIS), University Clinical Hospital of Santiago (CHUS/SERGAS), Santiago de Compostela, Spain
- Universidade de Santiago de Compostela (USC), Santiago de Compostela, Spain
- Galician Precision Oncology Research Group (ONCOGAL), Medicine and Dentistry School, Universidade de Santiago de Compostela (USC), Santiago de Compostela, Spain
| | - Nicolás Costa-Fraga
- Epigenomics Unit, Cancer Epigenomics, Translational Medical Oncology Group (ONCOMET), Health Research Institute of Santiago de Compostela (IDIS), University Clinical Hospital of Santiago (CHUS/SERGAS), Santiago de Compostela, Spain
- Universidade de Santiago de Compostela (USC), Santiago de Compostela, Spain
- Galician Precision Oncology Research Group (ONCOGAL), Medicine and Dentistry School, Universidade de Santiago de Compostela (USC), Santiago de Compostela, Spain
| | - Laure Cayrefourcq
- Laboratory of Rare Human Circulating Cells–The Liquid Biopsy Lab, University Medical Center of Montpellier, Montpellier, France
- Centre for Ecological and Evolutionary Cancer Research, Maladies infectieuses et vecteurs: génétique, èvolution et contrôle, University of Montpellier, CNRS, IRD, Montpellier, France
| | - Aitor Rodriguez-Casanova
- Epigenomics Unit, Cancer Epigenomics, Translational Medical Oncology Group (ONCOMET), Health Research Institute of Santiago de Compostela (IDIS), University Clinical Hospital of Santiago (CHUS/SERGAS), Santiago de Compostela, Spain
- Universidade de Santiago de Compostela (USC), Santiago de Compostela, Spain
- Galician Precision Oncology Research Group (ONCOGAL), Medicine and Dentistry School, Universidade de Santiago de Compostela (USC), Santiago de Compostela, Spain
- Roche-Chus Joint Unit, Translational Medical Oncology Group (ONCOMET), Health Research Institute of Santiago (IDIS), Santiago de Compostela, Spain
| | - Laura Muinelo-Romay
- Galician Precision Oncology Research Group (ONCOGAL), Medicine and Dentistry School, Universidade de Santiago de Compostela (USC), Santiago de Compostela, Spain
- Liquid Biopsy Analysis Unit, Translational Medical Oncology Group (ONCOMET), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), ISCIII, Madrid, Spain
| | - Rafael López-López
- Galician Precision Oncology Research Group (ONCOGAL), Medicine and Dentistry School, Universidade de Santiago de Compostela (USC), Santiago de Compostela, Spain
- Roche-Chus Joint Unit, Translational Medical Oncology Group (ONCOMET), Health Research Institute of Santiago (IDIS), Santiago de Compostela, Spain
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), ISCIII, Madrid, Spain
- Translational Medical Oncology Group (ONCOMET), Health Research Institute of Santiago de Compostela (IDIS), University Clinical Hospital of Santiago (CHUS/SERGAS), Santiago de Compostela, Spain
| | - Catherine Alix-Panabières
- Laboratory of Rare Human Circulating Cells–The Liquid Biopsy Lab, University Medical Center of Montpellier, Montpellier, France
- Centre for Ecological and Evolutionary Cancer Research, Maladies infectieuses et vecteurs: génétique, èvolution et contrôle, University of Montpellier, CNRS, IRD, Montpellier, France
- European Liquid Biopsy Society (ELBS), Hamburg, Germany
| | - Angel Díaz-Lagares
- Epigenomics Unit, Cancer Epigenomics, Translational Medical Oncology Group (ONCOMET), Health Research Institute of Santiago de Compostela (IDIS), University Clinical Hospital of Santiago (CHUS/SERGAS), Santiago de Compostela, Spain
- Galician Precision Oncology Research Group (ONCOGAL), Medicine and Dentistry School, Universidade de Santiago de Compostela (USC), Santiago de Compostela, Spain
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), ISCIII, Madrid, Spain
- Department of Clinical Analysis, University Hospital Complex of Santiago de Compostela (CHUS), Santiago de Compostela, Spain
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19
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Yang S, Li K, Zhang J, Liu J, Liu L, Tan Y, Xu C. Link between m6A modification and infiltration characterization of tumor microenvironment in lung adenocarcinoma. Exp Biol Med (Maywood) 2023; 248:2273-2288. [PMID: 38166412 PMCID: PMC10903232 DOI: 10.1177/15353702231214266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 08/30/2023] [Indexed: 01/04/2024] Open
Abstract
N6-methyladenosine (m6A) RNA methylation plays a pivotal role in immune responses and the onset and advancement of cancer. Nonetheless, the precise impact of m6A modification in lung adenocarcinoma (LUAD) and its associated tumor microenvironment (TME) remains to be fully elucidated. Here, we distinguished distinct m6A modification patterns within two separate LUAD cohorts using a set of 21 m6A regulators. The TME characteristics associated with these two patterns align with the immune-inflamed and immune-excluded phenotypes, respectively. We identified 2064 m6A-related genes, which were used as a basis to divide all LUAD samples into three distinct m6A gene clusters. We applied a scoring system to evaluate the m6A gene signature of the m6A modification pattern in individual patients. To authenticate the categorization significance of m6A modification patterns, we established a correlation between m6A score and TME infiltration profiling, tumor somatic mutations, and responses to immunotherapy. A high level of m6A modification may be associated with the aggressiveness and poor prognosis of LUAD. Further studies should investigate the mechanism of action of m6A regulators and m6A-related genes to improve the diagnosis and treatment of patients with LUAD.
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Affiliation(s)
- Sha Yang
- Guizhou University Medical College, Guiyang 550025, China
| | - Ke Li
- Department of Respiratory and Critical Care Medicine, Guizhou Provincial People’s Hospital, Guiyang 550002, China
| | - Jiqin Zhang
- Department of Anesthesiology, Guizhou Provincial People’s Hospital, Guiyang 550002, China
| | - Jian Liu
- Department of Neurosurgery, Guizhou Provincial People’s Hospital, Guiyang 550002, China
| | - Lin Liu
- Department of Respiratory and Critical Care Medicine, Guizhou Provincial People’s Hospital, Guiyang 550002, China
| | - Ying Tan
- Department of Neurosurgery, Guizhou Provincial People’s Hospital, Guiyang 550002, China
- Department of Thoracic Surgery, Guizhou Provincial People’s Hospital, Guiyang 550002, China
| | - Chuan Xu
- Department of Thoracic Surgery, Guizhou Provincial People’s Hospital, Guiyang 550002, China
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Choudhury H, Pandey M, Saravanan V, Mun ATY, Bhattamisra SK, Parikh A, Garg S, Gorain B. Recent progress of targeted nanocarriers in diagnostic, therapeutic, and theranostic applications in colorectal cancer. BIOMATERIALS ADVANCES 2023; 153:213556. [PMID: 37478770 DOI: 10.1016/j.bioadv.2023.213556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 06/28/2023] [Accepted: 07/06/2023] [Indexed: 07/23/2023]
Abstract
Cancer at the lower end of the digestive tract, colorectal cancer (CRC), starts with asymptomatic polyps, which can be diagnosed as cancer at a later stage. It is the fourth leading cause of malignancy-associated mortality worldwide. Despite progress in conventional treatment strategies, the possibility to overcome the mortality and morbidity issues with the enhancement of the lifespan of CRC patients is limited. With the advent of nanocarrier-based drug delivery systems, a promising revolution has been made in diagnosis, treatment, and theranostic purposes for cancer management. Herein, we reviewed the progress of miniaturized nanocarriers, such as liposomes, niosomes, solid lipid nanoparticles, micelles, and polymeric nanoparticles, employed in passive and active targeting and their role in theranostic applications in CRC. With this novel scope, the diagnosis and treatment of CRC have proceeded to the forefront of innovation, where specific characteristics of the nanocarriers, such as processability, flexibility in developing precise architecture, improved circulation, site-specific delivery, and rapid response, facilitate the management of cancer patients. Furthermore, surface-engineered technologies for the nanocarriers could involve receptor-mediated deliveries towards the overexpressed receptors on the CRC microenvironment. Moreover, the potential of clinical translation of these targeted miniaturized formulations as well as the possible limitations and barriers that could impact this translation into clinical practice were highlighted. The advancement of these newest developments in clinical research and progress into the commercialization stage gives hope for a better tomorrow.
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Affiliation(s)
- Hira Choudhury
- Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Manisha Pandey
- Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia.
| | - Vilashini Saravanan
- Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Amanda Tan Yee Mun
- Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Subrat Kumar Bhattamisra
- Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Ankit Parikh
- Centre for Pharmaceutical Innovation (CPI), Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia
| | - Sanjay Garg
- Centre for Pharmaceutical Innovation (CPI), Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia
| | - Bapi Gorain
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India.
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21
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Wang J, Niu Y, Yang M, Shu L, Wang H, Wu X, He Y, Chen P, Zhong G, Tang Z, Zhang S, Guo Q, Wang Y, Yu L, Gou D. Altered cfDNA fragmentation profile in hypomethylated regions as diagnostic markers in breast cancer. Epigenetics Chromatin 2023; 16:33. [PMID: 37740218 PMCID: PMC10517480 DOI: 10.1186/s13072-023-00508-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 09/15/2023] [Indexed: 09/24/2023] Open
Abstract
BACKGROUND Breast cancer, the most common malignancy in women worldwide, has been proven to have both altered plasma cell-free DNA (cfDNA) methylation and fragmentation profiles. Nevertheless, simultaneously detecting both of them for breast cancer diagnosis has never been reported. Moreover, although fragmentation pattern of cfDNA is determined by nuclease digestion of chromatin, structure of which may be affected by DNA methylation, whether cfDNA methylation and fragmentation are biologically related or not still remains unclear. METHODS Improved cfMeDIP-seq were utilized to characterize both cfDNA methylation and fragmentation profiles in 49 plasma samples from both healthy individuals and patients with breast cancer. The feasibility of using cfDNA fragmentation profile in hypo- and hypermethylated regions as diagnostic markers for breast cancer was evaluated. RESULTS Mean size of cfDNA fragments (100-220 bp) mapped to hypomethylated regions decreased more in patients with breast cancer (4.60 bp, 172.33 to 167.73 bp) than in healthy individuals (2.87 bp, 174.54 to 171.67 bp). Furthermore, proportion of short cfDNA fragments (100-150 bp) in hypomethylated regions when compared with it in hypermethylated regions was found to increase more in patients with breast cancer in two independent discovery cohort. The feasibility of using abnormality of short cfDNA fragments ratio in hypomethylated genomic regions for breast cancer diagnosis in validation cohort was evaluated. 7 out of 11 patients were detected as having breast cancer (63.6% sensitivity), whereas no healthy individuals were mis-detected (100% specificity). CONCLUSION We identified enriched short cfDNA fragments after 5mC-immunoprecipitation (IP) in patients with breast cancer, and demonstrated the enriched short cfDNA fragments might originated from hypomethylated genomic regions. Furthermore, we proved the feasibility of using differentially methylated regions (DMRs)-dependent cfDNA fragmentation profile for breast cancer diagnosis.
