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Li J, Pan J, Wang L, Ji G, Dang Y. Colorectal Cancer: Pathogenesis and Targeted Therapy. MedComm (Beijing) 2025; 6:e70127. [PMID: 40060193 PMCID: PMC11885891 DOI: 10.1002/mco2.70127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 02/12/2025] [Accepted: 02/13/2025] [Indexed: 04/29/2025] Open
Abstract
Colorectal cancer (CRC) ranks among the most prevalent malignant neoplasms globally. A growing body of evidence underscores the pivotal roles of genetic alterations and dysregulated epigenetic modifications in the pathogenesis of CRC. In recent years, the reprogramming of tumor cell metabolism has been increasingly acknowledged as a hallmark of cancer. Substantial evidence suggests a crosstalk between tumor cell metabolic reprogramming and epigenetic modifications, highlighting a complex interplay between metabolism and the epigenetic genome that warrants further investigation. Biomarkers associated with the pathogenesis and metabolic characteristics of CRC hold significant clinical implications. Nevertheless, elucidating the genetic, epigenetic, and metabolic landscapes of CRC continues to pose considerable challenges. Here, we attempt to summarize the key genes driving the onset and progression of CRC and the related epigenetic regulators, clarify the roles of gene expression and signaling pathways in tumor metabolism regulation, and explore the potential crosstalk between epigenetic events and tumor metabolic reprogramming, providing a comprehensive mechanistic explanation for the malignant progression of CRC. Finally, by integrating reliable targets from genetics, epigenetics, and metabolic processes that hold promise for translation into clinical practice, we aim to offer more strategies to overcome the bottlenecks in CRC treatment.
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Affiliation(s)
- Jingyuan Li
- Institute of Digestive DiseasesChina‐Canada Center of Research for Digestive DiseasesLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine (Shanghai University of Traditional Chinese Medicine)ShanghaiChina
| | - Jiashu Pan
- Institute of Digestive DiseasesChina‐Canada Center of Research for Digestive DiseasesLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine (Shanghai University of Traditional Chinese Medicine)ShanghaiChina
| | - Lisheng Wang
- Department of BiochemistryMicrobiology and ImmunologyFaculty of MedicineUniversity of OttawaOttawaOntarioCanada
- China‐Canada Centre of Research for Digestive DiseasesUniversity of OttawaOttawaOntarioCanada
| | - Guang Ji
- Institute of Digestive DiseasesChina‐Canada Center of Research for Digestive DiseasesLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine (Shanghai University of Traditional Chinese Medicine)ShanghaiChina
| | - Yanqi Dang
- Institute of Digestive DiseasesChina‐Canada Center of Research for Digestive DiseasesLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine (Shanghai University of Traditional Chinese Medicine)ShanghaiChina
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2
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Baba Y, Hara Y, Toihata T, Kosumi K, Iwatsuki M, Iwagami S, Miyamoto Y, Yoshida N, Komohara Y, Baba H. Relationship between gut microbiome Fusobacterium nucleatum and LINE-1 methylation level in esophageal cancer. Esophagus 2023; 20:704-712. [PMID: 37173453 DOI: 10.1007/s10388-023-01009-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Accepted: 04/17/2023] [Indexed: 05/15/2023]
Abstract
BACKGROUND We previously demonstrated the relationship of human microbiome Fusobacterium nucleatum with unfavorable clinical outcomes and inferior chemotherapeutic responses in esophageal cancer. Global DNA methylation is associated with the occurrence and development of various cancers. In our previous study, LINE-1 hypomethylation (i.e., global DNA hypomethylation) was associated with a poor prognosis in esophageal cancer. As the gut microbiota may play crucial roles in the DNA methylation of host cells, we hypothesized that F. nucleatum might influence LINE-1 methylation levels in esophageal cancer. METHODS We qualified the F. nucleatum DNA using a quantitative PCR assay and LINE-1 methylation via a pyrosequencing assay using formalin-fixed paraffin-embedded specimens from 306 esophageal cancer patients. RESULTS Intratumoral F. nucleatum DNA was detected in 65 cases (21.2%). The LINE-1 methylation scores ranged from 26.9 to 91.8 (median = 64.8) in tumors. F. nucleatum DNA was related to the LINE-1 hypomethylation of tumor lesions in esophageal cancer (P < 0.0001). The receiver operating characteristic curve analysis showed that the area under the curve was 0.71 for F. nucleatum positivity. Finally, we found that the impact of F. nucleatum on clinical outcomes was not modified by LINE-1 hypomethylation (P for interaction = 0.34). CONCLUSIONS F. nucleatum alters genome-wide methylation levels in cancer cells, which may be one of the mechanisms by which F. nucleatum affects the malignant behavior of esophageal cancer.
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Affiliation(s)
- Yoshifumi Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-Ku, Kumamoto, 860-8556, Japan.
- Department of Next-Generation Surgical Therapy Development, Kumamoto University Hospital, 1-1-1 Honjo, Chuo-Ku, Kumamoto, 860-8556, Japan.
| | - Yoshihiro Hara
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-Ku, Kumamoto, 860-8556, Japan
| | - Tasuku Toihata
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-Ku, Kumamoto, 860-8556, Japan
| | - Keisuke Kosumi
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-Ku, Kumamoto, 860-8556, Japan
- Department of Next-Generation Surgical Therapy Development, Kumamoto University Hospital, 1-1-1 Honjo, Chuo-Ku, Kumamoto, 860-8556, Japan
| | - Masaaki Iwatsuki
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-Ku, Kumamoto, 860-8556, Japan
| | - Shiro Iwagami
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-Ku, Kumamoto, 860-8556, Japan
| | - Yuji Miyamoto
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-Ku, Kumamoto, 860-8556, Japan
| | - Naoya Yoshida
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-Ku, Kumamoto, 860-8556, Japan
| | - Yoshihiro Komohara
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-Ku, Kumamoto, 860-8556, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-Ku, Kumamoto, 860-8556, Japan
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3
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Gebrie A. Transposable elements as essential elements in the control of gene expression. Mob DNA 2023; 14:9. [PMID: 37596675 PMCID: PMC10439571 DOI: 10.1186/s13100-023-00297-3] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 08/08/2023] [Indexed: 08/20/2023] Open
Abstract
Interspersed repetitions called transposable elements (TEs), commonly referred to as mobile elements, make up a significant portion of the genomes of higher animals. TEs contribute in controlling the expression of genes locally and even far away at the transcriptional and post-transcriptional levels, which is one of their significant functional effects on gene function and genome evolution. There are different mechanisms through which TEs control the expression of genes. First, TEs offer cis-regulatory regions in the genome with their inherent regulatory features for their own expression, making them potential factors for controlling the expression of the host genes. Promoter and enhancer elements contain cis-regulatory sites generated from TE, which function as binding sites for a variety of trans-acting factors. Second, a significant portion of miRNAs and long non-coding RNAs (lncRNAs) have been shown to have TEs that encode for regulatory RNAs, revealing the TE origin of these RNAs. Furthermore, it was shown that TE sequences are essential for these RNAs' regulatory actions, which include binding to the target mRNA. By being a member of cis-regulatory and regulatory RNA sequences, TEs therefore play essential regulatory roles. Additionally, it has been suggested that TE-derived regulatory RNAs and cis-regulatory regions both contribute to the evolutionary novelty of gene regulation. Additionally, these regulatory systems arising from TE frequently have tissue-specific functions. The objective of this review is to discuss TE-mediated gene regulation, with a particular emphasis on the processes, contributions of various TE types, differential roles of various tissue types, based mostly on recent studies on humans.
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Affiliation(s)
- Alemu Gebrie
- Department of Biomedical Sciences, School of Medicine, Debre Markos University, Debre Markos, Ethiopia.
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4
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Qin T, Li S, Henry LE, Chou E, Cavalcante RG, Garb BF, D'Silva NJ, Rozek LS, Sartor MA. Whole-genome CpG-resolution DNA Methylation Profiling of HNSCC Reveals Distinct Mechanisms of Carcinogenesis for Fine-scale HPV+ Cancer Subtypes. CANCER RESEARCH COMMUNICATIONS 2023; 3:1701-1715. [PMID: 37654626 PMCID: PMC10467604 DOI: 10.1158/2767-9764.crc-23-0009] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 05/24/2023] [Accepted: 07/28/2023] [Indexed: 09/02/2023]
Abstract
DNA methylation is a vital early step in carcinogenesis. Most findings of aberrant DNA methylation in head and neck squamous cell carcinomas (HNSCC) are array based with limited coverage and resolution, and mainly explored by human papillomavirus (HPV) status, ignoring the high heterogeneity of this disease. In this study, we performed whole-genome bisulfite sequencing on a well-studied HNSCC cohort (n = 36) and investigated the methylation changes between fine-scaled HNSCC subtypes in relation to genomic instability, repetitive elements, gene expression, and key carcinogenic pathways. The previously observed hypermethylation phenotype in HPV-positive (HPV+) tumors compared with HPV-negative tumors was robustly present in the immune-strong (IMU) HPV+ subtype but absent in the highly keratinized (KRT) HPV+ subtype. Methylation levels of IMU tumors were significantly higher in repetitive elements, and methylation showed a significant correlation with genomic stability, consistent with the IMU subtype having more genomic stability and better prognosis. Expression quantitative trait methylation (cis-eQTM) analysis revealed extensive functionally-relevant differences, and differential methylation pathway analysis recapitulated gene expression pathway differences between subtypes. Consistent with their characteristics, KRT and HPV-negative tumors had high regulatory potential for multiple regulators of keratinocyte differentiation, which positively correlated with an expression-based keratinization score. Together, our findings revealed distinct mechanisms of carcinogenesis between subtypes in HPV+ HNSCC and uncovered previously ignored epigenomic differences and clinical implications, illustrating the importance of fine-scale subtype analysis in cancer. Significance This study revealed that the previously observed hypermethylation of HPV(+) HNSCC is due solely to the IMU subtype, illustrating the importance of fine-scale subtype analysis in such a heterogeneous disease. Particularly, IMU has significantly higher methylation of transposable elements, which can be tested as a prognosis biomarker in future translational studies.
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Affiliation(s)
- Tingting Qin
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan
| | - Shiting Li
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan
| | - Leanne E. Henry
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan
| | - Elysia Chou
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan
| | - Raymond G. Cavalcante
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan
| | - Bailey F. Garb
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan
| | - Nisha J. D'Silva
- Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, Michigan
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
- Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan
| | - Laura S. Rozek
- Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, Michigan
| | - Maureen A. Sartor
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan
- Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan
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5
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Marx O, Mankarious M, Yochum G. Molecular genetics of early-onset colorectal cancer. World J Biol Chem 2023; 14:13-27. [PMID: 37034132 PMCID: PMC10080548 DOI: 10.4331/wjbc.v14.i2.13] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 12/20/2022] [Accepted: 02/13/2023] [Indexed: 03/24/2023] Open
Abstract
Early-onset colorectal cancer (EOCRC) has been rising in global prevalence and incidence over the past several decades. Environmental influences, including generational lifestyle changes and rising obesity, contribute to these increased rates. While the rise in EOCRC is best documented in western countries, it is seen throughout the world, although EOCRC may have distinct genetic mutations in patients of different ethnic backgrounds. Pathological and molecular characterizations show that EOCRC has a distinct presentation compared with later-onset colorectal cancer (LOCRC). Recent studies have identified DNA, RNA, and protein-level alterations unique to EOCRC, revealing much-needed biomarkers and potential novel therapeutic targets. Many molecular EOCRC studies have been performed with Caucasian and Asian EOCRC cohorts, however, studies of other ethnic backgrounds are limited. In addition, certain molecular characterizations that have been conducted for LOCRC have not yet been repeated in EOCRC, including high-throughput analyses of histone modifications, mRNA splicing, and proteomics on large cohorts. We propose that the complex relationship between cancer and aging should be considered when studying the molecular underpinnings of EOCRC. In this review, we summarize current EOCRC literature, focusing on sporadic molecular alterations in tumors, and their clinical implications. We conclude by discussing current challenges and future directions of EOCRC research efforts.