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Affiliation(s)
- Jun Wang
- Shenzhen Key Laboratory of Microbial Genetic Engineering, Vascular Disease Research Center, College of Life Sciences and Oceanography, Guangdong Provincial Key Laboratory of Regional Immunity and Disease, Carson International Cancer Center, School of Medicine, Shenzhen University, Shenzhen, 518060, China
| | - Yanqin Niu
- Shenzhen Key Laboratory of Microbial Genetic Engineering, Vascular Disease Research Center, College of Life Sciences and Oceanography, Guangdong Provincial Key Laboratory of Regional Immunity and Disease, Carson International Cancer Center, School of Medicine, Shenzhen University, Shenzhen, 518060, China
| | - Ming Yang
- Shenzhen Key Laboratory of Microbial Genetic Engineering, Vascular Disease Research Center, College of Life Sciences and Oceanography, Guangdong Provincial Key Laboratory of Regional Immunity and Disease, Carson International Cancer Center, School of Medicine, Shenzhen University, Shenzhen, 518060, China
| | - Lirong Shu
- Shenzhen Key Laboratory of Microbial Genetic Engineering, Vascular Disease Research Center, College of Life Sciences and Oceanography, Guangdong Provincial Key Laboratory of Regional Immunity and Disease, Carson International Cancer Center, School of Medicine, Shenzhen University, Shenzhen, 518060, China
| | - Hongxian Wang
- Department of Thyroid and Breast, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518052, China
| | - Xiaoqian Wu
- Department of Thyroid and Breast, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518052, China
| | - Yaqin He
- Surgical Department, General Hospital of Ningxia Medical University, Yinchuan, 750003, China
| | - Peng Chen
- Shenzhen Key Laboratory of Microbial Genetic Engineering, Vascular Disease Research Center, College of Life Sciences and Oceanography, Guangdong Provincial Key Laboratory of Regional Immunity and Disease, Carson International Cancer Center, School of Medicine, Shenzhen University, Shenzhen, 518060, China
| | - Guocheng Zhong
- Department of Hematology and Oncology, Shenzhen University General Hospital, Carson International Cancer Research Center, School of Medicine, Shenzhen University, Shenzhen, 518060, China
| | - Zhixiong Tang
- Shenzhen Key Laboratory of Microbial Genetic Engineering, Vascular Disease Research Center, College of Life Sciences and Oceanography, Guangdong Provincial Key Laboratory of Regional Immunity and Disease, Carson International Cancer Center, School of Medicine, Shenzhen University, Shenzhen, 518060, China
| | - Shasha Zhang
- Shenzhen Key Laboratory of Microbial Genetic Engineering, Vascular Disease Research Center, College of Life Sciences and Oceanography, Guangdong Provincial Key Laboratory of Regional Immunity and Disease, Carson International Cancer Center, School of Medicine, Shenzhen University, Shenzhen, 518060, China
| | - Qianwen Guo
- Shenzhen Key Laboratory of Microbial Genetic Engineering, Vascular Disease Research Center, College of Life Sciences and Oceanography, Guangdong Provincial Key Laboratory of Regional Immunity and Disease, Carson International Cancer Center, School of Medicine, Shenzhen University, Shenzhen, 518060, China
| | - Yun Wang
- Shenzhen Key Laboratory of Microbial Genetic Engineering, Vascular Disease Research Center, College of Life Sciences and Oceanography, Guangdong Provincial Key Laboratory of Regional Immunity and Disease, Carson International Cancer Center, School of Medicine, Shenzhen University, Shenzhen, 518060, China
| | - Li Yu
- Department of Hematology and Oncology, Shenzhen University General Hospital, Carson International Cancer Research Center, School of Medicine, Shenzhen University, Shenzhen, 518060, China
| | - Deming Gou
- Shenzhen Key Laboratory of Microbial Genetic Engineering, Vascular Disease Research Center, College of Life Sciences and Oceanography, Guangdong Provincial Key Laboratory of Regional Immunity and Disease, Carson International Cancer Center, School of Medicine, Shenzhen University, Shenzhen, 518060, China.
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22
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Bao-Caamano A, Costa-Fraga N, Cayrefourcq L, Jácome MA, Rodriguez-Casanova A, Muinelo-Romay L, López-López R, Alix-Panabières C, Díaz-Lagares A. Epigenomic analysis reveals a unique DNA methylation program of metastasis-competent circulating tumor cells in colorectal cancer. Sci Rep 2023; 13:15401. [PMID: 37717096 PMCID: PMC10505142 DOI: 10.1038/s41598-023-42037-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 09/04/2023] [Indexed: 09/18/2023] Open
Abstract
Circulating tumor cells (CTCs) and epigenetic alterations are involved in the development of metastasis from solid tumors, such as colorectal cancer (CRC). The aim of this study was to characterize the DNA methylation profile of metastasis-competent CTCs in CRC. The DNA methylome of the human CRC-derived cell line CTC-MCC-41 was analyzed and compared with primary (HT29, Caco2, HCT116, RKO) and metastatic (SW620 and COLO205) CRC cells. The association between methylation and the transcriptional profile of CTC-MCC-41 was also evaluated. Differentially methylated CpGs were validated with pyrosequencing and qMSP. Compared to primary and metastatic CRC cells, the methylation profile of CTC-MCC-41 was globally different and characterized by a slight predominance of hypomethylated CpGs mainly distributed in CpG-poor regions. Promoter CpG islands and shore regions of CTC-MCC-41 displayed a unique methylation profile that was associated with the transcriptional program and relevant cancer pathways, mainly Wnt signaling. The epigenetic regulation of relevant genes in CTC-MCC-41 was validated. This study provides new insights into the epigenomic landscape of metastasis-competent CTCs, revealing biological information for metastasis development, as well as new potential biomarkers and therapeutic targets for CRC patients.
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Grants
- ISCIII and the European Regional Development Fund (FEDER), reference number PI18/00307. Juan Rodés, Instituto de Salud Carlos III (ISCIII) and Servizo Galego de Saúde (SERGAS), reference number JR17/00016
- PFIS, Instituto de Salud Carlos III (ISCIII) and Fondo Social Europeo, reference number FI19/00240
- Xunta de Galicia, reference number IN606A-2020/004
- Axencia Galega de Innovación (GAIN), Vicepresidencia Segunda e Consellería de Economía, Empresa e Innovación. Reference number IN853B 2018/03
- ISCIII and the European Regional Development Fund (FEDER), reference number PI18/00307. Instituto de Salud Carlos III (ISCII), reference number CP20/00129
- European Union Horizon 2020 Research and Innovation program under the Marie Skłodowska-Curie grant agreement No. 765492, The National Institute of Cancer (INCa, http://www.e-cancer.fr), SIRIC Montpellier Cancer Grant INCa_Inserm_DGOS_12553, and the ERA-NET TRANSCAN 2 JTC 2016 PROLIPSY, la Fondation ARC pour la Recherche sur le cancer and les Fonds de dotation AFER pour la recherche médicale
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Affiliation(s)
- Aida Bao-Caamano
- Epigenomics Unit, Cancer Epigenomics, Translational Medical Oncology Group (ONCOMET), Health Research Institute of Santiago de Compostela (IDIS), University Clinical Hospital of Santiago (CHUS/SERGAS), 15706, Santiago de Compostela, Spain
- Universidade de Santiago de Compostela (USC), 15782, Santiago de Compostela, Spain
- Galician Precision Oncology Research Group (ONCOGAL), Medicine and Dentistry School, Universidade de Santiago de Compostela (USC), Santiago de Compostela, Spain
| | - Nicolás Costa-Fraga
- Epigenomics Unit, Cancer Epigenomics, Translational Medical Oncology Group (ONCOMET), Health Research Institute of Santiago de Compostela (IDIS), University Clinical Hospital of Santiago (CHUS/SERGAS), 15706, Santiago de Compostela, Spain
- Universidade de Santiago de Compostela (USC), 15782, Santiago de Compostela, Spain
- Galician Precision Oncology Research Group (ONCOGAL), Medicine and Dentistry School, Universidade de Santiago de Compostela (USC), Santiago de Compostela, Spain
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), ISCIII, 28029, Madrid, Spain
| | - Laure Cayrefourcq
- Laboratory of Rare Human Circulating Cells, University Medical Center of Montpellier, IURC, 641, Avenue du Doyen Gaston Giraud, 34093, Montpellier Cedex 5, France
- CREEC, MIVEGEC, University of Montpellier, CNRS, IRD, Montpellier, France
| | - María Amalia Jácome
- Department of Mathematics, MODES Group, CITIC, Faculty of Science, Universidade da Coruña, A Coruña, Spain
| | - Aitor Rodriguez-Casanova
- Epigenomics Unit, Cancer Epigenomics, Translational Medical Oncology Group (ONCOMET), Health Research Institute of Santiago de Compostela (IDIS), University Clinical Hospital of Santiago (CHUS/SERGAS), 15706, Santiago de Compostela, Spain
- Universidade de Santiago de Compostela (USC), 15782, Santiago de Compostela, Spain
- Galician Precision Oncology Research Group (ONCOGAL), Medicine and Dentistry School, Universidade de Santiago de Compostela (USC), Santiago de Compostela, Spain
- Roche-Chus Joint Unit, Translational Medical Oncology Group (ONCOMET), Health Research Institute of Santiago (IDIS), 15706, Santiago de Compostela, Spain
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), ISCIII, 28029, Madrid, Spain
| | - Laura Muinelo-Romay
- Galician Precision Oncology Research Group (ONCOGAL), Medicine and Dentistry School, Universidade de Santiago de Compostela (USC), Santiago de Compostela, Spain
- Liquid Biopsy Analysis Unit, Translational Medical Oncology Group (ONCOMET), Health Research Institute of Santiago de Compostela (IDIS), 15706, Santiago de Compostela, Spain
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), ISCIII, 28029, Madrid, Spain
| | - Rafael López-López
- Galician Precision Oncology Research Group (ONCOGAL), Medicine and Dentistry School, Universidade de Santiago de Compostela (USC), Santiago de Compostela, Spain.
- Roche-Chus Joint Unit, Translational Medical Oncology Group (ONCOMET), Health Research Institute of Santiago (IDIS), 15706, Santiago de Compostela, Spain.
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), ISCIII, 28029, Madrid, Spain.
- Translational Medical Oncology Group (ONCOMET), Health Research Institute of Santiago de Compostela (IDIS), University Clinical Hospital of Santiago (CHUS/SERGAS), 15706, Santiago de Compostela, Spain.
| | - Catherine Alix-Panabières
- Laboratory of Rare Human Circulating Cells, University Medical Center of Montpellier, IURC, 641, Avenue du Doyen Gaston Giraud, 34093, Montpellier Cedex 5, France.
- CREEC, MIVEGEC, University of Montpellier, CNRS, IRD, Montpellier, France.
- European Liquid Biopsy Society (ELBS), Hamburg, Germany.
| | - Angel Díaz-Lagares
- Epigenomics Unit, Cancer Epigenomics, Translational Medical Oncology Group (ONCOMET), Health Research Institute of Santiago de Compostela (IDIS), University Clinical Hospital of Santiago (CHUS/SERGAS), 15706, Santiago de Compostela, Spain.
- Galician Precision Oncology Research Group (ONCOGAL), Medicine and Dentistry School, Universidade de Santiago de Compostela (USC), Santiago de Compostela, Spain.
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), ISCIII, 28029, Madrid, Spain.
- Department of Clinical Analysis, University Hospital Complex of Santiago de Compostela (CHUS), 15706 Santiago de Compostela, Spain.
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23
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Zhou JS, Liu ZN, Chen YY, Liu YX, Shen H, Hou LJ, Ding Y. New advances in circulating tumor cell‑mediated metastasis of breast cancer (Review). Mol Clin Oncol 2023; 19:71. [PMID: 37614367 PMCID: PMC10442766 DOI: 10.3892/mco.2023.2667] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 06/20/2023] [Indexed: 08/25/2023] Open
Abstract
Breast cancer stands as the most prevalent form of cancer affecting women, with metastasis serving as a leading cause of mortality among patients with breast cancer. Gaining a comprehensive understanding of the metastatic mechanism in breast cancer is essential for early detection and precision treatment of the disease. Circulating tumor cells (CTCs) play a vital role in this context, representing cancer cells that detach from tumor tissues and enter the bloodstream of cancer patients. These cells travel in the blood circulation as single cells or clusters. Recent research has shed light on the enhanced metastatic potential of CTC clusters compared to single CTCs, despite their limited occurrence. The aim of the present review was to explore recent findings on CTCs with a particular focus on the clustering phenomenon of CTCs observed in breast cancer. Additionally, the present review delved into the comparison between single CTCs and CTC clusters regarding their implications for the treatment and prognosis of patients diagnosed with metastatic breast cancer. By examining the role and mechanisms of CTCs in breast cancer metastasis, the present review provided an improved understanding of CTCs and their significance in early detection of breast cancer metastasis through peripheral blood analysis. Moreover, it contributed to the comprehension of cancer prognosis and prediction by highlighting the implications of CTCs in these aspects. Ultimately, the present study seeks to advance knowledge in the field and pave the way for improved approaches to breast cancer management.
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Affiliation(s)
- Jiang-Shan Zhou
- Laboratory of Pathophysiology, Weifang Medical University, Weifang, Shandong 261053, P.R. China
| | - Zi-Ning Liu
- Laboratory of Pathophysiology, Weifang Medical University, Weifang, Shandong 261053, P.R. China
| | - Yuan-Yuan Chen
- Laboratory of Pathophysiology, Weifang Medical University, Weifang, Shandong 261053, P.R. China
| | - Yu-Xi Liu
- Laboratory of Pathophysiology, Weifang Medical University, Weifang, Shandong 261053, P.R. China
| | - Hua Shen
- Department of Mathematics and Statistics, University of Calgary, Alberta T2N 1N4, Canada
| | - Li-Jun Hou
- Laboratory of Pathophysiology, Weifang Medical University, Weifang, Shandong 261053, P.R. China
- Key Laboratory of Applied Pharmacology, Weifang Medical University, Weifang, Shandong 261053, P.R. China
| | - Yi Ding
- Laboratory of Pathophysiology, Weifang Medical University, Weifang, Shandong 261053, P.R. China
- Key Laboratory of Applied Pharmacology, Weifang Medical University, Weifang, Shandong 261053, P.R. China
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24
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Rabiee S, Hoveizi E, Barati M, Salehzadeh A, Joghataei MT, Tavakol S. Cancer cells same as zombies reprogram normal cells via the secreted microenvironment. PLoS One 2023; 18:e0288003. [PMID: 37506087 PMCID: PMC10381049 DOI: 10.1371/journal.pone.0288003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Accepted: 06/16/2023] [Indexed: 07/30/2023] Open
Abstract
The cancer microenvironment plays a crucial role in promoting metastasis and malignancy even in normal cells. In the present study, the effect of acidic and conditioned media of cancer cells (MDA-MB-231), separately and in combination, was studied for the first time on the cell death mechanisms and DNA methylation of normal fibroblasts (NIH/3T3). Cell survival of conditioned media was rescued by the addition of acidic media to conditioned media, as shown by the results. Cell metabolic activity is deviated in a direction other than the Krebs cycle by acidic media The mitochondrial metabolic activity of all groups was enhanced over time, except for acidic media. Unlike the highest amount of ROS in conditioned media, its level decreased to the level of acidic media in the combination group. Furthermore, cells were deviated towards autophagy, rather than apoptosis, by the addition of acidic media to the conditioned media, unlike the conditioned media. Global DNA methylation analysis revealed significantly higher DNA hypomethylation in acidic media than in normal and combination media. Not only were cells treated with conditioned media rescued by acidic media, but also DNA hypomethylation and apoptosis in the combination group were decreased through epigenetic modifications. The acidic and conditioned media produced by cancer cells can remotely activate malignant signaling pathways, much like zombies, which can cause metabolic and epigenetic changes in normal cells.
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Affiliation(s)
- Shadi Rabiee
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Biology, Rasht Branch, Islamic Azad University, Rasht, Iran
| | - Elham Hoveizi
- Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
- Stem Cells and Transgenic Technology Research Center (STTRC), Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Mahmood Barati
- Department of Medical Biotechnology, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Salehzadeh
- Department of Biology, Rasht Branch, Islamic Azad University, Rasht, Iran
| | - Mohammad Taghi Joghataei
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Anatomy, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Shima Tavakol
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
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25
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Yoodee S, Thongboonkerd V. Epigenetic regulation of epithelial-mesenchymal transition during cancer development. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2023; 380:1-61. [PMID: 37657856 DOI: 10.1016/bs.ircmb.2023.05.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/03/2023]
Abstract
Epithelial-mesenchymal transition (EMT) plays essential roles in promoting malignant transformation of epithelial cells, leading to cancer progression and metastasis. During EMT-induced cancer development, a wide variety of genes are dramatically modified, especially down-regulation of epithelial-related genes and up-regulation of mesenchymal-related genes. Expression of other EMT-related genes is also modified during the carcinogenic process. Especially, epigenetic modifications are observed in the EMT-related genes, indicating their involvement in cancer development. Mechanically, epigenetic modifications of histone, DNA, mRNA and non-coding RNA stably change the EMT-related gene expression at transcription and translation levels. Herein, we summarize current knowledge on epigenetic regulatory mechanisms observed in EMT process relate to cancer development in humans. The better understanding of epigenetic regulation of EMT during cancer development may lead to improvement of drug design and preventive strategies in cancer therapy.
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Affiliation(s)
- Sunisa Yoodee
- Medical Proteomics Unit, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Visith Thongboonkerd
- Medical Proteomics Unit, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
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26
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Trinh A, Huang Y, Shao H, Ram A, Morival J, Wang J, Chung EJ, Downing TL. Targeting the ADPKD methylome using nanoparticle-mediated combination therapy. APL Bioeng 2023; 7:026111. [PMID: 37305656 PMCID: PMC10257530 DOI: 10.1063/5.0151408] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 05/16/2023] [Indexed: 06/13/2023] Open
Abstract
DNA methylation aberrancies are found in autosomal dominant polycystic kidney disease (ADPKD), which suggests the methylome to be a promising therapeutic target. However, the impact of combining DNA methylation inhibitors (DNMTi) and ADPKD drugs in treating ADPKD and on disease-associated methylation patterns has not been fully explored. To test this, ADPKD drugs, metformin and tolvaptan (MT), were delivered in combination with DNMTi 5-aza-2'-deoxycytidine (Aza) to 2D or 3D cystic Pkd1 heterozygous renal epithelial cells (PKD1-Het cells) as free drugs or within nanoparticles to enable direct delivery for future in vivo applications. We found Aza synergizes with MT to reduce cell viability and cystic growth. Reduced representation bisulfite sequencing (RRBS) was performed across four groups: PBS, Free-Aza (Aza), Free-Aza+MT (F-MTAza), and Nanoparticle-Aza+MT (NP-MTAza). Global methylation patterns showed that while Aza alone induces a unimodal intermediate methylation landscape, Aza+MT recovers the bimodality reminiscent of somatic methylomes. Importantly, site-specific methylation changes associated with F-MTAza and NP-MTAza were largely conserved including hypomethylation at ADPKD-associated genes. Notably, we report hypomethylation of cancer-associated genes implicated in ADPKD pathogenesis as well as new target genes that may provide additional therapeutic effects. Overall, this study motivates future work to further elucidate the regulatory mechanisms of observed drug synergy and apply these combination therapies in vivo.