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Affiliation(s)
- Olivia Marx
- Department of Biochemistry & Molecular Biology, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States
| | - Marc Mankarious
- Department of Surgery, Division of Colon & Rectal Surgery, Pennsylvania State University Milton S. Hershey Medical Center, Hershey, PA 17033, United States
| | - Gregory Yochum
- Department of Biochemistry & Molecular Biology & Surgery, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States
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6
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Liu Z, Georgakopoulos-Soares I, Ahituv N, Wong KC. Risk scoring based on DNA methylation-driven related DEGs for colorectal cancer prognosis with systematic insights. Life Sci 2023; 316:121413. [PMID: 36682524 DOI: 10.1016/j.lfs.2023.121413] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 01/13/2023] [Accepted: 01/16/2023] [Indexed: 01/22/2023]
Abstract
Colorectal cancer is a common malignant tumor of the digestive tract. Despite advances in diagnostic techniques and medications. Its prognosis remains challenging. DNA methylation-driven related circulating tumor cells have attracted enormous interest in diagnosing owing to their non-invasive nature and early recognition properties. However, the mechanism through which risk biomarkers act remains elusive. Here, we designed a risk model based on differentially expressed genes, DNA methylation, robust, and survival-related factors in the framework of Cox regression. The model has satisfactory performance and is independently verified by an external and isolated dataset in terms of C-index value, ROC, and tROC. The model was applied to Colorectal cancer patients who were subsequently divided into high- and low-risk groups. Functional annotations, genomic alterations, tumor immune environment, and drug sensitivity were analyzed. We observed that up-regulated genes are associated with epithelial cell differentiation and MAPK signaling pathways. The down-regulated genes are related to IL-7 signaling and apoptosis-induced DNA fragmentation. Interestingly, the immune system was inhibited in high-risk groups. High-frequency mutation genes tend to co-occur. High-risk score patients are related to copy number amplification events. To address the challenges, we suggested eleven and twenty-one drugs that are sensitive to low- and high-risk patients. Finally, an artificial neural network was provided to evaluate the immunotherapeutic efficiency. Taken together, the findings demonstrated that our risk score model is robust and reliable for evaluating the prognosis with novel diagnostic and treatment targets. It also yields benefits for the treatment and provides unique insights into developing therapeutic strategies.
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Affiliation(s)
- Zhe Liu
- Department of Computer Science, City University of Hong Kong, Hong Kong, China
| | - Ilias Georgakopoulos-Soares
- Institute for Personalized Medicine, Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, USA; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA; Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
| | - Nadav Ahituv
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA; Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
| | - Ka-Chun Wong
- Department of Computer Science, City University of Hong Kong, Hong Kong, China.
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7
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Anugwom C, Braimoh G, Sultan A, Johnson WM, Debes JD, Mohammed A. Epidemiology and genetics of early onset colorectal cancer—African overview with a focus on Ethiopia. Semin Oncol 2023:S0093-7754(23)00040-4. [PMID: 37032270 DOI: 10.1053/j.seminoncol.2023.03.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 03/28/2023] [Accepted: 03/28/2023] [Indexed: 04/03/2023]
Abstract
Colorectal cancer (CRC) is a common cause of cancer-related death worldwide, with high rates of late diagnosis and increased mortality in sub-Saharan Africa. Furthermore, there is an alarming uptrend in the incidence of early onset colorectal cancer (EOCRC) across the globe, thus necessitating the need for early screening in general and special populations. There is, however, limited data available on the incidence and genetic characteristics of EOCRC from resource-poor countries, particularly Africa. Moreover, there is lack of clarity if recommendations and mechanisms proposed based on data from resource-rich countries applies to other regions of the world. In this review, we appraise the literature on EOCRC, its overall incidence, and genetic components as it pertains to sub-Saharan Africa. In addition, we highlight epidemiologic and epigenetic findings of our EOCRC cohort in Ethiopia.
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8
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Liu S, Morihiro K, Takeuchi F, Li Y, Okamoto A. Interstrand crosslinking oligonucleotides elucidate the effect of metal ions on the methylation status of repetitive DNA elements. Front Chem 2023; 11:1122474. [PMID: 36711237 PMCID: PMC9881727 DOI: 10.3389/fchem.2023.1122474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 01/02/2023] [Indexed: 01/15/2023] Open
Abstract
DNA methylation plays an important physiological function in cells, and environmental changes result in fluctuations in DNA methylation levels. Metal ions have become both environmental and health concerns, as they have the potential to disrupt the genomic DNA methylation status, even on specific sequences. In the current research, the methylation status of two typical repetitive DNA elements, i.e., long-interspersed nuclear element-1 (LINE-1) and alpha satellite (α-sat), was imaged and assessed using methylation-specific fluorescence in situ hybridization (MeFISH). This technique elucidated the effect of several metal ions on the methylation levels of repetitive DNA sequences. The upregulation and downregulation of the methylation levels of repetitive DNA elements by various metal ions were confirmed and depended on their concentration. This is the first example to investigate the effects of metal ions on DNA methylation in a sequence-specific manner.
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Affiliation(s)
- Shan Liu
- Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan
| | - Kunihiko Morihiro
- Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan
| | - Fumika Takeuchi
- Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan
| | - Yufeng Li
- The Key Laboratory of Molecular Oncology of Hebei Province, Tangshan People’s Hospital, Tangshan, Hebei, China
| | - Akimitsu Okamoto
- Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan,*Correspondence: Akimitsu Okamoto,
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9
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Nishikawa S, Iwakuma T. Drugs Targeting p53 Mutations with FDA Approval and in Clinical Trials. Cancers (Basel) 2023; 15:429. [PMID: 36672377 PMCID: PMC9856662 DOI: 10.3390/cancers15020429] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 01/01/2023] [Accepted: 01/06/2023] [Indexed: 01/11/2023] Open
Abstract
Mutations in the tumor suppressor p53 (p53) promote cancer progression. This is mainly due to loss of function (LOS) as a tumor suppressor, dominant-negative (DN) activities of missense mutant p53 (mutp53) over wild-type p53 (wtp53), and wtp53-independent oncogenic activities of missense mutp53 by interacting with other tumor suppressors or oncogenes (gain of function: GOF). Since p53 mutations occur in ~50% of human cancers and rarely occur in normal tissues, p53 mutations are cancer-specific and ideal therapeutic targets. Approaches to target p53 mutations include (1) restoration or stabilization of wtp53 conformation from missense mutp53, (2) rescue of p53 nonsense mutations, (3) depletion or degradation of mutp53 proteins, and (4) induction of p53 synthetic lethality or targeting of vulnerabilities imposed by p53 mutations (enhanced YAP/TAZ activities) or deletions (hyperactivated retrotransposons). This review article focuses on clinically available FDA-approved drugs and drugs in clinical trials that target p53 mutations and summarizes their mechanisms of action and activities to suppress cancer progression.
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Affiliation(s)
- Shigeto Nishikawa
- Department of Pediatrics, Division of Hematology & Oncology, Children’s Mercy Research Institute, Kansas City, MO 64108, USA
| | - Tomoo Iwakuma
- Department of Pediatrics, Division of Hematology & Oncology, Children’s Mercy Research Institute, Kansas City, MO 64108, USA
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA
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10
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Kim M, Delgado E, Ko S. DNA methylation in cell plasticity and malignant transformation in liver diseases. Pharmacol Ther 2023; 241:108334. [PMID: 36535346 PMCID: PMC9841769 DOI: 10.1016/j.pharmthera.2022.108334] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 12/09/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022]
Abstract
The liver possesses extraordinary regenerative capacity mainly attributable to the ability of hepatocytes (HCs) and biliary epithelial cells (BECs) to self-replicate. This ability is left over from their bipotent parent cell, the hepatoblast, during development. When this innate regeneration is compromised due to the absence of proliferative parenchymal cells, such as during cirrhosis, HCs and BEC can transdifferentiate; thus, adding another layer of complexity to the process of liver repair. In addition, dysregulated lineage maintenance in these two cell populations has been shown to promote malignant growth in experimental conditions. Here, malignant transformation, driven in part by insufficient maintenance of lineage reprogramming, contributes to end-stage liver disease. Epigenetic changes are key drivers for cell fate decisions as well as transformation by finetuning overall transcription and gene expression. In this review, we address how altered DNA methylation contributes to the initiation and progression of hepatic cell fate conversion and cancer formation. We also discussed the diagnostic and therapeutic potential of targeting DNA methylation in liver cancer, its current limitations, and what future research is necessary to facilitate its contribution to clinical translation.
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Affiliation(s)
- Minwook Kim
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America
| | - Evan Delgado
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America; Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America
| | - Sungjin Ko
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America; Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America.
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11
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Omar M, Alexiou M, Rekhi UR, Lehmann K, Bhardwaj A, Delyea C, Elahi S, Febbraio M. DNA methylation changes underlie the long-term association between periodontitis and atherosclerotic cardiovascular disease. Front Cardiovasc Med 2023; 10:1164499. [PMID: 37153468 PMCID: PMC10160482 DOI: 10.3389/fcvm.2023.1164499] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Accepted: 03/22/2023] [Indexed: 05/09/2023] Open
Abstract
Periodontitis, the leading cause of adult tooth loss, has been identified as an independent risk factor for cardiovascular disease (CVD). Studies suggest that periodontitis, like other CVD risk factors, shows the persistence of increased CVD risk even after mitigation. We hypothesized that periodontitis induces epigenetic changes in hematopoietic stem cells in the bone marrow (BM), and such changes persist after the clinical elimination of the disease and underlie the increased CVD risk. We used a BM transplant approach to simulate the clinical elimination of periodontitis and the persistence of the hypothesized epigenetic reprogramming. Using the low-density lipoprotein receptor knockout (LDLRo ) atherosclerosis mouse model, BM donor mice were fed a high-fat diet to induce atherosclerosis and orally inoculated with Porphyromonas gingivalis (Pg), a keystone periodontal pathogen; the second group was sham-inoculated. Naïve LDLR o mice were irradiated and transplanted with BM from one of the two donor groups. Recipients of BM from Pg-inoculated donors developed significantly more atherosclerosis, accompanied by cytokine/chemokines that suggested BM progenitor cell mobilization and were associated with atherosclerosis and/or PD. Using whole-genome bisulfite sequencing, 375 differentially methylated regions (DMRs) and global hypomethylation in recipients of BM from Pg-inoculated donors were observed. Some DMRs pointed to the involvement of enzymes with major roles in DNA methylation and demethylation. In validation assays, we found a significant increase in the activity of ten-eleven translocase-2 and a decrease in the activity of DNA methyltransferases. Plasma S-adenosylhomocysteine levels were significantly higher, and the S-adenosylmethionine to S-adenosylhomocysteine ratio was decreased, both of which have been associated with CVD. These changes may be related to increased oxidative stress as a result of Pg infection. These data suggest a novel and paradigm-shifting mechanism in the long-term association between periodontitis and atherosclerotic CVD.
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12
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Xu R, Li S, Wu Y, Yue X, Wong EM, Southey MC, Hopper JL, Abramson MJ, Li S, Guo Y. Wildfire-related PM 2.5 and DNA methylation: An Australian twin and family study. ENVIRONMENT INTERNATIONAL 2023; 171:107704. [PMID: 36542997 DOI: 10.1016/j.envint.2022.107704] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 11/24/2022] [Accepted: 12/16/2022] [Indexed: 06/17/2023]
Abstract
BACKGROUND Wildfire-related fine particulate matter (PM2.5) has many adverse health impacts, but its impacts on human epigenome are unknown. We aimed to evaluate the associations between long-term exposure to wildfire-related PM2.5 and blood DNA methylation, and whether the associations differ from those with non-wildfire-related PM2.5. METHODS We studied 479 Australian women comprising 132 twin pairs and 215 of their sisters. Blood-derived DNA methylation was measured using the HumanMethylation450 BeadChip array. Data on 3-year (year of blood collection and previous two years) average wildfire-related and non-wildfire-related PM2.5 at 0.01°×0.01° spatial resolution were created by combining information from satellite observations, chemical transport models, and ground-based observations. Exposure data were linked to each participant's home address, assuming the address did not change during the exposure window. For DNA methylation of each cytosine-guanine dinucleotide (CpG), and for global DNA methylation represented by the average of all measured CpGs or CpGs in repetitive elements, we evaluated their associations with wildfire- or non-wildfire-related PM2.5 using a within-sibship analysis controlling for factors shared between siblings and other important covariates. Differentially methylated regions (DMRs) were defined by comb-p and DMRcate. RESULTS The 3-year average wildfire-related PM2.5 (range: 0.3 to 7.6 µg/m3, mean: 1.6 µg/m3) was negatively, but not significantly (p-values greater than 0.05) associated with all seven global DNA methylation measures. There were 26 CpGs and 33 DMRs associated with wildfire-related PM2.5 (Bonferroni adjusted p-value < 0.05) mapped to 47 genes enriched for pathways related to inflammatory regulation and platelet activation. These genes have been related to many human diseases or phenotypes e.g., cancer, mental disorders, diabetes, obesity, asthma, blood pressure. These CpGs, DMRs and enriched pathways did not overlap with the 1 CpG and 7 DMRs associated with non-wildfire-related PM2.5. CONCLUSIONS Long-term exposure to wildfire-related PM2.5 was associated with various blood DNA methylation signatures in Australian women, and these were distinct from those associated with non-wildfire-related PM2.5.