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Affiliation(s)
| | - Yi Huang
- Department of Biomedical Engineering, University of Southern California, Los Angeles, California 90089, USA
| | | | - Aparna Ram
- Department of Biomedical Engineering, University of Southern California, Los Angeles, California 90089, USA
| | | | - Jonathan Wang
- Department of Biomedical Engineering, University of Southern California, Los Angeles, California 90089, USA
| | - Eun Ji Chung
- Authors to whom correspondence should be addressed: and
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Besselink N, Keijer J, Vermeulen C, Boymans S, de Ridder J, van Hoeck A, Cuppen E, Kuijk E. The genome-wide mutational consequences of DNA hypomethylation. Sci Rep 2023; 13:6874. [PMID: 37106015 PMCID: PMC10140063 DOI: 10.1038/s41598-023-33932-3] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 04/21/2023] [Indexed: 04/29/2023] Open
Abstract
DNA methylation is important for establishing and maintaining cell identity and for genomic stability. This is achieved by regulating the accessibility of regulatory and transcriptional elements and the compaction of subtelomeric, centromeric, and other inactive genomic regions. Carcinogenesis is accompanied by a global loss in DNA methylation, which facilitates the transformation of cells. Cancer hypomethylation may also cause genomic instability, for example through interference with the protective function of telomeres and centromeres. However, understanding the role(s) of hypomethylation in tumor evolution is incomplete because the precise mutational consequences of global hypomethylation have thus far not been systematically assessed. Here we made genome-wide inventories of all possible genetic variation that accumulates in single cells upon the long-term global hypomethylation by CRISPR interference-mediated conditional knockdown of DNMT1. Depletion of DNMT1 resulted in a genomewide reduction in DNA methylation. The degree of DNA methylation loss was similar to that observed in many cancer types. Hypomethylated cells showed reduced proliferation rates, increased transcription of genes, reactivation of the inactive X-chromosome and abnormal nuclear morphologies. Prolonged hypomethylation was accompanied by increased chromosomal instability. However, there was no increase in mutational burden, enrichment for certain mutational signatures or accumulation of structural variation to the genome. In conclusion, the primary consequence of hypomethylation is genomic instability, which in cancer leads to increased tumor heterogeneity and thereby fuels cancer evolution.
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Affiliation(s)
- Nicolle Besselink
- Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Janneke Keijer
- Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Carlo Vermeulen
- Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Sander Boymans
- Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Jeroen de Ridder
- Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Arne van Hoeck
- Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Edwin Cuppen
- Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht, The Netherlands
- Hartwig Medical Foundation, Amsterdam, The Netherlands
| | - Ewart Kuijk
- Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht, The Netherlands.
- Division of Pediatric Gastroenterology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
- Regenerative Medicine Center Utrecht, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands.
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Robeck TR, Haghani A, Fei Z, Lindemann DM, Russell J, Herrick KES, Montano G, Steinman KJ, Katsumata E, Zoller JA, Horvath S. Multi-tissue DNA methylation aging clocks for sea lions, walruses and seals. Commun Biol 2023; 6:359. [PMID: 37005462 PMCID: PMC10067968 DOI: 10.1038/s42003-023-04734-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 03/21/2023] [Indexed: 04/04/2023] Open
Abstract
Age determination of wild animals, including pinnipeds, is critical for accurate population assessment and management. For most pinnipeds, current age estimation methodologies utilize tooth or bone sectioning which makes antemortem estimations problematic. We leveraged recent advances in the development of epigenetic age estimators (epigenetic clocks) to develop highly accurate pinniped epigenetic clocks. For clock development, we applied the mammalian methylation array to profile 37,492 cytosine-guanine sites (CpGs) across highly conserved stretches of DNA in blood and skin samples (n = 171) from primarily three pinniped species representing the three phylogenetic families: Otariidae, Phocidae and Odobenidae. We built an elastic net model with Leave-One-Out-Cross Validation (LOOCV) and one with a Leave-One-Species-Out-Cross-Validation (LOSOCV). After identifying the top 30 CpGs, the LOOCV produced a highly correlated (r = 0.95) and accurate (median absolute error = 1.7 years) age estimation clock. The LOSOCV elastic net results indicated that blood and skin clock (r = 0.84) and blood (r = 0.88) pinniped clocks could predict age of animals from pinniped species not used for clock development to within 3.6 and 4.4 years, respectively. These epigenetic clocks provide an improved and relatively non-invasive tool to determine age in skin or blood samples from all pinniped species.
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Affiliation(s)
- Todd R Robeck
- Zoological Operations, SeaWorld Parks and Entertainment, Orlando, FL, USA.
- Species Preservation Lab, SeaWorld Parks and Entertainment, San Diego, CA, USA.
| | - Amin Haghani
- Department of Human Genetics, Gonda Research Center, David Geffen School of Medicine, Los Angeles, CA, USA
- Altos Labs, San Diego, USA
| | - Zhe Fei
- Department of Biostatistics, School of Public Health, University of California-Los Angeles, Los Angeles, CA, USA
| | | | | | | | - Gisele Montano
- Zoological Operations, SeaWorld Parks and Entertainment, Orlando, FL, USA
- Species Preservation Lab, SeaWorld Parks and Entertainment, San Diego, CA, USA
| | - Karen J Steinman
- Species Preservation Lab, SeaWorld Parks and Entertainment, San Diego, CA, USA
| | | | - Joseph A Zoller
- Department of Biostatistics, School of Public Health, University of California-Los Angeles, Los Angeles, CA, USA
| | - Steve Horvath
- Department of Human Genetics, Gonda Research Center, David Geffen School of Medicine, Los Angeles, CA, USA.
- Altos Labs, San Diego, USA.
- Department of Biostatistics, School of Public Health, University of California-Los Angeles, Los Angeles, CA, USA.
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Ohshima K, Nagashima T, Fujiya K, Hatakeyama K, Watanabe Y, Morimoto K, Kamada F, Shimoda Y, Ohnami S, Naruoka A, Serizawa M, Ohnami S, Kenmotsu H, Shiomi A, Tsubosa Y, Bando E, Sugiura T, Sugino T, Terashima M, Uesaka K, Urakami K, Akiyama Y, Yamaguchi K. Whole-genome and Epigenomic Landscapes of Malignant Gastrointestinal Stromal Tumors Harboring KIT Exon 11 557-558 Deletion Mutations. CANCER RESEARCH COMMUNICATIONS 2023; 3:684-696. [PMID: 37377752 PMCID: PMC10124575 DOI: 10.1158/2767-9764.crc-22-0364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 12/12/2022] [Accepted: 03/17/2023] [Indexed: 06/29/2023]
Abstract
Gastrointestinal stromal tumors (GIST) with KIT exon 11 deletions involving in codons 557-558 (KIT Δ557-558) exhibit higher proliferation rates and shorter disease-free survival times compared with GISTs with other KIT exon 11 mutations. We analyzed 30 GIST cases and observed genomic instability and global DNA hypomethylation only in high-risk malignant GISTs with KIT Δ557-558. Whole-genome sequencing revealed that the high-risk malignant GISTs with KIT Δ557-558 (12 cases) had more structural variations (SV), single-nucleotide variants, and insertions and deletions compared with the low-risk, less malignant GISTs with KIT Δ557-558 (six cases) and the high-risk (six cases) or low-risk (6 cases) GISTs with other KIT exon 11 mutations. The malignant GISTs with KIT Δ557-558 showed higher frequency and significance in copy number (CN) reduction on chromosome arms 9p and 22q, and 50% of them had LOH or CN-dependent expression reduction in CDKN2A. In addition, SVs with driver potential were detected in 75% of them, in which AKT3 and MGMT were recurrently identified. Genome-wide DNA methylation and gene expression analyses showed global intergenic DNA hypomethylation, SNAI2 upregulation, and higher expression signatures, including p53 inactivation and chromosomal instability, as characteristics of malignant GISTs with KIT Δ557-558 that distinguished them from other GISTs. These genomic and epigenomic profiling results revealed that KIT Δ557-558 mutations are associated with increased genomic instability in malignant GISTs. Significance We present genomic and epigenomic insights into the malignant progression of GISTs with KIT exon 11 deletions involving in 557-558, demonstrating their unique chromosomal instability and global intergenic DNA hypomethylation.
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Affiliation(s)
- Keiichi Ohshima
- Medical Genetics Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Takeshi Nagashima
- Cancer Diagnostics Research Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
- SRL, Inc., Tokyo, Japan
| | - Keiichi Fujiya
- Division of Gastric Surgery, Shizuoka Cancer Center Hospital, Shizuoka, Japan
| | - Keiichi Hatakeyama
- Cancer Multiomics Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Yuko Watanabe
- Medical Genetics Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Kimiko Morimoto
- Medical Genetics Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Fukumi Kamada
- Cancer Diagnostics Research Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Yuji Shimoda
- Cancer Diagnostics Research Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Sumiko Ohnami
- Cancer Diagnostics Research Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Akane Naruoka
- Drug Discovery and Development Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Masakuni Serizawa
- Drug Discovery and Development Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Shumpei Ohnami
- Cancer Diagnostics Research Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Hirotsugu Kenmotsu
- Division of Genetic Medicine Promotion, Shizuoka Cancer Center Hospital, Shizuoka, Japan
- Division of Thoracic Oncology, Shizuoka Cancer Center Hospital, Shizuoka, Japan
| | - Akio Shiomi
- Division of Colon and Rectal Surgery, Shizuoka Cancer Center Hospital, Shizuoka, Japan
| | - Yasuhiro Tsubosa
- Division of Esophageal Surgery, Shizuoka Cancer Center Hospital, Shizuoka, Japan
| | - Etsuro Bando
- Division of Gastric Surgery, Shizuoka Cancer Center Hospital, Shizuoka, Japan
| | - Teiichi Sugiura
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center Hospital, Shizuoka, Japan
| | - Takashi Sugino
- Division of Pathology, Shizuoka Cancer Center Hospital, Shizuoka, Japan
| | - Masanori Terashima
- Division of Gastric Surgery, Shizuoka Cancer Center Hospital, Shizuoka, Japan
| | - Katsuhiko Uesaka
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center Hospital, Shizuoka, Japan
| | - Kenichi Urakami
- Cancer Diagnostics Research Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Yasuto Akiyama
- Immunotherapy Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Ken Yamaguchi
- Shizuoka Cancer Center Hospital and Research Institute, Shizuoka, Japan
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30
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Castro-Muñoz LJ, Vázquez Ulloa E, Sahlgren C, Lizano M, De La Cruz-Hernández E, Contreras-Paredes A. Modulating epigenetic modifications for cancer therapy (Review). Oncol Rep 2023; 49:59. [PMID: 36799181 PMCID: PMC9942256 DOI: 10.3892/or.2023.8496] [Citation(s) in RCA: 47] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 11/08/2022] [Indexed: 02/12/2023] Open
Abstract
Cancer is a global public health concern. Alterations in epigenetic processes are among the earliest genomic aberrations occurring during cancer development and are closely related to progression. Unlike genetic mutations, aberrations in epigenetic processes are reversible, which opens the possibility for novel pharmacological treatments. Non‑coding RNAs (ncRNAs) represent an essential epigenetic mechanism, and emerging evidence links ncRNAs to carcinogenesis. Epigenetic drugs (epidrugs) are a group of promising target therapies for cancer treatment acting as coadjuvants to reverse drug resistance in cancer. The present review describes central epigenetic aberrations during malignant transformation and explains how epidrugs target DNA methylation, histone modifications and ncRNAs. Furthermore, clinical trials focused on evaluating the effect of these epidrugs alone or in combination with other anticancer therapies and other ncRNA‑based therapies are discussed. The use of epidrugs promises to be an effective tool for reversing drug resistance in some patients with cancer.
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Affiliation(s)
| | - Elenaé Vázquez Ulloa
- Faculty of Science and Engineering/Cell Biology, University of Turku and Åbo Akademi University, Turku 20500, Finland
- Turku Bioscience, University of Turku and Åbo Akademi University, Turku 20500, Finland
| | - Cecilia Sahlgren
- Faculty of Science and Engineering/Cell Biology, University of Turku and Åbo Akademi University, Turku 20500, Finland
- Turku Bioscience, University of Turku and Åbo Akademi University, Turku 20500, Finland
- Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven 5600 MB, The Netherlands
- Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven 5600 MB, The Netherlands
| | - Marcela Lizano
- Unidad de Investigacion Biomedica en Cancer, Instituto Nacional de Cancerología-Universidad Nacional Autonoma de Mexico, Ciudad de Mexico 14080, Mexico
- Departamento de Medicina Genomica y Toxicologia Ambiental, Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico, Mexico 04510, Mexico
| | - Erick De La Cruz-Hernández
- Laboratory of Research in Metabolic and Infectious Diseases, Multidisciplinary Academic Division of Comalcalco, Juarez Autonomous University of Tabasco, Comalcalco, Tabasco 86650, Mexico
| | - Adriana Contreras-Paredes
- Unidad de Investigacion Biomedica en Cancer, Instituto Nacional de Cancerología-Universidad Nacional Autonoma de Mexico, Ciudad de Mexico 14080, Mexico
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31
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Carvalho CM, Coimbra BM, Bugiga A, Marques DF, Kiyomi Ota V, Mello AF, Mello MF, Belangero SI. Hyperarousal Symptom Severity in Women with Posttraumatic Stress Disorder Might Be Associated with LINE-1 Hypomethylation in Childhood Sexual Abuse Victims. Complex Psychiatry 2023; 9:44-56. [PMID: 37034826 PMCID: PMC10080193 DOI: 10.1159/000529698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 02/02/2023] [Indexed: 02/17/2023] Open
Abstract
Introduction Sexual assault and a history of childhood sexual abuse (CSA) are related to posttraumatic stress disorder (PTSD) development. Long interspersed nuclear elements (LINE-1) are transposable elements, and their methylation is used to infer DNA global methylation. DNA methylation can be affected by trauma exposition which in turn would be associated with PTSD. Thus, we investigated if the LINE-1 methylation pattern is related to PTSD symptoms in females with a history of CSA. Methods This is a case-control study that examined, at baseline (W1), 64 women victims of sexual assault diagnosed with PTSD and 31 patients with PTSD who completed the 1-year follow-up (W2). Participants were categorized into two groups according to the presence of CSA (PTSDCSA+: NW1 = 19, NW2 = 10; PTSDCSA-: NW1 = 45, NW2 = 21). PTSD symptoms (re-experiencing, avoidance, hyperarousal, alterations in cognition/mood) were assessed using the Clinician-Administered PTSD Scale, and the history of CSA was assessed by the Childhood Trauma Questionnaire. LINE-1 methylation was measured in three sites (CpG1, CpG2, CpG3) located in the 5'UTR region using bisulfite conversion followed by pyrosequencing. Linear regression models were performed to test the relation between LINE-1 CpG sites methylation and PTSD symptoms. Results We found a negative association between CpG2 methylation and hyperarousal symptoms among those in the PTSDCSA+ group in W1 (adjusted p = 0.003) compared to the PTSDCSA- group (p > 0.05). Still, no association was observed between other PTSD symptoms and other CpG sites. Further, in the longitudinal analysis, LINE-1 hypomethylation was no longer observed in PTSD participants exposed to CSA. Conclusion Our findings suggest that LINE-1 methylation may help understand the relationship between trauma and PTSD. However, more studies are needed to investigate LINE-1 as an epigenetic marker of psychiatric disorders.
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Affiliation(s)
- Carolina Muniz Carvalho
- Department of Psychiatry of Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
- LiNC - Laboratory of Integrative Neuroscience of Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
| | - Bruno Messina Coimbra
- Department of Psychiatry of Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
- Department of Psychiatry, Amsterdam Public Health Research Institute and Amsterdam Neuroscience Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Amanda Bugiga
- LiNC - Laboratory of Integrative Neuroscience of Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
- Genetics Division of Department of Morphology and Genetics of Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
| | - Diogo Ferri Marques
- Department of Psychiatry of Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
- LiNC - Laboratory of Integrative Neuroscience of Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
- Department of Medical Genetics, University of Calgary, Calgary, AB, Canada
| | - Vanessa Kiyomi Ota
- LiNC - Laboratory of Integrative Neuroscience of Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
- Genetics Division of Department of Morphology and Genetics of Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
| | - Andrea Feijó Mello
- Department of Psychiatry of Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
| | - Marcelo Feijó Mello
- Department of Psychiatry of Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
| | - Sintia Iole Belangero
- LiNC - Laboratory of Integrative Neuroscience of Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
- Genetics Division of Department of Morphology and Genetics of Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
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32
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Mishra S, Raval M, Kachhawaha AS, Tiwari BS, Tiwari AK. Aging: Epigenetic modifications. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2023; 197:171-209. [PMID: 37019592 DOI: 10.1016/bs.pmbts.2023.02.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/15/2023]
Abstract
Aging is one of the most complex and irreversible health conditions characterized by continuous decline in physical/mental activities that eventually poses an increased risk of several diseases and ultimately death. These conditions cannot be ignored by anyone but there are evidences that suggest that exercise, healthy diet and good routines may delay the Aging process significantly. Several studies have demonstrated that Epigenetics plays a key role in Aging and Aging-associated diseases through methylation of DNA, histone modification and non-coding RNA (ncRNA). Comprehension and relevant alterations in these epigenetic modifications can lead to new therapeutic avenues of age-delaying contrivances. These processes affect gene transcription, DNA replication and DNA repair, comprehending epigenetics as a key factor in understanding Aging and developing new avenues for delaying Aging, clinical advancements in ameliorating aging-related diseases and rejuvenating health. In the present article, we have described and advocated the epigenetic role in Aging and associated diseases.
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33
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Endicott JL, Nolte PA, Shen H, Laird PW. Cell division drives DNA methylation loss in late-replicating domains in primary human cells. Nat Commun 2022; 13:6659. [PMID: 36347867 PMCID: PMC9643452 DOI: 10.1038/s41467-022-34268-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 10/18/2022] [Indexed: 11/11/2022] Open
Abstract
DNA methylation undergoes dramatic age-related changes, first described more than four decades ago. Loss of DNA methylation within partially methylated domains (PMDs), late-replicating regions of the genome attached to the nuclear lamina, advances with age in normal tissues, and is further exacerbated in cancer. We present here experimental evidence that this DNA hypomethylation is directly driven by proliferation-associated DNA replication. Within PMDs, loss of DNA methylation at low-density CpGs in A:T-rich immediate context (PMD solo-WCGWs) tracks cumulative population doublings in primary cell culture. Cell cycle deceleration results in a proportional decrease in the rate of DNA hypomethylation. Blocking DNA replication via Mitomycin C treatment halts methylation loss. Loss of methylation continues unabated after TERT immortalization until finally reaching a severely hypomethylated equilibrium. Ambient oxygen culture conditions increases the rate of methylation loss compared to low-oxygen conditions, suggesting that some methylation loss may occur during unscheduled, oxidative damage repair-associated DNA synthesis. Finally, we present and validate a model to estimate the relative cumulative replicative histories of human cells, which we call "RepliTali" (Replication Times Accumulated in Lifetime).
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Affiliation(s)
- Jamie L Endicott
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA
| | - Paula A Nolte
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA
| | - Hui Shen
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA.
| | - Peter W Laird
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA.
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Rahmy S, Mishra SJ, Murphy S, Blagg BSJ, Lu X. Hsp90β inhibition upregulates interferon response and enhances immune checkpoint blockade therapy in murine tumors. Front Immunol 2022; 13:1005045. [PMID: 36341371 PMCID: PMC9630337 DOI: 10.3389/fimmu.2022.1005045] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 10/04/2022] [Indexed: 12/02/2022] Open
Abstract
Response resistance to the immune checkpoint blockade (ICB) immunotherapy remains a major clinical challenge that may be overcome through the rational combination of ICB and specific targeted therapeutics. One emerging combination strategy is based on sensitizing ICB-refractory tumors with antagonists of 90kD heat shock protein (Hsp90) that target all four isoforms. However, pan-Hsp90 inhibitors are limited by the modest efficacy, on-target and off-tumor toxicities, and induction of the heat shock response (HSR) that overrides the effect of Hsp90 inhibition. Recently, we developed Hsp90β-selective inhibitors that were cytotoxic to cancer cells but did not induce HSR in vitro. Here, we report that the Hsp90β inhibitor NDNB1182 downregulated CDK4 (an Hsp90β-dependent client protein) and induced the expression of endogenous retroviral elements and interferon-stimulated genes. In syngeneic mouse models of prostate cancer and breast cancer, NDNB1182 significantly augmented the efficacy of ICB therapy. Furthermore, NDNB1182 showed superior tolerability to the pan-Hsp90 inhibitor Ganetespib in mice. Our findings provide evidence that Hsp90β inhibition is a potentially effective and safe regimen to combine with ICB to treat immunotherapy-refractory solid tumors.