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Affiliation(s)
- Rongbin Xu
- School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC 3004, Australia
| | - Shanshan Li
- School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC 3004, Australia
| | - Yao Wu
- School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC 3004, Australia
| | - Xu Yue
- Jiangsu Key Laboratory of Atmospheric Environment Monitoring and Pollution Control, Collaborative Innovation Center of Atmospheric Environment and Equipment Technology, School of Environmental Science and Engineering, Nanjing University of Information Science and Technology, Nanjing, China
| | - Ee Ming Wong
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC 3800, Australia; Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Melbourne, VIC 3010, Australia
| | - Melissa C Southey
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC 3800, Australia; Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Melbourne, VIC 3010, Australia; Cancer Epidemiology Division, Cancer Council Victoria, VIC 3004, Australia
| | - John L Hopper
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC 3010, Australia
| | - Michael J Abramson
- School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC 3004, Australia
| | - Shuai Li
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC 3800, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC 3010, Australia; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK; Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia
| | - Yuming Guo
- School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC 3004, Australia.
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Wang Q, Xiong F, Wu G, Liu W, Chen J, Wang B, Chen Y. Gene body methylation in cancer: molecular mechanisms and clinical applications. Clin Epigenetics 2022; 14:154. [PMID: 36443876 PMCID: PMC9706891 DOI: 10.1186/s13148-022-01382-9] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 11/18/2022] [Indexed: 11/29/2022] Open
Abstract
DNA methylation is an important epigenetic mechanism that regulates gene expression. To date, most DNA methylation studies have focussed on CpG islands in the gene promoter region, and the mechanism of methylation and the regulation of gene expression after methylation have been clearly elucidated. However, genome-wide methylation studies have shown that DNA methylation is widespread not only in promoters but also in gene bodies. Gene body methylation is widely involved in the expression regulation of many genes and is closely related to the occurrence and progression of malignant tumours. This review focusses on the formation of gene body methylation patterns, its regulation of transcription, and its relationship with tumours, providing clues to explore the mechanism of gene body methylation in regulating gene transcription and its significance and application in the field of oncology.
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Affiliation(s)
- Qi Wang
- grid.33199.310000 0004 0368 7223Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Road, Wuhan, 430074 Hubei Province China
| | - Fei Xiong
- grid.33199.310000 0004 0368 7223Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Road, Wuhan, 430074 Hubei Province China
| | - Guanhua Wu
- grid.33199.310000 0004 0368 7223Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Road, Wuhan, 430074 Hubei Province China
| | - Wenzheng Liu
- grid.33199.310000 0004 0368 7223Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Road, Wuhan, 430074 Hubei Province China
| | - Junsheng Chen
- grid.33199.310000 0004 0368 7223Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Road, Wuhan, 430074 Hubei Province China
| | - Bing Wang
- grid.33199.310000 0004 0368 7223Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Road, Wuhan, 430074 Hubei Province China
| | - Yongjun Chen
- grid.33199.310000 0004 0368 7223Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Road, Wuhan, 430074 Hubei Province China
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14
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Volovat SR, Augustin I, Zob D, Boboc D, Amurariti F, Volovat C, Stefanescu C, Stolniceanu CR, Ciocoiu M, Dumitras EA, Danciu M, Apostol DGC, Drug V, Shurbaji SA, Coca LG, Leon F, Iftene A, Herghelegiu PC. Use of Personalized Biomarkers in Metastatic Colorectal Cancer and the Impact of AI. Cancers (Basel) 2022; 14:4834. [PMID: 36230757 PMCID: PMC9562853 DOI: 10.3390/cancers14194834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Revised: 09/18/2022] [Accepted: 09/29/2022] [Indexed: 12/09/2022] Open
Abstract
Colorectal cancer is a major cause of cancer-related death worldwide and is correlated with genetic and epigenetic alterations in the colonic epithelium. Genetic changes play a major role in the pathophysiology of colorectal cancer through the development of gene mutations, but recent research has shown an important role for epigenetic alterations. In this review, we try to describe the current knowledge about epigenetic alterations, including DNA methylation and histone modifications, as well as the role of non-coding RNAs as epigenetic regulators and the prognostic and predictive biomarkers in metastatic colorectal disease that can allow increases in the effectiveness of treatments. Additionally, the intestinal microbiota's composition can be an important biomarker for the response to strategies based on the immunotherapy of CRC. The identification of biomarkers in mCRC can be enhanced by developing artificial intelligence programs. We present the actual models that implement AI technology as a bridge connecting ncRNAs with tumors and conducted some experiments to improve the quality of the model used as well as the speed of the model that provides answers to users. In order to carry out this task, we implemented six algorithms: the naive Bayes classifier, the random forest classifier, the decision tree classifier, gradient boosted trees, logistic regression and SVM.
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Affiliation(s)
- Simona-Ruxandra Volovat
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania
| | - Iolanda Augustin
- Department of Medical Oncology, AI.Trestioreanu Institute of Oncology, 022328 Bucharest, Romania
| | - Daniela Zob
- Department of Medical Oncology, AI.Trestioreanu Institute of Oncology, 022328 Bucharest, Romania
| | - Diana Boboc
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania
| | - Florin Amurariti
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania
| | - Constantin Volovat
- Department of Medical Oncology, “Euroclinic” Center of Oncology, 2 Vasile Conta Str., 700106 Iasi, Romania
| | - Cipriana Stefanescu
- Department of Biophysics and Medical Physics-Nuclear Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania
| | - Cati Raluca Stolniceanu
- Department of Biophysics and Medical Physics-Nuclear Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania
| | - Manuela Ciocoiu
- Department of Pathophysiology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Eduard Alexandru Dumitras
- Department of Pathophysiology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
- Department of Anesthesiology and Intensive Care, Regional Institute of Oncology, 700115 Iasi, Romania
| | - Mihai Danciu
- Pathology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | | | - Vasile Drug
- Department of Gastroenterology, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania
- Gastroenterology Clinic, Institute of Gastroenterology and Hepatology, ‘St. Spiridon’ Clinical Hospital, 700115 Iasi, Romania
| | - Sinziana Al Shurbaji
- Gastroenterology Clinic, Institute of Gastroenterology and Hepatology, ‘St. Spiridon’ Clinical Hospital, 700115 Iasi, Romania
| | - Lucia-Georgiana Coca
- Faculty of Computer Science, Alexandru Ioan Cuza University, 700115 Iasi, Romania
| | - Florin Leon
- Faculty of Automatic Control and Computer Engineering, Gheorghe Asachi Technical University, 700115 Iasi, Romania
| | - Adrian Iftene
- Faculty of Computer Science, Alexandru Ioan Cuza University, 700115 Iasi, Romania
| | - Paul-Corneliu Herghelegiu
- Faculty of Automatic Control and Computer Engineering, Gheorghe Asachi Technical University, 700115 Iasi, Romania
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15
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Khayami R, Goltzman D, Rabbani SA, Kerachian MA. Epigenomic effects of vitamin D in colorectal cancer. Epigenomics 2022; 14:1213-1228. [PMID: 36325830 DOI: 10.2217/epi-2022-0288] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Vitamin D regulates a plethora of physiological processes in the human body and has been proposed to exert several anticancer effects. Epigenetics plays an important role in regulating vitamin D actions. In this review, we highlight the recent advances in the understanding of different epigenetic factors such as lncRNAs, miRNAs, methylation and acetylation influenced by vitamin D and its downstream targets in colorectal cancer to find more potential therapeutic targets. We discuss how vitamin D exerts anticancer properties through interactions between the vitamin D receptor and genes (e.g., SLC30A10), the microenvironment, microbiota and other factors in colorectal cancer. Developing therapeutic approaches targeting the vitamin D signaling system will be aided by a better knowledge of the epigenetic impact of vitamin D.
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Affiliation(s)
- Reza Khayami
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - David Goltzman
- Department of Medicine, McGill University Health Center, Montreal, QC, H3G 1A4, Canada
| | - Shafaat A Rabbani
- Department of Medicine, McGill University Health Center, Montreal, QC, H3G 1A4, Canada
| | - Mohammad Amin Kerachian
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Chemistry and Biology, Toronto Metropolitan University, Toronto, On, H3A 1A4, Canada
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16
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Ghavami S, Zamani M, Ahmadi M, Erfani M, Dastghaib S, Darbandi M, Darbandi S, Vakili O, Siri M, Grabarek BO, Boroń D, Zarghooni M, Wiechec E, Mokarram P. Epigenetic regulation of autophagy in gastrointestinal cancers. Biochim Biophys Acta Mol Basis Dis 2022; 1868:166512. [PMID: 35931405 DOI: 10.1016/j.bbadis.2022.166512] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 07/11/2022] [Accepted: 07/28/2022] [Indexed: 11/09/2022]
Abstract
The development of novel therapeutic approaches is necessary to manage gastrointestinal cancers (GICs). Considering the effective molecular mechanisms involved in tumor growth, the therapeutic response is pivotal in this process. Autophagy is a highly conserved catabolic process that acts as a double-edged sword in tumorigenesis and tumor inhibition in a context-dependent manner. Depending on the stage of malignancy and cellular origin of the tumor, autophagy might result in cancer cell survival or death during the GICs' progression. Moreover, autophagy can prevent the progression of GIC in the early stages but leads to chemoresistance in advanced stages. Therefore, targeting specific arms of autophagy could be a promising strategy in the prevention of chemoresistance and treatment of GIC. It has been revealed that autophagy is a cytoplasmic event that is subject to transcriptional and epigenetic regulation inside the nucleus. The effect of epigenetic regulation (including DNA methylation, histone modification, and expression of non-coding RNAs (ncRNAs) in cellular fate is still not completely understood. Recent findings have indicated that epigenetic alterations can modify several genes and modulators, eventually leading to inhibition or promotion of autophagy in different cancer stages, and mediating chemoresistance or chemosensitivity. The current review focuses on the links between autophagy and epigenetics in GICs and discusses: 1) How autophagy and epigenetics are linked in GICs, by considering different epigenetic mechanisms; 2) how epigenetics may be involved in the alteration of cancer-related phenotypes, including cell proliferation, invasion, and migration; and 3) how epidrugs modulate autophagy in GICs to overcome chemoresistance.