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Affiliation(s)
- Sharif Rahmy
- Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN, United States
- Integrated Biomedical Sciences Graduate Program, University of Notre Dame, Notre Dame, IN, United States
| | - Sanket J. Mishra
- Department of Chemistry and Biochemistry, Warren Family Research Center for Drug Discovery and Development, University of Notre Dame, Notre Dame, IN, United States
| | - Sean Murphy
- Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN, United States
| | - Brian S. J. Blagg
- Department of Chemistry and Biochemistry, Warren Family Research Center for Drug Discovery and Development, University of Notre Dame, Notre Dame, IN, United States
| | - Xin Lu
- Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN, United States
- Integrated Biomedical Sciences Graduate Program, University of Notre Dame, Notre Dame, IN, United States
- Tumor Microenvironment and Metastasis Program, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, United States
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35
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RNA m 6A regulates transcription via DNA demethylation and chromatin accessibility. Nat Genet 2022; 54:1427-1437. [PMID: 36071173 DOI: 10.1038/s41588-022-01173-1] [Citation(s) in RCA: 97] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 07/26/2022] [Indexed: 12/12/2022]
Abstract
Transcriptional regulation, which integrates chromatin accessibility, transcription factors and epigenetic modifications, is crucial for establishing and maintaining cell identity. The interplay between different epigenetic modifications and its contribution to transcriptional regulation remains elusive. Here, we show that METTL3-mediated RNA N6-methyladenosine (m6A) formation leads to DNA demethylation in nearby genomic loci in normal and cancer cells, which is mediated by the interaction between m6A reader FXR1 and DNA 5-methylcytosine dioxygenase TET1. Upon recognizing RNA m6A, FXR1 recruits TET1 to genomic loci to demethylate DNA, leading to reprogrammed chromatin accessibility and gene transcription. Therefore, we have characterized a regulatory mechanism of chromatin accessibility and gene transcription mediated by RNA m6A formation coupled with DNA demethylation, highlighting the importance of the crosstalk between RNA m6A and DNA modification in physiologic and pathogenic process.
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36
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Thongsroy J, Mutirangura A. The association between Alu hypomethylation and the severity of hypertension. PLoS One 2022; 17:e0270004. [PMID: 35802708 PMCID: PMC9269909 DOI: 10.1371/journal.pone.0270004] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 06/02/2022] [Indexed: 11/18/2022] Open
Abstract
Introduction Epigenetic changes that cause genomic instability may be the basis of pathogenic processes of age-associated noncommunicable diseases (NCDs). Essential hypertension is one of the most common NCDs. Alu hypomethylation is an epigenetic event that is commonly found in elderly individuals. Epigenomic alterations are also found in age-associated NCDs such as osteoporosis and diabetes mellitus. Alu methylation prevents DNA from being damaged. Therefore, Alu hypomethylated DNA accumulates DNA damage and, as a result, causes organ function deterioration. Here, we report that Alu hypomethylation is a biomarker for essential hypertension. Results We investigated Alu methylation levels in white blood cells from normal controls, patients with prehypertension, and patients with hypertension. The hypertension group possessed the lowest Alu methylation level when classified by systolic blood pressure and diastolic blood pressure (P = 0.0002 and P = 0.0088, respectively). In the hypertension group, a higher diastolic blood pressure and a lower Alu methylation level were observed (r = -0.6278). Moreover, we found that changes in Alu hypomethylation in the four years of follow-up in the same person were directly correlated with increased diastolic blood pressure. Conclusions Similar to other age-associated NCDs, Alu hypomethylation is found in essential hypertension and is directly correlated with severity, particularly with diastolic blood pressure. Therefore, Alu hypomethylation may be linked with the molecular pathogenesis of high blood pressure and can be used for monitoring the clinical outcome of this disease.
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Affiliation(s)
- Jirapan Thongsroy
- School of Medicine, Walailak University, Nakhon Si Thammarat, Thailand
- * E-mail:
| | - Apiwat Mutirangura
- Center of Excellence in Molecular Genetics of Cancer and Human Disease, Department of Anatomy, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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37
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Watcharanurak P, Mutirangura A. Human RNA-directed DNA methylation methylates high-mobility group box 1 protein-produced DNA gaps. Epigenomics 2022; 14:741-756. [PMID: 35762252 DOI: 10.2217/epi-2022-0022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Background: DNA sequences around HMGB1-produced DNA gaps are hypermethylates. DNA methylation of interspersed repetitive sequences (IRS) such as Alu elements can be established through AGO4-mediating, RNA-directed DNA methylation (RdDM). HMGB1 depletion, DNA gap reduction and global hypomethylation promote genomic instability. Methods: HMGB1, SIRT1, AGO4 and DNA gap colocalizations were evaluated. Then, Alu methylation was analyzed in HMGB1-deficient or HMGB1-overexpressing cells and Alu siRNA-transfected HMGB1-deficient cells. Results: HMGB1, SIRT1, AGO4 and DNA gap are colocalized in the nucleus. Moreover, HMGB1 or Alu siRNA increased Alu methylation, whereas Alu siRNA could not methylate HMGB1-deficient cells. Conclusion: AGO4 play a role in methylating DNA sequence around HMGB1-produced DNA gaps and localize DNA gap in IRS, and loss of intranuclear HMGB1 causes global hypomethylation.
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Affiliation(s)
- Papitchaya Watcharanurak
- Interdisciplinary Program of Biomedical Sciences, Graduate School, Chulalongkorn University, Bangkok, 10330, Thailand.,Department of Anatomy, Center of Excellence in Molecular Genetics of Cancer & Human Disease, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Apiwat Mutirangura
- Department of Anatomy, Center of Excellence in Molecular Genetics of Cancer & Human Disease, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
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The Utility of Repetitive Cell-Free DNA in Cancer Liquid Biopsies. Diagnostics (Basel) 2022; 12:diagnostics12061363. [PMID: 35741173 PMCID: PMC9221655 DOI: 10.3390/diagnostics12061363] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 05/27/2022] [Accepted: 05/30/2022] [Indexed: 02/05/2023] Open
Abstract
Liquid biopsy is a broad term that refers to the testing of body fluids for biomarkers that correlate with a pathological condition. While a variety of body-fluid components (e.g., circulating tumor cells, extracellular vesicles, RNA, proteins, and metabolites) are studied as potential liquid biopsy biomarkers, cell-free DNA (cfDNA) has attracted the most attention in recent years. The total cfDNA population in a typical biospecimen represents an immensely rich source of biological and pathological information and has demonstrated significant potential as a versatile biomarker in oncology, non-invasive prenatal testing, and transplant monitoring. As a significant portion of cfDNA is composed of repeat DNA sequences and some families (e.g., pericentric satellites) were recently shown to be overrepresented in cfDNA populations vs their genomic abundance, it holds great potential for developing liquid biopsy-based biomarkers for the early detection and management of patients with cancer. By outlining research that employed cell-free repeat DNA sequences, in particular the ALU and LINE-1 elements, we highlight the clinical potential of the repeat-element content of cfDNA as an underappreciated marker in the cancer liquid biopsy repertoire.
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Oryani MA, Tavasoli A, Ghalavand MA, Ashtiani RZ, Rezaee A, Mahmoudi R, Golvari H, Owrangi S, Soleymani-Goloujeh M. Epigenetics and its therapeutic potential in colorectal cancer. Epigenomics 2022; 14:683-697. [PMID: 35473313 DOI: 10.2217/epi-2022-0067] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
It is estimated that colorectal cancer (CRC) is the leading cause of cancer-related death around the globe. 'Epigenetics' refers to changes in the chromosome rather than the DNA sequence, which may be transmitted down to daughter cells. Epigenetics is an essential part of controlling the development and variation of a single cell. ncRNAs have a role in epigenetic regulation in CRC, which will be discussed in this review in the context of DNA methylation and histone modifications. A greater survival rate for CRC patients might be achieved by addressing epigenetic mediators, as the authors show. In this review, they aim to thoroughly examine the role of epigenetics in the prognosis, diagnosis and treatment of CRC.
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Affiliation(s)
- Mahsa Akbari Oryani
- Department of Pathology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Afsaneh Tavasoli
- Department of Biotechnology, Faculty of Pharmacy, Alborz University of Medical Sciences, Karaj, Iran
| | - Mohammad Amin Ghalavand
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | | | - Alisam Rezaee
- Faculty of Medical Sciences & Technologies, Science & Research Branch, Islamic Azad University, Tehran, Iran
| | | | - Hossein Golvari
- School of Nursing & Paramedical Sciences, Mazandaran University of Medical Sciences, Sari, Iran
| | - Soroor Owrangi
- Student Research Committee, Fasa University of Medical Sciences, Fasa, Iran
| | - Mehdi Soleymani-Goloujeh
- Department of Stem Cells & Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology & Technology, ACECR, Tehran, Iran
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Tu K, Lee S, Roy S, Sawant A, Shukla H. Dysregulated Epigenetics of Chordoma: Prognostic Markers and Therapeutic Targets. Curr Cancer Drug Targets 2022; 22:678-690. [PMID: 35440334 DOI: 10.2174/1568009622666220419122716] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 02/08/2022] [Accepted: 02/10/2022] [Indexed: 11/22/2022]
Abstract
Chordoma is a rare, slow-growing sarcoma that is locally aggressive, and typically resistant to conventional chemo- and radiotherapies. Despite its low incidence, chordoma remains a clinical challenge because therapeutic options for chordoma are limited, and little is known about the molecular mechanisms involved in resistance to therapies. Furthermore, there are currently no established predictive or prognostic biomarkers to follow disease progression or treatment. Whole-genome sequencing of chordoma tissues has demonstrated a low-frequency mutation rate compared to other cancers. This has generated interest in the role of epigenetic events in chordoma pathogenesis. In this review, we discuss the current understanding of the epigenetic drivers of chordoma and their potential applications in prognosis and the development of new therapies.
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Affiliation(s)
- Kevin Tu
- Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland school of Medicine, Baltimore, MD, USA.,Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, College Park, MD, USA
| | - Sang Lee
- Department of Orthopedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States
| | - Sanjit Roy
- Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland school of Medicine, Baltimore, MD, USA
| | - Amit Sawant
- Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland school of Medicine, Baltimore, MD, USA
| | - Hem Shukla
- Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland school of Medicine, Baltimore, MD, USA
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Lin W, Huang Z, Ping S, Zhang S, Wen X, He Y, Ren Y. Toxicological effects of atenolol and venlafaxine on zebrafish tissues: Bioaccumulation, DNA hypomethylation, and molecular mechanism. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2022; 299:118898. [PMID: 35081461 DOI: 10.1016/j.envpol.2022.118898] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Revised: 01/02/2022] [Accepted: 01/22/2022] [Indexed: 06/14/2023]
Abstract
The beta-blocker atenolol (ATE), and the selective serotonin and norepinephrine reuptake inhibitor, venlafaxine (VEN) are frequently detected in municipal wastewater effluents, but little is known about their ecotoxicological effect on aquatic animals. Herein, ATE and VEN were selected to explore their accumulation and global DNA methylation (GDM) in zebrafish tissues after a 30-day exposure. Molecular dynamics (MD) stimulation was used to investigate the toxic mechanism of ATE and VEN exposure. The results demonstrated that ATE and VEN could reduce the condition factor of zebrafish. The bioaccumulation capacity for ATE and VEN was in the order of liver > gut > gill > brain and liver > gut > brain > gill, respectively. After a 30-day recovery, ATE and VEN could still be detected in zebrafish tissues when exposure concentrations were ≥10 μg/L. Moreover, ATE and VEN induced global DNA hypomethylation in different tissues with a dose-dependent manner and their main target tissues were liver and brain. When the exposure concentrations of ATE and VEN were increased to 100 μg/L, the global DNA hypomethylation of liver and brain were reduced to 27% and 18%, respectively. In the same tissue exposed to the same concentration, DNA hypomethylation induced by VEN was more serious than that of ATE. After a 30-day recovery, the global DNA hypomethylations caused by the two drugs were still persistent, and the recovery of VEN was slower than that of ATE. The MD simulation results showed that both ATE and VEN could reduce the catalytic activity of DNA Methyltransferase 1 (DNMT1), while the effect of VEN on the 3D conformational changes of the DNMT1 domain was more significant, resulting in a lower DNA methylation rate. The current study shed new light on the toxic mechanism and potential adverse impacts of ATE and VEN on zebrafish, providing essential information to the further ecotoxicological risk assessment of these drugs in the aquatic environment.
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Affiliation(s)
- Wenting Lin
- School of Environment and Energy, South China University of Technology, Guangzhou, 510006, PR China
| | - Zhishan Huang
- School of Environment and Energy, South China University of Technology, Guangzhou, 510006, PR China
| | - Senwen Ping
- School of Environment and Energy, South China University of Technology, Guangzhou, 510006, PR China
| | - Shuan Zhang
- School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou, 510640, PR China
| | - Xiufang Wen
- School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou, 510640, PR China
| | - Yuhe He
- School of Energy and Environment, City University of Hong Kong, Hong Kong, China
| | - Yuan Ren
- School of Environment and Energy, South China University of Technology, Guangzhou, 510006, PR China; The Key Lab of Pollution Control and Ecosystem Restoration in Industry Clusters, Ministry of Education, China; The Key Laboratory of Environmental Protection and Eco-Remediation of Guangdong Regular Higher Education Institutions, China.
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DNA Methylation Malleability and Dysregulation in Cancer Progression: Understanding the Role of PARP1. Biomolecules 2022; 12:biom12030417. [PMID: 35327610 PMCID: PMC8946700 DOI: 10.3390/biom12030417] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 02/28/2022] [Accepted: 03/04/2022] [Indexed: 02/05/2023] Open
Abstract
Mammalian genomic DNA methylation represents a key epigenetic modification and its dynamic regulation that fine-tunes the gene expression of multiple pathways during development. It maintains the gene expression of one generation of cells; particularly, the mitotic inheritance of gene-expression patterns makes it the key governing mechanism of epigenetic change to the next generation of cells. Convincing evidence from recent discoveries suggests that the dynamic regulation of DNA methylation is accomplished by the enzymatic action of TET dioxygenase, which oxidizes the methyl group of cytosine and activates transcription. As a result of aberrant DNA modifications, genes are improperly activated or inhibited in the inappropriate cellular context, contributing to a plethora of inheritable diseases, including cancer. We outline recent advancements in understanding how DNA modifications contribute to tumor suppressor gene silencing or oncogenic-gene stimulation, as well as dysregulation of DNA methylation in cancer progression. In addition, we emphasize the function of PARP1 enzymatic activity or inhibition in the maintenance of DNA methylation dysregulation. In the context of cancer remediation, the impact of DNA methylation and PARP1 pharmacological inhibitors, and their relevance as a combination therapy are highlighted.
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BMP4 preserves the developmental potential of mESCs through Ube2s- and Chmp4b-mediated chromosomal stability safeguarding. Protein Cell 2022; 13:580-601. [PMID: 35147915 PMCID: PMC9232672 DOI: 10.1007/s13238-021-00896-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Chemically defined medium is widely used for culturing mouse embryonic stem cells (mESCs), in which N2B27 works as a substitution for serum, and GSK3β and MEK inhibitors (2i) help to promote ground-state pluripotency. However, recent studies suggested that MEKi might cause irreversible defects that compromise the developmental potential of mESCs. Here, we demonstrated the deficient bone morphogenetic protein (BMP) signal in the chemically defined condition is one of the main causes for the impaired pluripotency. Mechanistically, activating the BMP signal pathway by BMP4 could safeguard the chromosomal integrity and proliferation capacity of mESCs through regulating downstream targets Ube2s and Chmp4b. More importantly, BMP4 promotes a distinct in vivo developmental potential and a long-term pluripotency preservation. Besides, the pluripotent improvements driven by BMP4 are superior to those by attenuating MEK suppression. Taken together, our study shows appropriate activation of BMP signal is essential for regulating functional pluripotency and reveals that BMP4 should be applied in the serum-free culture system.
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44
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Liang Y, Turcan S. Epigenetic Drugs and Their Immune Modulating Potential in Cancers. Biomedicines 2022; 10:biomedicines10020211. [PMID: 35203421 PMCID: PMC8868629 DOI: 10.3390/biomedicines10020211] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 01/14/2022] [Accepted: 01/16/2022] [Indexed: 11/19/2022] Open
Abstract
Epigenetic drugs are used for the clinical treatment of hematologic malignancies; however, their therapeutic potential in solid tumors is still under investigation. Current evidence suggests that epigenetic drugs may lead to antitumor immunity by increasing antigen presentation and may enhance the therapeutic effect of immune checkpoint inhibitors. Here, we highlight their impact on the tumor epigenome and discuss the recent evidence that epigenetic agents may optimize the immune microenvironment and promote antiviral response.
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45
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Aleotti V, Catoni C, Poggiana C, Rosato A, Facchinetti A, Scaini MC. Methylation Markers in Cutaneous Melanoma: Unravelling the Potential Utility of Their Tracking by Liquid Biopsy. Cancers (Basel) 2021; 13:6217. [PMID: 34944843 PMCID: PMC8699653 DOI: 10.3390/cancers13246217] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/02/2021] [Accepted: 12/08/2021] [Indexed: 01/19/2023] Open
Abstract
Malignant melanoma is the most serious, life-threatening form of all dermatologic diseases, with a poor prognosis in the presence of metastases and advanced disease. Despite recent advances in targeted therapy and immunotherapy, there is still a critical need for a better understanding of the fundamental mechanisms behind melanoma progression and resistance onset. Recent advances in genome-wide methylation methods have revealed that aberrant changes in the pattern of DNA methylation play an important role in many aspects of cancer progression, including cell proliferation and migration, evasion of cell death, invasion, and metastasization. The purpose of the current review was to gather evidence regarding the usefulness of DNA methylation tracking in liquid biopsy as a potential biomarker in melanoma. We investigated the key genes and signal transduction pathways that have been found to be altered epigenetically in melanoma. We then highlighted the circulating tumor components present in blood, including circulating melanoma cells (CMC), circulating tumor DNA (ctDNA), and tumor-derived extracellular vesicles (EVs), as a valuable source for identifying relevant aberrations in DNA methylation. Finally, we focused on DNA methylation signatures as a marker for tracking response to therapy and resistance, thus facilitating personalized medicine and decision-making in the treatment of melanoma patients.
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Affiliation(s)
- Valentina Aleotti
- Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padua, Italy; (V.A.); (C.C.); (A.F.); (M.C.S.)
| | - Cristina Catoni
- Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padua, Italy; (V.A.); (C.C.); (A.F.); (M.C.S.)
| | - Cristina Poggiana
- Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padua, Italy; (V.A.); (C.C.); (A.F.); (M.C.S.)
| | - Antonio Rosato
- Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padua, Italy; (V.A.); (C.C.); (A.F.); (M.C.S.)
- Department of Surgery, Oncology and Gastroenterology, Oncology and Immunology Section, University of Padua, 35128 Padua, Italy
| | - Antonella Facchinetti
- Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padua, Italy; (V.A.); (C.C.); (A.F.); (M.C.S.)
- Department of Surgery, Oncology and Gastroenterology, Oncology and Immunology Section, University of Padua, 35128 Padua, Italy
| | - Maria Chiara Scaini
- Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padua, Italy; (V.A.); (C.C.); (A.F.); (M.C.S.)
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Genetic and immunologic features of recurrent stage I lung adenocarcinoma. Sci Rep 2021; 11:23690. [PMID: 34880292 PMCID: PMC8654957 DOI: 10.1038/s41598-021-02946-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 11/24/2021] [Indexed: 12/12/2022] Open
Abstract
Although surgery for early-stage lung cancer offers the best chance of cure, recurrence still occurs between 30 and 50% of the time. Why patients frequently recur after complete resection of early-stage lung cancer remains unclear. Using a large cohort of stage I lung adenocarcinoma patients, distinct genetic, genomic, epigenetic, and immunologic profiles of recurrent tumors were analyzed using a novel recurrence classifier. To characterize the tumor immune microenvironment of recurrent stage I tumors, unique tumor-infiltrating immune population markers were identified using single cell RNA-seq on a separate cohort of patients undergoing stage I lung adenocarcinoma resection and applied to a large study cohort using digital cytometry. Recurrent stage I lung adenocarcinomas demonstrated higher mutation and lower methylation burden than non-recurrent tumors, as well as widespread activation of known cancer and cell cycle pathways. Simultaneously, recurrent tumors displayed downregulation of immune response pathways including antigen presentation and Th1/Th2 activation. Recurrent tumors were depleted in adaptive immune populations, and depletion of adaptive immune populations and low cytolytic activity were prognostic of stage I recurrence. Genomic instability and impaired adaptive immune responses are key features of stage I lung adenocarcinoma immunosurveillance escape and recurrence after surgery.