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Affiliation(s)
- Saeid Ghavami
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Research Institute of Hematology and Oncology, Cancer Care Manitoba, Winnipeg, MB R3E 0V9, Canada; Faculty of Medicine in Zabrze, University of Technology in Katowice, Academia of Silesia, 41-800 Zabrze, Poland.
| | - Mozhdeh Zamani
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mazaher Ahmadi
- Department of Analytical Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran
| | - Mehran Erfani
- Department of Biochemistry, School of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Sanaz Dastghaib
- Endocrinology and Metabolism Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahsa Darbandi
- Fetal Health Research Center, Hope Generation Foundation, Tehran, Iran; Gene Therapy and Regenerative Medicine Research Center, Hope Generation Foundation, Tehran, Iran
| | - Sara Darbandi
- Fetal Health Research Center, Hope Generation Foundation, Tehran, Iran; Gene Therapy and Regenerative Medicine Research Center, Hope Generation Foundation, Tehran, Iran
| | - Omid Vakili
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Morvarid Siri
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Beniamin Oskar Grabarek
- Department of Histology, Cytophysiology, and Embryology in Zabrze, Faculty of Medicine in Zabrze, University of Technology in Katowice, Academia of Silesia, 41-800 Zabrze, Poland; Department of Gynecology and Obstetrics in Zabrze, Faculty of Medicine in Zabrze, University of Technology in Katowice, Academia of Silesia, 41-800 Zabrze, Poland
| | - Dariusz Boroń
- Department of Histology, Cytophysiology, and Embryology in Zabrze, Faculty of Medicine in Zabrze, University of Technology in Katowice, Academia of Silesia, 41-800 Zabrze, Poland; Department of Gynecology and Obstetrics in Zabrze, Faculty of Medicine in Zabrze, University of Technology in Katowice, Academia of Silesia, 41-800 Zabrze, Poland
| | - Maryam Zarghooni
- Department of Laboratory Medicine and Pathobiology, University of Toronto Alumni, Toronto, Canada
| | - Emilia Wiechec
- Division of Cell Biology, Department of Biomedical and Clinical Sciences, Linköping University, 58185 Linköping, Sweden
| | - Pooneh Mokarram
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
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17
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Filipenko ML, Boyarskikh UA, Leskov LS, Subbotina KV, Khrapov EA, Sokolov AV, Stilidi IS, Kushlinskii NE. The Level of LINE-1 mRNA Is Increased in Extracellular Circulating Plasma RNA in Patients with Colorectal Cancer. Bull Exp Biol Med 2022; 173:261-264. [DOI: 10.1007/s10517-022-05530-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Indexed: 10/17/2022]
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18
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Endo Y, Suzuki K, Kimura Y, Tamaki S, Aizawa H, Abe I, Watanabe F, Kato T, Saito M, Futsuhara K, Noda H, Konishi F, Rikiyama T. Genome‑wide DNA hypomethylation drives a more invasive pancreatic cancer phenotype and has predictive occult distant metastasis and prognosis potential. Int J Oncol 2022; 60:61. [PMID: 35419613 PMCID: PMC9015190 DOI: 10.3892/ijo.2022.5351] [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: 01/01/2022] [Accepted: 03/22/2022] [Indexed: 11/06/2022] Open
Abstract
Genome‑wide DNA hypomethylation is the most common molecular feature in human cancers associated with chromosomal instability (CIN), which is involved in the mechanisms that regulate pancreatic cancer (PC) metastasis. It was investigated whether genome‑wide DNA hypomethylation affects the phenotype in PC via CIN in vitro, and its significance on the biological behavior of PC was verified. The relative demethylation level (RDL) of long interspersed nucleotide element‑1 (LINE‑1) in human PC cell lines was used to characterize DNA hypomethylation using methylation‑specific quantitative (q)PCR. CIN was estimated by changes in chromosomal copy number using comparative genomic hybridization analysis. Abnormal segregation of chromosomes was assessed by immunocytochemistry, and the DNA damage response was evaluated using the number of anti‑γH2AX positive cells. Invasion ability was assessed using a Matrigel invasion assay. Clinical specimens from 49 patients with PC who underwent curative surgery were evaluated for a correlation of DNA hypomethylation with clinical outcome. Successful induction of genome‑wide DNA hypomethylation in PC cells led to copy number changes in specific chromosomal regions. The number of cells with abnormal segregation of chromosomes significantly increased with the number of anti‑γH2AX positive cells. The invasive potential of these cells also significantly increased. The occurrence of occult distant metastasis in the clinical specimens and receiver operating characteristic analysis clearly identified those who were and were not likely to have occult distant metastasis, with high LINE‑1 RDL significantly correlated with the presence of occult distant metastasis (P=0.035) and poor prognosis (P=0.048). The significance of genome‑wide DNA hypomethylation on the biological behavior of PC, which promotes a more invasive phenotype via CIN in vitro and predicts the susceptibility to occult distant metastasis and poor prognosis in patients with PC was revealed.
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Affiliation(s)
- Yuhei Endo
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Koichi Suzuki
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Yasuaki Kimura
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Sawako Tamaki
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Hidetoshi Aizawa
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Iku Abe
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Fumiaki Watanabe
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Takaharu Kato
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Masaaki Saito
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Kazushige Futsuhara
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Hiroshi Noda
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | | | - Toshiki Rikiyama
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
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Olive Oil Improves While Trans Fatty Acids Further Aggravate the Hypomethylation of LINE-1 Retrotransposon DNA in an Environmental Carcinogen Model. Nutrients 2022; 14:nu14040908. [PMID: 35215560 PMCID: PMC8878525 DOI: 10.3390/nu14040908] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 02/13/2022] [Accepted: 02/14/2022] [Indexed: 02/08/2023] Open
Abstract
DNA methylation is an epigenetic mechanism that is crucial for mammalian development and genomic stability. Aberrant DNA methylation changes have been detected not only in malignant tumor tissues; the decrease of global DNA methylation levels is also characteristic for aging. The consumption of extra virgin olive oil (EVOO) as part of a balanced diet shows preventive effects against age-related diseases and cancer. On the other hand, consuming trans fatty acids (TFA) increases the risk of cardiovascular diseases as well as cancer. The aim of the study was to investigate the LINE-1 retrotransposon (L1-RTP) DNA methylation pattern in liver, kidney, and spleen of mice as a marker of genetic instability. For that, mice were fed with EVOO or TFA and were pretreated with environmental carcinogen 7,12-dimethylbenz[a]anthracene (DMBA)-a harmful substance known to cause L1-RTP DNA hypomethylation. Our results show that DMBA and its combination with TFA caused significant L1-RTP DNA hypomethylation compared to the control group via inhibition of DNA methyltransferase (DNMT) enzymes. EVOO had the opposite effect by significantly decreasing DMBA and DMBA + TFA-induced hypomethylation, thereby counteracting their effects.
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20
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Integrated single-cell multiomics analysis reveals novel candidate markers for prognosis in human pancreatic ductal adenocarcinoma. Cell Discov 2022; 8:13. [PMID: 35165277 PMCID: PMC8844066 DOI: 10.1038/s41421-021-00366-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 12/14/2021] [Indexed: 12/13/2022] Open
Abstract
The epigenomic abnormality of pancreatic ductal adenocarcinoma (PDAC) has rarely been investigated due to its strong heterogeneity. Here, we used single-cell multiomics sequencing to simultaneously analyze the DNA methylome, chromatin accessibility and transcriptome in individual tumor cells of PDAC patients. We identified normal epithelial cells in the tumor lesion, which have euploid genomes, normal patterns of DNA methylation, and chromatin accessibility. Using all these normal epithelial cells as controls, we determined that DNA demethylation in the cancer genome was strongly enriched in heterochromatin regions but depleted in euchromatin regions. There were stronger negative correlations between RNA expression and promoter DNA methylation in cancer cells compared to those in normal epithelial cells. Through in-depth integrated analyses, a set of novel candidate biomarkers were identified, including ZNF667 and ZNF667-AS1, whose expressions were linked to a better prognosis for PDAC patients by affecting the proliferation of cancer cells. Our work systematically revealed the critical epigenomic features of cancer cells in PDAC patients at the single-cell level.
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21
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Maiuolo J, Gliozzi M, Carresi C, Musolino V, Oppedisano F, Scarano F, Nucera S, Scicchitano M, Bosco F, Macri R, Ruga S, Cardamone A, Coppoletta A, Mollace A, Cognetti F, Mollace V. Nutraceuticals and Cancer: Potential for Natural Polyphenols. Nutrients 2021; 13:nu13113834. [PMID: 34836091 PMCID: PMC8619660 DOI: 10.3390/nu13113834] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/20/2021] [Accepted: 10/25/2021] [Indexed: 12/14/2022] Open
Abstract
Cancer is one of the leading causes of death globally, associated with multifactorial pathophysiological components. In particular, genetic mutations, infection or inflammation, unhealthy eating habits, exposition to radiation, work stress, and/or intake of toxins have been found to contribute to the development and progression of cancer disease states. Early detection of cancer and proper treatment have been found to enhance the chances of survival and healing, but the side effects of anticancer drugs still produce detrimental responses that counteract the benefits of treatment in terms of hospitalization and survival. Recently, several natural bioactive compounds were found to possess anticancer properties, capable of killing transformed or cancerous cells without being toxic to their normal counterparts. This effect occurs when natural products are associated with conventional treatments, thereby suggesting that nutraceutical supplementation may contribute to successful anticancer therapy. This review aims to discuss the current literature on four natural bioactive extracts mostly characterized by a specific polyphenolic profile. In particular, several activities have been reported to contribute to nutraceutical support in anticancer treatment: (1) inhibition of cell proliferation, (2) antioxidant activity, and (3) anti-inflammatory activity. On the other hand, owing to their attenuation of the toxic effect of current anticancer therapies, natural antioxidants may contribute to improving the compliance of patients undergoing anticancer treatment. Thus, nutraceutical supplementation, along with current anticancer drug treatment, may be considered for better responses and compliance in patients with cancer. It should be noted, however, that when data from studies with bioactive plant preparations are discussed, it is appropriate to ensure that experiments have been conducted in accordance with accepted pharmacological research practices so as not to disclose information that is only partially correct.
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Affiliation(s)
- Jessica Maiuolo
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (J.M.); (M.G.); (C.C.); (V.M.); (F.O.); (F.S.); (S.N.); (M.S.); (F.B.); (R.M.); (S.R.); (A.C.); (A.C.)
- Nutramed S.c.a.r.l, Complesso Ninì Barbieri, Roccelletta di Borgia, 88021 Catanzaro, Italy
| | - Micaela Gliozzi
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (J.M.); (M.G.); (C.C.); (V.M.); (F.O.); (F.S.); (S.N.); (M.S.); (F.B.); (R.M.); (S.R.); (A.C.); (A.C.)
- Nutramed S.c.a.r.l, Complesso Ninì Barbieri, Roccelletta di Borgia, 88021 Catanzaro, Italy
| | - Cristina Carresi
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (J.M.); (M.G.); (C.C.); (V.M.); (F.O.); (F.S.); (S.N.); (M.S.); (F.B.); (R.M.); (S.R.); (A.C.); (A.C.)
- Nutramed S.c.a.r.l, Complesso Ninì Barbieri, Roccelletta di Borgia, 88021 Catanzaro, Italy
| | - Vincenzo Musolino
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (J.M.); (M.G.); (C.C.); (V.M.); (F.O.); (F.S.); (S.N.); (M.S.); (F.B.); (R.M.); (S.R.); (A.C.); (A.C.)
- Nutramed S.c.a.r.l, Complesso Ninì Barbieri, Roccelletta di Borgia, 88021 Catanzaro, Italy
| | - Francesca Oppedisano
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (J.M.); (M.G.); (C.C.); (V.M.); (F.O.); (F.S.); (S.N.); (M.S.); (F.B.); (R.M.); (S.R.); (A.C.); (A.C.)
- Nutramed S.c.a.r.l, Complesso Ninì Barbieri, Roccelletta di Borgia, 88021 Catanzaro, Italy
| | - Federica Scarano
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (J.M.); (M.G.); (C.C.); (V.M.); (F.O.); (F.S.); (S.N.); (M.S.); (F.B.); (R.M.); (S.R.); (A.C.); (A.C.)
- Nutramed S.c.a.r.l, Complesso Ninì Barbieri, Roccelletta di Borgia, 88021 Catanzaro, Italy
| | - Saverio Nucera
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (J.M.); (M.G.); (C.C.); (V.M.); (F.O.); (F.S.); (S.N.); (M.S.); (F.B.); (R.M.); (S.R.); (A.C.); (A.C.)
- Nutramed S.c.a.r.l, Complesso Ninì Barbieri, Roccelletta di Borgia, 88021 Catanzaro, Italy
| | - Miriam Scicchitano
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (J.M.); (M.G.); (C.C.); (V.M.); (F.O.); (F.S.); (S.N.); (M.S.); (F.B.); (R.M.); (S.R.); (A.C.); (A.C.)
- Nutramed S.c.a.r.l, Complesso Ninì Barbieri, Roccelletta di Borgia, 88021 Catanzaro, Italy
| | - Francesca Bosco
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (J.M.); (M.G.); (C.C.); (V.M.); (F.O.); (F.S.); (S.N.); (M.S.); (F.B.); (R.M.); (S.R.); (A.C.); (A.C.)
- Nutramed S.c.a.r.l, Complesso Ninì Barbieri, Roccelletta di Borgia, 88021 Catanzaro, Italy
| | - Roberta Macri
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (J.M.); (M.G.); (C.C.); (V.M.); (F.O.); (F.S.); (S.N.); (M.S.); (F.B.); (R.M.); (S.R.); (A.C.); (A.C.)
- Nutramed S.c.a.r.l, Complesso Ninì Barbieri, Roccelletta di Borgia, 88021 Catanzaro, Italy
| | - Stefano Ruga
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (J.M.); (M.G.); (C.C.); (V.M.); (F.O.); (F.S.); (S.N.); (M.S.); (F.B.); (R.M.); (S.R.); (A.C.); (A.C.)
| | - Antonio Cardamone
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (J.M.); (M.G.); (C.C.); (V.M.); (F.O.); (F.S.); (S.N.); (M.S.); (F.B.); (R.M.); (S.R.); (A.C.); (A.C.)
| | - Annarita Coppoletta
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (J.M.); (M.G.); (C.C.); (V.M.); (F.O.); (F.S.); (S.N.); (M.S.); (F.B.); (R.M.); (S.R.); (A.C.); (A.C.)
| | - Annachiara Mollace
- Medical Oncology 1, Regina Elena National Cancer Institute, IRCCS, 00144 Rome, Italy; (A.M.); (F.C.)
| | - Francesco Cognetti
- Medical Oncology 1, Regina Elena National Cancer Institute, IRCCS, 00144 Rome, Italy; (A.M.); (F.C.)
| | - Vincenzo Mollace
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (J.M.); (M.G.); (C.C.); (V.M.); (F.O.); (F.S.); (S.N.); (M.S.); (F.B.); (R.M.); (S.R.); (A.C.); (A.C.)
- Nutramed S.c.a.r.l, Complesso Ninì Barbieri, Roccelletta di Borgia, 88021 Catanzaro, Italy
- IRCCS San Raffaele, Via di Valcannuta 247, 00133 Rome, Italy
- Correspondence:
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Pham DAT, Le SD, Doan TM, Luu PT, Nguyen UQ, Ho SV, Vo LTT. Standardization of DNA amount for bisulfite conversion for analyzing the methylation status of LINE-1 in lung cancer. PLoS One 2021; 16:e0256254. [PMID: 34403448 PMCID: PMC8370637 DOI: 10.1371/journal.pone.0256254] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 08/04/2021] [Indexed: 11/18/2022] Open
Abstract
Highly methylated Long Interspersed Nucleotide Elements 1 (LINE-1) constitute approximately 20% of the human genome, thus serving as a surrogate marker of global genomic DNA methylation. To date, there is still lacking a consensus about the precise location in LINE-1 promoter and its methylation threshold value, making challenging the use of LINE-1 methylation as a diagnostic, prognostic markers in cancer. This study reports on a technical standardization of bisulfite-based DNA methylation analysis, which ensures the complete bisulfite conversion of repeated LINE-1 sequences, thus allowing accurate LINE-1 methylation value. In addition, the study also indicated the precise location in LINE-1 promoter of which significant variance in methylation level makes LINE-1 methylation as a potential diagnostic biomarker for lung cancer. A serial concentration of 5-50-500 ng of DNA from 275 formalin-fixed paraffin-embedded lung tissues were converted by bisulfite; methylation level of two local regions (at nucleotide position 300–368 as LINE-1.1 and 368–460 as LINE-1.2) in LINE-1 promoter was measured by real time PCR. The use of 5 ng of genomic DNA but no more allowed to detect LINE-1 hypomethylation in lung cancer tissue (14.34% versus 16.69% in non-cancerous lung diseases for LINE-1.1, p < 0.0001, and 30.28% versus 32.35% for LINE-1.2, p < 0.05). Our study thus highlighted the optimal and primordial concentration less than 5 ng of genomic DNA guarantees the complete LINE-1 bisulfite conversion, and significant variance in methylation level of the LINE-1 sequence position from 300 to 368 allowed to discriminate lung cancer from non-cancer samples.
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Affiliation(s)
| | - Son Duc Le
- Faculty of Biology, University of Science, Vietnam National University, Hanoi, Vietnam
| | - Trang Mai Doan
- Faculty of Biology, University of Science, Vietnam National University, Hanoi, Vietnam
| | - Phuong Thu Luu
- Faculty of Biology, University of Science, Vietnam National University, Hanoi, Vietnam
| | - Uyen Quynh Nguyen
- Department of Biology, VNU Institute of Microbiology and Biotechnology, Hanoi, Vietnam
| | - Son Van Ho
- Department of Biochemistry, 175 Hospital, Ho Chi Minh City, Vietnam
| | - Lan Thi Thuong Vo
- Faculty of Biology, University of Science, Vietnam National University, Hanoi, Vietnam
- * E-mail:
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23
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Kong C, Fu T. Value of methylation markers in colorectal cancer (Review). Oncol Rep 2021; 46:177. [PMID: 34212989 DOI: 10.3892/or.2021.8128] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 06/18/2021] [Indexed: 11/05/2022] Open
Abstract
Colorectal cancer (CRC) is a multifactorial and multistage process that occurs due to both genetic and epigenetic variations in normal epithelial cells. Analysis of the CRC epigenome has revealed that almost all CRC types have a large number of abnormally methylated genes. Hypermethylation of cell‑free DNA from CRC in the blood or stool is considered as a potential non‑invasive cancer biomarker, and various methylation markers have shown high sensitivity and specificity. The aim of the present review was to examine potential methylation markers in CRC that have been used or are expected to be used in the clinical setting, focusing on their screening, predictive, prognostic and therapeutic roles in CRC.
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Affiliation(s)
- Can Kong
- Department of Gastrointestinal Surgery II, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Tao Fu
- Department of Gastrointestinal Surgery II, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
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24
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Deregulation of Transcriptional Enhancers in Cancer. Cancers (Basel) 2021; 13:cancers13143532. [PMID: 34298745 PMCID: PMC8303223 DOI: 10.3390/cancers13143532] [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: 06/03/2021] [Revised: 06/29/2021] [Accepted: 07/08/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary One of the major challenges in cancer treatments is the dynamic adaptation of tumor cells to cancer therapies. In this regard, tumor cells can modify their response to environmental cues without altering their DNA sequence. This cell plasticity enables cells to undergo morphological and functional changes, for example, during the process of tumour metastasis or when acquiring resistance to cancer therapies. Central to cell plasticity, are the dynamic changes in gene expression that are controlled by a set of molecular switches called enhancers. Enhancers are DNA elements that determine when, where and to what extent genes should be switched on and off. Thus, defects in enhancer function can disrupt the gene expression program and can lead to tumour formation. Here, we review how enhancers control the activity of cancer-associated genes and how defects in these regulatory elements contribute to cell plasticity in cancer. Understanding enhancer (de)regulation can provide new strategies for modulating cell plasticity in tumour cells and can open new research avenues for cancer therapy. Abstract Epigenetic regulations can shape a cell’s identity by reversible modifications of the chromatin that ultimately control gene expression in response to internal and external cues. In this review, we first discuss the concept of cell plasticity in cancer, a process that is directly controlled by epigenetic mechanisms, with a particular focus on transcriptional enhancers as the cornerstone of epigenetic regulation. In the second part, we discuss mechanisms of enhancer deregulation in adult stem cells and epithelial-to-mesenchymal transition (EMT), as two paradigms of cell plasticity that are dependent on epigenetic regulation and serve as major sources of tumour heterogeneity. Finally, we review how genetic variations at enhancers and their epigenetic modifiers contribute to tumourigenesis, and we highlight examples of cancer drugs that target epigenetic modifications at enhancers.
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25
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El-Osaily HH, Ibrahim IH, Essawi ML, Salem SM. Impact of miRNAs expression modulation on the methylation status of breast cancer stem cell-related genes. Clin Transl Oncol 2021; 23:1440-1451. [PMID: 33433838 DOI: 10.1007/s12094-020-02542-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 12/13/2020] [Indexed: 12/24/2022]
Abstract
PURPOSE Altered miRNAs play a crucial role in the emergence of the breast cancer stem cell (BCSC) phenotype. The interplay between miRNAs and methylation enzymes has been documented. One of the most aggressive breast cancer cell lines, MDA-MB-231, has expressed much more DNMT3B than DNMT3A. This study aims to evaluate the ability of miR-203 restoration and miR-150 inhibition to regulate DNMT3B and DNMT3A to modify the methylation level of BCSC-associated genes. METHODS MDA-MB-231 cells were transfected with miR-203 mimic or miR-150 inhibitor or DNMT3B siRNA, and downstream analysis was performed by flow cytometry, real-time PCR and Western blotting. RESULTS DNMT3A and DNMT3B are regulated both by miR-203a-3p and miR-150-5p. Transfection with miR-203 mimic and miR-150 inhibitor significantly reduced the CD44+CD24- subpopulation and down-regulated the expression of CD44 mRNA by increasing promoter methylation levels. SiRNA knockdown of DNMT3B increased the CD44+CD24- subpopulation and the expression of CD44 and ALDH1A3 by decreasing methylation density. The inhibition of miR-150 down-regulated OCT3/4 and SOX2 expression without affecting methylation levels, while miR-203 restoration and miR-150 inhibition down-regulated NANOG expression by elevating the methylation level. A positive-feedback loop was found between miR-203 and its target DNMT3B, as restoring miR-203 suppressed DNMT3B, while knocking down DNMT3B up-regulated miR-203. The restoration of miR-203 and knockdown of DNMT3B decreased methylation levels and increased the expression of miR-141 and miR-200c. CONCLUSIONS The study concluded that miR-203 and miR-150 play a role in the regulation of genes involved in BCSC methylation, including other miRNAs, by targeting DNMT3B and DNMT3A.
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Affiliation(s)
- H H El-Osaily
- Biochemistry Department, Faculty of Pharmacy, Ahram Canadian University, 4th industrial region, 6th of October City, 12585, Giza, Egypt.
| | - I H Ibrahim
- Biochemistry Department, Faculty of Pharmacy for Girls, Al-Azhar University, Cairo, 11651, Egypt
| | - M L Essawi
- Medical Molecular Genetics Department, National Research Centre, Giza, 12622, Egypt
| | - S M Salem
- Molecular Genetics and Enzymology Department, National Research Centre, Giza, 12622, Egypt
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26
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Pappalardo XG, Barra V. Losing DNA methylation at repetitive elements and breaking bad. Epigenetics Chromatin 2021; 14:25. [PMID: 34082816 PMCID: PMC8173753 DOI: 10.1186/s13072-021-00400-z] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Accepted: 05/21/2021] [Indexed: 02/08/2023] Open
Abstract
Background DNA methylation is an epigenetic chromatin mark that allows heterochromatin formation and gene silencing. It has a fundamental role in preserving genome stability (including chromosome stability) by controlling both gene expression and chromatin structure. Therefore, the onset of an incorrect pattern of DNA methylation is potentially dangerous for the cells. This is particularly important with respect to repetitive elements, which constitute the third of the human genome. Main body Repetitive sequences are involved in several cell processes, however, due to their intrinsic nature, they can be a source of genome instability. Thus, most repetitive elements are usually methylated to maintain a heterochromatic, repressed state. Notably, there is increasing evidence showing that repetitive elements (satellites, long interspersed nuclear elements (LINEs), Alus) are frequently hypomethylated in various of human pathologies, from cancer to psychiatric disorders. Repetitive sequences’ hypomethylation correlates with chromatin relaxation and unscheduled transcription. If these alterations are directly involved in human diseases aetiology and how, is still under investigation. Conclusions Hypomethylation of different families of repetitive sequences is recurrent in many different human diseases, suggesting that the methylation status of these elements can be involved in preservation of human health. This provides a promising point of view towards the research of therapeutic strategies focused on specifically tuning DNA methylation of DNA repeats.