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Mensah IK, Norvil AB, AlAbdi L, McGovern S, Petell CJ, He M, Gowher H. Misregulation of the expression and activity of DNA methyltransferases in cancer. NAR Cancer 2021; 3:zcab045. [PMID: 34870206 PMCID: PMC8634572 DOI: 10.1093/narcan/zcab045] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 10/29/2021] [Accepted: 11/10/2021] [Indexed: 12/15/2022] Open
Abstract
In mammals, DNA methyltransferases DNMT1 and DNMT3's (A, B and L) deposit and maintain DNA methylation in dividing and nondividing cells. Although these enzymes have an unremarkable DNA sequence specificity (CpG), their regional specificity is regulated by interactions with various protein factors, chromatin modifiers, and post-translational modifications of histones. Changes in the DNMT expression or interacting partners affect DNA methylation patterns. Consequently, the acquired gene expression may increase the proliferative potential of cells, often concomitant with loss of cell identity as found in cancer. Aberrant DNA methylation, including hypermethylation and hypomethylation at various genomic regions, therefore, is a hallmark of most cancers. Additionally, somatic mutations in DNMTs that affect catalytic activity were mapped in Acute Myeloid Leukemia cancer cells. Despite being very effective in some cancers, the clinically approved DNMT inhibitors lack specificity, which could result in a wide range of deleterious effects. Elucidating distinct molecular mechanisms of DNMTs will facilitate the discovery of alternative cancer therapeutic targets. This review is focused on: (i) the structure and characteristics of DNMTs, (ii) the prevalence of mutations and abnormal expression of DNMTs in cancer, (iii) factors that mediate their abnormal expression and (iv) the effect of anomalous DNMT-complexes in cancer.
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Affiliation(s)
- Isaiah K Mensah
- Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA
| | | | - Lama AlAbdi
- Department of Zoology, Collage of Science, King Saud University, Riyadh, Saudi Arabia
| | - Sarah McGovern
- Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA
| | | | - Ming He
- Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA
| | - Humaira Gowher
- Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA
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Koklesova L, Mazurakova A, Samec M, Biringer K, Samuel SM, Büsselberg D, Kubatka P, Golubnitschaja O. Homocysteine metabolism as the target for predictive medical approach, disease prevention, prognosis, and treatments tailored to the person. EPMA J 2021; 12:477-505. [PMID: 34786033 PMCID: PMC8581606 DOI: 10.1007/s13167-021-00263-0] [Citation(s) in RCA: 94] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 10/29/2021] [Indexed: 02/07/2023]
Abstract
Homocysteine (Hcy) metabolism is crucial for regulating methionine availability, protein homeostasis, and DNA-methylation presenting, therefore, key pathways in post-genomic and epigenetic regulation mechanisms. Consequently, impaired Hcy metabolism leading to elevated concentrations of Hcy in the blood plasma (hyperhomocysteinemia) is linked to the overproduction of free radicals, induced oxidative stress, mitochondrial impairments, systemic inflammation and increased risks of eye disorders, coronary artery diseases, atherosclerosis, myocardial infarction, ischemic stroke, thrombotic events, cancer development and progression, osteoporosis, neurodegenerative disorders, pregnancy complications, delayed healing processes, and poor COVID-19 outcomes, among others. This review focuses on the homocysteine metabolism impairments relevant for various pathological conditions. Innovative strategies in the framework of 3P medicine consider Hcy metabolic pathways as the specific target for in vitro diagnostics, predictive medical approaches, cost-effective preventive measures, and optimized treatments tailored to the individualized patient profiles in primary, secondary, and tertiary care.
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Affiliation(s)
- Lenka Koklesova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
| | - Alena Mazurakova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
| | - Marek Samec
- Jessenius Faculty of Medicine in Martin, Biomedical Centre Martin, Comenius University in Bratislava, Mala Hora 4D, 036 01 Martin, Slovakia
| | - Kamil Biringer
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
| | - Samson Mathews Samuel
- Department of Physiology and Biophysics, Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, 24144 Doha, Qatar
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, 24144 Doha, Qatar
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
| | - Olga Golubnitschaja
- Predictive, Preventive, Personalised (3P) Medicine, Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, 53127 Bonn, Germany
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Xu B, Wang H, Tan L. Dysregulated TET Family Genes and Aberrant 5mC Oxidation in Breast Cancer: Causes and Consequences. Cancers (Basel) 2021; 13:cancers13236039. [PMID: 34885145 PMCID: PMC8657367 DOI: 10.3390/cancers13236039] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Revised: 11/27/2021] [Accepted: 11/27/2021] [Indexed: 02/08/2023] Open
Abstract
Simple Summary Both genetic and epigenetic mechanisms contribute to the pathogenesis of breast cancer. Since Tahiliani et al. identified TET1 as the first methyl-cytosine dioxygenase in 2009, accumulating evidence has shown that aberrant 5mC oxidation and dysregulated TET family genes are associated with diseases, including breast cancer. In this review we provide an overview on the diagnosis and prognosis values of aberrant 5mC oxidation in breast cancer and emphasize the causes and consequences of such epigenetic alterations. Abstract DNA methylation (5-methylcytosine, 5mC) was once viewed as a stable epigenetic modification until Rao and colleagues identified Ten-eleven translocation 1 (TET1) as the first 5mC dioxygenase in 2009. TET family genes (including TET1, TET2, and TET3) encode proteins that can catalyze 5mC oxidation and consequently modulate DNA methylation, not only regulating embryonic development and cellular differentiation, but also playing critical roles in various physiological and pathophysiological processes. Soon after the discovery of TET family 5mC dioxygenases, aberrant 5mC oxidation and dysregulation of TET family genes have been reported in breast cancer as well as other malignancies. The impacts of aberrant 5mC oxidation and dysregulated TET family genes on the different aspects (so-called cancer hallmarks) of breast cancer have also been extensively investigated in the past decade. In this review, we summarize current understanding of the causes and consequences of aberrant 5mC oxidation in the pathogenesis of breast cancer. The challenges and future perspectives of this field are also discussed.
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Affiliation(s)
- Bo Xu
- Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China;
| | - Hao Wang
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Correspondence: (H.W.); (L.T.); Tel.: +86-21-54237876 (L.T.)
| | - Li Tan
- Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China;
- Correspondence: (H.W.); (L.T.); Tel.: +86-21-54237876 (L.T.)
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Farhana A, Koh AEH, Ling Mok P, Alsrhani A, Khan YS, Subbiah SK. Camptothecin Encapsulated in β-Cyclodextrin-EDTA-Fe 3O 4 Nanoparticles Induce Metabolic Reprogramming Repair in HT29 Cancer Cells through Epigenetic Modulation: A Bioinformatics Approach. NANOMATERIALS 2021; 11:nano11123163. [PMID: 34947512 PMCID: PMC8705212 DOI: 10.3390/nano11123163] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Revised: 09/25/2021] [Accepted: 09/28/2021] [Indexed: 11/16/2022]
Abstract
Cancer progresses through a distinctive reprogramming of metabolic pathways directed by genetic and epigenetic modifications. The hardwired changes induced by genetic mutations are resilient, while epigenetic modifications are softwired and more vulnerable to therapeutic intervention. Colon cancer is no different. This gives us the need to explore the mechanism as an attractive therapeutic target to combat colon cancer cells. We have previously established the enhanced therapeutic efficacy of a newly formulated camptothecin encapsulated in β-cyclodextrin-EDTA-Fe3O4 nanoparticles (CPT-CEF) in colon cancer cells. We furthered this study by carrying out RNA sequencing (RNA-seq) to underscore specific regulatory signatures in the CPT-CEF treated versus untreated HT29 cells. In the study, we identified 95 upregulated and 146 downregulated genes spanning cellular components and molecular and metabolic functions. We carried out extensive bioinformatics analysis to harness genes potentially involved in epigenetic modulation as either the cause or effect of metabolic rewiring exerted by CPT-CEF. Significant downregulation of 13 genes involved in the epigenetic modulation and 40 genes from core metabolism was identified. Three genes, namely, DNMT-1, POLE3, and PKM-2, were identified as the regulatory overlap between epigenetic drivers and metabolic reprogramming in HT29 cells. Based on our results, we propose a possible mechanism that intercepts the two functional axes, namely epigenetic control, and metabolic modulation via CPT-CEF in colon cancer cells, which could skew cancer-induced metabolic deregulation towards metabolic repair. Thus, the study provides avenues for further validation of transcriptomic changes affected by these deregulated genes at epigenetic level, and ultimately may be harnessed as targets for regenerating normal metabolism in colon cancer with better treatment potential, thereby providing new avenues for colon cancer therapy.
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Affiliation(s)
- Aisha Farhana
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 72388, Saudi Arabia; (P.L.M.); (A.A.)
- Correspondence: (A.F.); (S.K.S.)
| | - Avin Ee-Hwan Koh
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia (UPM), Serdang 43400, Malaysia;
| | - Pooi Ling Mok
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 72388, Saudi Arabia; (P.L.M.); (A.A.)
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia (UPM), Serdang 43400, Malaysia;
| | - Abdullah Alsrhani
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 72388, Saudi Arabia; (P.L.M.); (A.A.)
| | - Yusuf Saleem Khan
- Department of Anatomy, College of Medicine, Jouf University, Sakaka 72388, Saudi Arabia;
| | - Suresh Kumar Subbiah
- Department of Medical Microbiology and Parasitology, Universiti Putra Malaysia (UPM), Serdang 43400, Malaysia
- Centre for Materials Engineering and Regenerative Medicine, Bharath Institute of Higher Education and Research, Bharath University, Selaiyur, Chennai 600073, India
- Institute of Bioscience, Universiti Putra Malaysia (UPM), Serdang 43400, Malaysia
- Correspondence: (A.F.); (S.K.S.)
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