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Affiliation(s)
- Xena Giada Pappalardo
- Department of Biomedical and Biotechnological Sciences (BIOMETEC), University of Catania, 95125, Catania, Italy.,National Council of Research, Institute for Biomedical Research and Innovation (IRIB), Unit of Catania, 95125, Catania, Italy
| | - Viviana Barra
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90128, Palermo, Italy.
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27
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Awada Z, Bouaoun L, Nasr R, Tfayli A, Cuenin C, Akika R, Boustany RM, Makoukji J, Tamim H, Zgheib NK, Ghantous A. LINE-1 methylation mediates the inverse association between body mass index and breast cancer risk: A pilot study in the Lebanese population. ENVIRONMENTAL RESEARCH 2021; 197:111094. [PMID: 33839117 DOI: 10.1016/j.envres.2021.111094] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 02/28/2021] [Accepted: 03/24/2021] [Indexed: 06/12/2023]
Abstract
INTRODUCTION Lebanon is among the top countries worldwide in combined incidence and mortality of breast cancer, which raises concern about risk factors peculiar to this country. The underlying molecular mechanisms of breast cancer require elucidation, particularly epigenetics, which is recognized as a molecular sensor to environmental exposures. PURPOSE We aim to explore whether DNA methylation levels of AHRR (marker of cigarette smoking), SLC1A5 and TXLNA (markers of alcohol consumption), and LINE-1 (a genome-wide repetitive retrotransposon) can act as molecular mediators underlying putative associations between breast cancer risk and pertinent extrinsic (tobacco smoking and alcohol consumption) and intrinsic factors [age and body mass index (BMI)]. METHODS This is a cross-sectional pilot study which includes breast cancer cases (N = 65) and controls (N = 54). DNA methylation levels were measured using bisulfite pyrosequencing on available peripheral blood samples (N = 119), and Multivariate Imputation by Chained Equations (MICE) was used to impute missing DNA methylation values in remaining samples. Multiple mediation analysis was performed to assess direct and indirect (via DNA methylation) effects of intrinsic and extrinsic factors on breast cancer risk. RESULTS In relation to exposure, AHRR hypo-methylation was associated with cigarette but not waterpipe smoking, suggesting potentially different biomarkers of these two forms of tobacco use; SLC1A5 and TXLNA methylation were not associated with alcohol consumption; LINE-1 methylation was inversely associated with BMI (β-value [95% confidence interval (CI)] = -0.04 [-0.07, -0.02]), which remained significant after adjustment for age, smoking and alcohol consumption. In relation to breast cancer, there was no detectable association between AHRR, SLC1A5 or TXLNA methylation and cancer risk, but LINE-1 methylation was significantly higher in breast cancer cases when compared to controls (mean ± SD: 72.00 ± 0.66 versus 70.89 ± 0.73, P = 4.67 × 10-14). This difference remained significant after adjustment for confounders (odds ratio (OR) [95% CI] = 9.75[3.74, 25.39]). Moreover, LINE-1 hypo-methylation mediated 83% of the inverse effect of BMI on breast cancer risk. CONCLUSION This pilot study demonstrates that alterations in blood LINE-1 methylation mediate the inverse effect of BMI on breast cancer risk. This warrants large scale studies and stratification based on clinic-pathological types of breast cancer.
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Affiliation(s)
- Zainab Awada
- Department of Pharmacology and Toxicology, American University of Beirut Faculty of Medicine, Beirut, Lebanon; International Agency for Research on Cancer, Lyon, France
| | | | - Rihab Nasr
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut Faculty of Medicine, Beirut, Lebanon
| | - Arafat Tfayli
- Division of Hematology and Oncology, Department of Internal Medicine, American University of Beirut Faculty of Medicine, Beirut, Lebanon
| | - Cyrille Cuenin
- International Agency for Research on Cancer, Lyon, France
| | - Reem Akika
- Department of Pharmacology and Toxicology, American University of Beirut Faculty of Medicine, Beirut, Lebanon
| | - Rose-Mary Boustany
- Department of Biochemistry and Molecular Genetics, American University of Beirut Faculty of Medicine, Beirut, Lebanon; Department of Neurology, American University of Beirut Faculty of Medicine, Beirut, Lebanon
| | - Joelle Makoukji
- Department of Biochemistry and Molecular Genetics, American University of Beirut Faculty of Medicine, Beirut, Lebanon
| | - Hani Tamim
- Department of Internal Medicine and Clinical Research Institute, American University of Beirut Faculty of Medicine, Beirut, Lebanon
| | - Nathalie K Zgheib
- Department of Pharmacology and Toxicology, American University of Beirut Faculty of Medicine, Beirut, Lebanon.
| | - Akram Ghantous
- International Agency for Research on Cancer, Lyon, France.
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28
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Akimoto N, Zhao M, Ugai T, Zhong R, Lau MC, Fujiyoshi K, Kishikawa J, Haruki K, Arima K, Twombly TS, Zhang X, Giovannucci EL, Wu K, Song M, Chan AT, Cao Y, Meyerhardt JA, Ng K, Giannakis M, Väyrynen JP, Nowak JA, Ogino S. Tumor Long Interspersed Nucleotide Element-1 (LINE-1) Hypomethylation in Relation to Age of Colorectal Cancer Diagnosis and Prognosis. Cancers (Basel) 2021; 13:2016. [PMID: 33922024 PMCID: PMC8122644 DOI: 10.3390/cancers13092016] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 04/17/2021] [Accepted: 04/18/2021] [Indexed: 12/12/2022] Open
Abstract
Evidence indicates the pathogenic role of epigenetic alterations in early-onset colorectal cancers diagnosed before age 50. However, features of colorectal cancers diagnosed at age 50-54 (hereafter referred to as "intermediate-onset") remain less known. We hypothesized that tumor long interspersed nucleotide element-1 (LINE-1) hypomethylation might be increasingly more common with decreasing age of colorectal cancer diagnosis. In 1356 colorectal cancers, including 28 early-onset and 66 intermediate-onset cases, the tumor LINE-1 methylation level measured by bisulfite-PCR-pyrosequencing (scaled 0 to 100) showed a mean of 63.6 (standard deviation (SD) 10.1). The mean tumor LINE-1 methylation level decreased with decreasing age (mean 64.7 (SD 10.4) in age ≥70, 62.8 (SD 9.4) in age 55-69, 61.0 (SD 10.2) in age 50-54, and 58.9 (SD 12.0) in age <50; p < 0.0001). In linear regression analysis, the multivariable-adjusted β coefficient (95% confidence interval (CI)) (vs. age ≥70) was -1.38 (-2.47 to -0.30) for age 55-69, -2.82 (-5.29 to -0.34) for age 50-54, and -4.54 (-8.24 to -0.85) for age <50 (Ptrend = 0.0003). Multivariable-adjusted hazard ratios (95% CI) for LINE-1 methylation levels of ≤45, 45-55, and 55-65 (vs. >65) were 2.33 (1.49-3.64), 1.39 (1.05-1.85), and 1.29 (1.02-1.63), respectively (Ptrend = 0.0005). In conclusion, tumor LINE-1 hypomethylation is increasingly more common with decreasing age of colorectal cancer diagnosis, suggesting a role of global DNA hypomethylation in colorectal cancer arising in younger adults.
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Affiliation(s)
- Naohiko Akimoto
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (N.A.); (M.Z.); (T.U.); (R.Z.); (M.C.L.); (K.F.); (J.K.); (K.H.); (K.A.); (T.S.T.); (J.A.N.)
- Department of Gastroenterology, Nippon Medical School, Graduate School of Medicine, Tokyo 1138602, Japan
| | - Melissa Zhao
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (N.A.); (M.Z.); (T.U.); (R.Z.); (M.C.L.); (K.F.); (J.K.); (K.H.); (K.A.); (T.S.T.); (J.A.N.)
| | - Tomotaka Ugai
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (N.A.); (M.Z.); (T.U.); (R.Z.); (M.C.L.); (K.F.); (J.K.); (K.H.); (K.A.); (T.S.T.); (J.A.N.)
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston 02115, MA, USA; (E.L.G.); (K.W.)
| | - Rong Zhong
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (N.A.); (M.Z.); (T.U.); (R.Z.); (M.C.L.); (K.F.); (J.K.); (K.H.); (K.A.); (T.S.T.); (J.A.N.)
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston 02115, MA, USA; (E.L.G.); (K.W.)
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Mai Chan Lau
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (N.A.); (M.Z.); (T.U.); (R.Z.); (M.C.L.); (K.F.); (J.K.); (K.H.); (K.A.); (T.S.T.); (J.A.N.)
| | - Kenji Fujiyoshi
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (N.A.); (M.Z.); (T.U.); (R.Z.); (M.C.L.); (K.F.); (J.K.); (K.H.); (K.A.); (T.S.T.); (J.A.N.)
| | - Junko Kishikawa
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (N.A.); (M.Z.); (T.U.); (R.Z.); (M.C.L.); (K.F.); (J.K.); (K.H.); (K.A.); (T.S.T.); (J.A.N.)
| | - Koichiro Haruki
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (N.A.); (M.Z.); (T.U.); (R.Z.); (M.C.L.); (K.F.); (J.K.); (K.H.); (K.A.); (T.S.T.); (J.A.N.)
| | - Kota Arima
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (N.A.); (M.Z.); (T.U.); (R.Z.); (M.C.L.); (K.F.); (J.K.); (K.H.); (K.A.); (T.S.T.); (J.A.N.)
| | - Tyler S. Twombly
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (N.A.); (M.Z.); (T.U.); (R.Z.); (M.C.L.); (K.F.); (J.K.); (K.H.); (K.A.); (T.S.T.); (J.A.N.)
| | - Xuehong Zhang
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA; (X.Z.); (A.T.C.)
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA;
| | - Edward L. Giovannucci
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston 02115, MA, USA; (E.L.G.); (K.W.)
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA; (X.Z.); (A.T.C.)
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA;
| | - Kana Wu
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston 02115, MA, USA; (E.L.G.); (K.W.)
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA; (X.Z.); (A.T.C.)
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA;
| | - Mingyang Song
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA;
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
- Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Andrew T. Chan
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA; (X.Z.); (A.T.C.)
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
- Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114, USA
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
| | - Yin Cao
- Division of Public Health Sciences, Department of Surgery, Washington University in St. Louis, St. Louis, MO 63110, USA;
- Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Jeffrey A. Meyerhardt
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; (J.A.M.); (K.N.); (M.G.)
| | - Kimmie Ng
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; (J.A.M.); (K.N.); (M.G.)
| | - Marios Giannakis
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; (J.A.M.); (K.N.); (M.G.)
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Juha P. Väyrynen
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (N.A.); (M.Z.); (T.U.); (R.Z.); (M.C.L.); (K.F.); (J.K.); (K.H.); (K.A.); (T.S.T.); (J.A.N.)
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; (J.A.M.); (K.N.); (M.G.)
- Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital, and University of Oulu, 90220 Oulu, Finland
| | - Jonathan A. Nowak
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (N.A.); (M.Z.); (T.U.); (R.Z.); (M.C.L.); (K.F.); (J.K.); (K.H.); (K.A.); (T.S.T.); (J.A.N.)
| | - Shuji Ogino
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (N.A.); (M.Z.); (T.U.); (R.Z.); (M.C.L.); (K.F.); (J.K.); (K.H.); (K.A.); (T.S.T.); (J.A.N.)
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston 02115, MA, USA; (E.L.G.); (K.W.)
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- Cancer Immunology and Cancer Epidemiology Programs, Dana-Farber Harvard Cancer Center, Boston, MA 02215, USA
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Szabo L, Molnar R, Tomesz A, Deutsch A, Darago R, Nowrasteh G, Varjas T, Nemeth B, Budan F, Kiss I. The effects of flavonoids, green tea polyphenols and coffee on DMBA induced LINE-1 DNA hypomethylation. PLoS One 2021; 16:e0250157. [PMID: 33878138 PMCID: PMC8057585 DOI: 10.1371/journal.pone.0250157] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 03/31/2021] [Indexed: 12/22/2022] Open
Abstract
The intake of carcinogenic and chemopreventive compounds are important nutritional factors related to the development of malignant tumorous diseases. Repetitive long interspersed element-1 (LINE-1) DNA methylation pattern plays a key role in both carcinogenesis and chemoprevention. In our present in vivo animal model, we examined LINE-1 DNA methylation pattern as potential biomarker in the liver, spleen and kidney of mice consuming green tea (Camellia sinensis) extract (catechins 80%), a chinese bayberry (Morella rubra) extract (myricetin 80%), a flavonoid extract (with added resveratrol) and coffee (Coffee arabica) extract. In the organs examined, carcinogen 7,12-dimethylbenz(a)anthracene (DMBA)-induced hypomethylation was prevented by all test materials except chinese bayberry extract in the kidneys. Moreover, the flavonoid extract caused significant hypermethylation in the liver compared to untreated controls and to other test materials. The tested chemopreventive substances have antioxidant, anti-inflammatory properties and regulate molecular biological signaling pathways. They increase glutathione levels, induce antioxidant enzymes, which decrease free radical damage caused by DMBA, and ultimately, they are able to increase the activity of DNA methyltransferase enzymes. Furthermore, flavonoids in the liver may inhibit the procarcinogen to carcinogen activation of DMBA through the inhibition of CYP1A1 enzyme. At the same time, paradoxically, myricetin can act as a prooxidant as a result of free radical damage, which can explain that it did not prevent hypomethylation in the kidneys. Our results demonstrated that LINE-1 DNA methylation pattern is a useful potential biomarker for detecting and monitoring carcinogenic and chemopreventive effects of dietary compounds.
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Affiliation(s)
- Laszlo Szabo
- Department of Public Health Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Richard Molnar
- Department of Public Health Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Andras Tomesz
- Department of Public Health Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Arpad Deutsch
- Department of Public Health Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Richard Darago
- Department of Public Health Medicine, Medical School, University of Pécs, Pécs, Hungary
| | | | - Timea Varjas
- Department of Public Health Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Balazs Nemeth
- Department of Public Health Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Ferenc Budan
- Department of Public Health Medicine, Medical School, University of Pécs, Pécs, Hungary
- Institute of Physiology, Medical School, University of Pécs, Pécs, Hungary
- Institute of Environmental Engineering, Faculty of Engineering, University of Pannonia, Veszprém, Hungary
- Szentagothai Research Centre, University of Pécs, Pécs, Hungary
| | - Istvan Kiss
- Department of Public Health Medicine, Medical School, University of Pécs, Pécs, Hungary
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30
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Ye W, Siwko S, Tsai RYL. Sex and Race-Related DNA Methylation Changes in Hepatocellular Carcinoma. Int J Mol Sci 2021; 22:ijms22083820. [PMID: 33917049 PMCID: PMC8067720 DOI: 10.3390/ijms22083820] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 04/01/2021] [Accepted: 04/05/2021] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common cancer and fourth leading cause of cancer-related death worldwide. The number of HCC cases continues to rise despite advances in screening and therapeutic inventions. More importantly, HCC poses two major health disparity issues. First, HCC occurs more commonly in men than women. Second, with the global increase in non-alcoholic fatty liver diseases (NAFLD), it has also become evident that HCC is more prevalent in some races and/or ethnic groups compared to others, depending on its predisposing etiology. Most studies on HCC in the past have been focused on genetic factors as the driving force for HCC development, and the results revealed that genetic mutations associated with HCC are often heterogeneous and involve multiple pathogenic pathways. An emerging new research field is epigenetics, in which gene expression is modified without altering DNA sequences. In this article, we focus on reviewing current knowledge on HCC-related DNA methylation changes that show disparities among different sexes or different racial/ethnic groups, in an effort to establish a point of departure for resolving the broader issue of health disparities in gastrointestinal malignancies using cutting-edge epigenetic approaches.
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31
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Soundararajan S, Agrawal A, Purushottam M, Anand SD, Shankarappa B, Sharma P, Jain S, Murthy P. Changes in DNA methylation persist over time in males with severe alcohol use disorder-A longitudinal follow-up study. Am J Med Genet B Neuropsychiatr Genet 2021; 186:183-192. [PMID: 33491855 DOI: 10.1002/ajmg.b.32833] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 12/31/2020] [Accepted: 01/08/2021] [Indexed: 12/25/2022]
Abstract
Treatment strategies for alcohol use disorder (AUD) aim for abstinence or harm reduction. While deranged biochemical parameters reverse with alcohol abstinence, whether molecular changes at the epigenetic level reverse is not clearly understood. We investigated whether the reduction from high alcohol use reflects DNA methylation at the gene-specific and global level. In subjects seeking treatment for severe AUD, we assessed gene-specific (aldehyde dehydrogenase [ALDH2]/methylene tetrahydrofolate reductase [MTHFR]) and global (long interspersed elements [LINE-1]) methylation across three-time points (baseline, after detoxification and at an early remission period of 3 months), in peripheral blood leukocytes. We observed that both gene-specific and global DNA methylation did not change over time, irrespective of the drinking status at 3 months (52% abstained from alcohol). Further, we also compared DNA methylation in AUD subjects with healthy controls. At baseline, there was a significantly higher gene-specific DNA methylation (ALDH2: p < .001 and MTHFR: p = .001) and a significant lower global methylation (LINE-1: p = .014) in AUD as compared to controls. Our results suggest that epigenetic changes at the DNA methylation level associated with severe AUD persist for at least 3 months of treatment.
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Affiliation(s)
- Soundarya Soundararajan
- Department of Clinical Neurosciences, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India.,Centre for Addiction Medicine, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India.,Molecular Genetics Laboratory, Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India
| | - Arpana Agrawal
- Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Meera Purushottam
- Molecular Genetics Laboratory, Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India.,Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India
| | - Shravanthi Daphne Anand
- Centre for Addiction Medicine, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India
| | - Bhagyalakshmi Shankarappa
- Molecular Genetics Laboratory, Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India
| | - Priyamvada Sharma
- Centre for Addiction Medicine, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India.,Department of Clinical Pharmacology and Neurotoxicology, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India
| | - Sanjeev Jain
- Molecular Genetics Laboratory, Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India.,Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India
| | - Pratima Murthy
- Centre for Addiction Medicine, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India.,Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India
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32
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Rusetska N, Kober P, Król SK, Boresowicz J, Maksymowicz M, Kunicki J, Bonicki W, Bujko M. Invasive and Noninvasive Nonfunctioning Gonadotroph Pituitary Tumors Differ in DNA Methylation Level of LINE-1 Repetitive Elements. J Clin Med 2021; 10:560. [PMID: 33546126 PMCID: PMC7913198 DOI: 10.3390/jcm10040560] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 01/22/2021] [Accepted: 01/26/2021] [Indexed: 12/11/2022] Open
Abstract
PURPOSE Epigenetic dysregulation plays a role in pituitary tumor pathogenesis. Some differences in DNA methylation were observed between invasive and noninvasive nonfunctioning gonadotroph tumors. This study sought to determine the role of DNA methylation changes in repetitive LINE-1 elements in nonfunctioning gonadotroph pituitary tumors. METHODS We investigated LINE-1 methylation levels in 80 tumors and normal pituitary glands with bisulfite-pyrosequencing. Expression of two LINE-1 open reading frames (L1-ORF1 and L1-ORF2) was analyzed with qRT-PCR in tumor samples and mouse gonadotroph pituitary cells treated with DNA methyltransferase inhibitor. Immunohistochemical staining against L1-ORF1p was also performed in normal pituitary glands and tumors. RESULTS Hypomethylation of LINE-1 was observed in pituitary tumors. Tumors characterized by invasive growth revealed lower LINE-1 methylation level than noninvasive ones. LINE-1 methylation correlated with overall DNA methylation assessed with HM450K arrays and negatively correlated with L1-ORF1 and L1-ORF2 expression. Treatment of αT3-1 gonadotroph cells with 5-Azacytidine clearly increased the level of L1-ORF1 and L1-ORF2 mRNA; however, its effect on LβT2 cells was less pronounced. Immunoreactivity against L1-ORF1p was higher in tumors than normal tissue. No difference in L1-ORF1p expression was observed in invasive and noninvasive tumors. CONCLUSION Hypomethylation of LINE-1 is related to invasive growth and influences transcriptional activity of transposable elements.
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Affiliation(s)
- Natalia Rusetska
- Department of Molecular and Translational Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; (N.R.); (P.K.); (S.K.K.); (J.B.)
| | - Paulina Kober
- Department of Molecular and Translational Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; (N.R.); (P.K.); (S.K.K.); (J.B.)
| | - Sylwia Katarzyna Król
- Department of Molecular and Translational Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; (N.R.); (P.K.); (S.K.K.); (J.B.)
| | - Joanna Boresowicz
- Department of Molecular and Translational Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; (N.R.); (P.K.); (S.K.K.); (J.B.)
| | - Maria Maksymowicz
- Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland;
| | - Jacek Kunicki
- Department of Neurosurgery, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; (J.K.); (W.B.)
| | - Wiesław Bonicki
- Department of Neurosurgery, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; (J.K.); (W.B.)
| | - Mateusz Bujko
- Department of Molecular and Translational Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; (N.R.); (P.K.); (S.K.K.); (J.B.)
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Paredes-Céspedes DM, Rojas-García AE, Medina-Díaz IM, Ramos KS, Herrera-Moreno JF, Barrón-Vivanco BS, González-Arias CA, Bernal-Hernández YY. Environmental and socio-cultural impacts on global DNA methylation in the indigenous Huichol population of Nayarit, Mexico. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:4472-4487. [PMID: 32940839 DOI: 10.1007/s11356-020-10804-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 09/09/2020] [Indexed: 06/11/2023]
Abstract
Alterations of global DNA methylation have been evaluated in several studies worldwide; however, Long Interspersed Nuclear Elements-1 (LINE-1) methylation in genetically conserved populations such as indigenous communities have not, to our knowledge, been reported. The aim of this study was to evaluate the relationship between LINE-1 methylation patterns and factors such as pesticide exposure and socio-cultural characteristics in the Indigenous Huichol Population of Nayarit, Mexico. A cross-sectional study was conducted in 140 Huichol indigenous individuals. A structured questionnaire was used to determine general and anthropometric characteristics, diet, harmful habits, and pesticide exposure. DNA methylation was determined by pyrosequencing of bisulfite-treated DNA. A lower level of LINE-1 methylation was found in the indigenous population when compared to a Mestizo population previously studied by our group. This difference might be due to the influence of the genetic admixture and differing dietary and lifestyle habits. The males in the indigenous population exhibited increased LINE-1 methylation in comparison to the females. Sex and alcohol consumption showed positive associations with LINE-1 methylation, while weight, current work in the field, current pesticide usage, and folate intake exhibited negative associations with LINE-1 methylation. The results suggest that ethnicity, as well as other internal and environmental factors, might influence LINE-1 methylation.
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Affiliation(s)
- Diana Marcela Paredes-Céspedes
- Posgrado en Ciencias Biológico Agropecuarias, Unidad Académica de Agricultura, Km. 9 Carretera Tepic-Compostela, Xalisco, Nayarit, México
- Laboratorio de Contaminación y Toxicología Ambiental, Secretaría de Investigación y Posgrado, Universidad Autónoma de Nayarit, Ciudad de la Cultura s/n. C.P, 6300, Tepic, Nayarit, México
| | - Aurora Elizabeth Rojas-García
- Laboratorio de Contaminación y Toxicología Ambiental, Secretaría de Investigación y Posgrado, Universidad Autónoma de Nayarit, Ciudad de la Cultura s/n. C.P, 6300, Tepic, Nayarit, México
| | - Irma Martha Medina-Díaz
- Laboratorio de Contaminación y Toxicología Ambiental, Secretaría de Investigación y Posgrado, Universidad Autónoma de Nayarit, Ciudad de la Cultura s/n. C.P, 6300, Tepic, Nayarit, México
| | - Kenneth S Ramos
- Institute of Biosciences and Technology, Texas A&M University Health Science Center, 121 W. Holcombe Blvd, Houston, TX, 77030 m EE,UU, USA
| | - José Francisco Herrera-Moreno
- Posgrado en Ciencias Biológico Agropecuarias, Unidad Académica de Agricultura, Km. 9 Carretera Tepic-Compostela, Xalisco, Nayarit, México
- Laboratorio de Contaminación y Toxicología Ambiental, Secretaría de Investigación y Posgrado, Universidad Autónoma de Nayarit, Ciudad de la Cultura s/n. C.P, 6300, Tepic, Nayarit, México
| | - Briscia Socorro Barrón-Vivanco
- Laboratorio de Contaminación y Toxicología Ambiental, Secretaría de Investigación y Posgrado, Universidad Autónoma de Nayarit, Ciudad de la Cultura s/n. C.P, 6300, Tepic, Nayarit, México
| | - Cyndia Azucena González-Arias
- Laboratorio de Contaminación y Toxicología Ambiental, Secretaría de Investigación y Posgrado, Universidad Autónoma de Nayarit, Ciudad de la Cultura s/n. C.P, 6300, Tepic, Nayarit, México
| | - Yael Yvette Bernal-Hernández
- Laboratorio de Contaminación y Toxicología Ambiental, Secretaría de Investigación y Posgrado, Universidad Autónoma de Nayarit, Ciudad de la Cultura s/n. C.P, 6300, Tepic, Nayarit, México.
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Goodrich JM, Hector EC, Tang L, LaBarre JL, Dolinoy DC, Mercado-Garcia A, Cantoral A, Song PX, Téllez-Rojo MM, Peterson KE. Integrative Analysis of Gene-Specific DNA Methylation and Untargeted Metabolomics Data from the ELEMENT Cohort. Epigenet Insights 2020; 13:2516865720977888. [PMID: 33354655 PMCID: PMC7734565 DOI: 10.1177/2516865720977888] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 11/04/2020] [Indexed: 12/18/2022] Open
Abstract
Epigenetic modifications, such as DNA methylation, influence gene expression and cardiometabolic phenotypes that are manifest in developmental periods in later life, including adolescence. Untargeted metabolomics analysis provide a comprehensive snapshot of physiological processes and metabolism and have been related to DNA methylation in adults, offering insights into the regulatory networks that influence cellular processes. We analyzed the cross-sectional correlation of blood leukocyte DNA methylation with 3758 serum metabolite features (574 of which are identifiable) in 238 children (ages 8-14 years) from the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) study. Associations between these features and percent DNA methylation in adolescent blood leukocytes at LINE-1 repetitive elements and genes that regulate early life growth (IGF2, H19, HSD11B2) were assessed by mixed effects models, adjusting for sex, age, and puberty status. After false discovery rate correction (FDR q < 0.05), 76 metabolites were significantly associated with LINE-1 DNA methylation, 27 with HSD11B2, 103 with H19, and 4 with IGF2. The ten identifiable metabolites included dicarboxylic fatty acids (five associated with LINE-1 or H19 methylation at q < 0.05) and 1-octadecanoyl-rac-glycerol (q < 0.0001 for association with H19 and q = 0.04 for association with LINE-1). We then assessed the association between these ten known metabolites and adiposity 3 years later. Two metabolites, dicarboxylic fatty acid 17:3 and 5-oxo-7-octenoic acid, were inversely associated with measures of adiposity (P < .05) assessed approximately 3 years later in adolescence. In stratified analyses, sex-specific and puberty-stage specific (Tanner stage = 2 to 5 vs Tanner stage = 1) associations were observed. Most notably, hundreds of statistically significant associations were observed between H19 and LINE-1 DNA methylation and metabolites among children who had initiated puberty. Understanding relationships between subclinical molecular biomarkers (DNA methylation and metabolites) may increase our understanding of genes and biological pathways contributing to metabolic changes that underlie the development of adiposity during adolescence.
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Affiliation(s)
- Jaclyn M Goodrich
- Deptartment of Environmental Health Sciences, University of Michigan, Ann Arbor, MI, USA
| | - Emily C Hector
- Deptartment of Biostatistics, University of Michigan, Ann Arbor, MI, USA.,Deptartment of Statistics, North Carolina State University, USA
| | - Lu Tang
- Deptartment of Biostatistics, University of Pittsburgh, USA
| | - Jennifer L LaBarre
- Deptartment of Nutritional Sciences, University of Michigan, Ann Arbor, MI, USA
| | - Dana C Dolinoy
- Deptartment of Environmental Health Sciences, University of Michigan, Ann Arbor, MI, USA.,Deptartment of Nutritional Sciences, University of Michigan, Ann Arbor, MI, USA
| | - Adriana Mercado-Garcia
- Center for Nutrition and Health Research, National Institute of Public Health, Cuernavaca, Morelos, México
| | - Alejandra Cantoral
- Center for Nutrition and Health Research, National Institute of Public Health, Cuernavaca, Morelos, México
| | - Peter Xk Song
- Deptartment of Biostatistics, University of Michigan, Ann Arbor, MI, USA
| | - Martha Maria Téllez-Rojo
- Center for Nutrition and Health Research, National Institute of Public Health, Cuernavaca, Morelos, México
| | - Karen E Peterson
- Deptartment of Environmental Health Sciences, University of Michigan, Ann Arbor, MI, USA.,Deptartment of Nutritional Sciences, University of Michigan, Ann Arbor, MI, USA
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Misawa K, Yamada S, Mima M, Nakagawa T, Kurokawa T, Imai A, Mochizuki D, Shinmura D, Yamada T, Kita J, Ishikawa R, Yamaguchi Y, Misawa Y, Kanazawa T, Kawasaki H, Mineta H. Long interspersed nuclear element 1 hypomethylation has novel prognostic value and potential utility in liquid biopsy for oral cavity cancer. Biomark Res 2020; 8:53. [PMID: 33110605 PMCID: PMC7585304 DOI: 10.1186/s40364-020-00235-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 10/12/2020] [Indexed: 02/08/2023] Open
Abstract
Background New biomarkers are urgently needed to improve personalized treatment approaches for head and neck squamous cell carcinoma (HNSCC). Global DNA hypomethylation has wide-ranging functions in multistep carcinogenesis, and the hypomethylation of long interspersed nucleotide element-1 (LINE-1) is related to increased retrotransposon activity and induced genome instability. However, little information is available regarding LINE-1 hypomethylation and its prognostic implications in HNSCC. Methods In this study, we analyzed LINE-1 hypomethylation levels in a well-characterized dataset of 317 primary HNSCC tissues and 225 matched pairs of normal mucosa tissues, along with five oral cavity cancer (OCC) circulating tumor DNA (ctDNA) samples using quantitative real-time methylation and unmethylation PCR. The analysis was performed according to various clinical characteristics and prognostic implications. Results The results demonstrated that LINE-1 hypomethylation levels were significantly higher in the HNSCC tissues than in corresponding normal tissues from the same individuals (P < 0.001). Univariate analysis revealed that high levels of LINE-1 hypomethylation were correlated with poor disease-free survival (DFS; log-rank test, P = 0.038), whereas multivariate analysis demonstrated that they were significant independent prognostic factor for DFS (hazard ratio: 2.10, 95% confidence interval: 1.02–4.36; P = 0.045). Moreover, samples with high LINE-1 hypomethylation levels exhibited the greatest decrease in 5-hydroxymethylcytosine (5-hmC) levels and increase in tumor-suppressor gene methylation index (P = 0.006 and P < 0.001, respectively). Further, ctDNA studies also showed that LINE-1 hypomethylation had high predictive ability in OCC. Conclusions LINE-1 hypomethylation is associated with a higher risk of early OCC relapse, and is hence, a potential predictive biomarker for OCC. Furthermore, 5-hmC levels also exhibited predictive potential in OCC, based on their inverse correlation with LINE-1 hypomethylation levels. LINE-1 hypomethylation analysis, therefore, has applications in determining patient prognosis and real-time surveillance of disease recurrence, and could serve as an alternative method for OCC screening. Supplementary information Supplementary information accompanies this paper at 10.1186/s40364-020-00235-y.
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Affiliation(s)
- Kiyoshi Misawa
- Department of Otorhinolaryngology /Head and Neck Surgery, 1-20-1 Handayama, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192 Japan
| | - Satoshi Yamada
- Department of Otorhinolaryngology /Head and Neck Surgery, 1-20-1 Handayama, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192 Japan
| | - Masato Mima
- Department of Otorhinolaryngology /Head and Neck Surgery, 1-20-1 Handayama, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192 Japan
| | - Takuya Nakagawa
- Department of Otorhinolaryngology/Head and Neck Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tomoya Kurokawa
- Department of Otorhinolaryngology/Head and Neck Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Atsushi Imai
- Department of Otorhinolaryngology /Head and Neck Surgery, 1-20-1 Handayama, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192 Japan
| | - Daiki Mochizuki
- Department of Otorhinolaryngology /Head and Neck Surgery, 1-20-1 Handayama, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192 Japan
| | - Daichi Shinmura
- Department of Otorhinolaryngology /Head and Neck Surgery, 1-20-1 Handayama, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192 Japan
| | - Taiki Yamada
- Department of Otorhinolaryngology /Head and Neck Surgery, 1-20-1 Handayama, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192 Japan
| | - Junya Kita
- Department of Otorhinolaryngology /Head and Neck Surgery, 1-20-1 Handayama, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192 Japan
| | - Ryuji Ishikawa
- Department of Otorhinolaryngology /Head and Neck Surgery, 1-20-1 Handayama, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192 Japan
| | - Yuki Yamaguchi
- Department of Otorhinolaryngology /Head and Neck Surgery, 1-20-1 Handayama, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192 Japan
| | - Yuki Misawa
- Department of Otorhinolaryngology /Head and Neck Surgery, 1-20-1 Handayama, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192 Japan
| | - Takeharu Kanazawa
- Department of Otorhinolaryngology/Head and Neck Surgery, Jichi Medical University, Shimotsuke, Tochigi Japan
| | - Hideya Kawasaki
- Preeminent Medical Photonics Education and Research Center Institute for NanoSuit Research, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Hiroyuki Mineta
- Department of Otorhinolaryngology /Head and Neck Surgery, 1-20-1 Handayama, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192 Japan
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Shademan M, Zare K, Zahedi M, Mosannen Mozaffari H, Bagheri Hosseini H, Ghaffarzadegan K, Goshayeshi L, Dehghani H. Promoter methylation, transcription, and retrotransposition of LINE-1 in colorectal adenomas and adenocarcinomas. Cancer Cell Int 2020; 20:426. [PMID: 32905102 PMCID: PMC7466817 DOI: 10.1186/s12935-020-01511-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 08/21/2020] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND The methylation of the CpG islands of the LINE-1 promoter is a tight control mechanism on the function of mobile elements. However, simultaneous quantification of promoter methylation and transcription of LINE-1 has not been performed in progressive stages of colorectal cancer. In addition, the insertion of mobile elements in the genome of advanced adenoma stage, a precancerous stage before colorectal carcinoma has not been emphasized. In this study, we quantify promoter methylation and transcripts of LINE-1 in three stages of colorectal non-advanced adenoma, advanced adenoma, and adenocarcinoma. In addition, we analyze the insertion of LINE-1, Alu, and SVA elements in the genome of patient tumors with colorectal advanced adenomas. METHODS LINE-1 hypomethylation status was evaluated by absolute quantitative analysis of methylated alleles (AQAMA) assay. To quantify the level of transcripts for LINE-1, quantitative RT-PCR was performed. To find mobile element insertions, the advanced adenoma tissue samples were subjected to whole genome sequencing and MELT analysis. RESULTS We found that the LINE-1 promoter methylation in advanced adenoma and adenocarcinoma was significantly lower than that in non-advanced adenomas. Accordingly, the copy number of LINE-1 transcripts in advanced adenoma was significantly higher than that in non-advanced adenomas, and in adenocarcinomas was significantly higher than that in the advanced adenomas. Whole-genome sequencing analysis of colorectal advanced adenomas revealed that at this stage polymorphic insertions of LINE-1, Alu, and SVA comprise approximately 16%, 51%, and 74% of total insertions, respectively. CONCLUSIONS Our correlative analysis showing a decreased methylation of LINE-1 promoter accompanied by the higher level of LINE-1 transcription, and polymorphic genomic insertions in advanced adenoma, suggests that the early and advanced polyp stages may host very important pathogenic processes concluding to cancer.
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Affiliation(s)
- Milad Shademan
- Graduate Program in Physiology, Department of Basic Sciences, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Khadijeh Zare
- Stem Cell Biology and Regenerative Medicine Research Group, Research Institute of Biotechnology, Ferdowsi University of Mashhad, Azadi Square, Mashhad, 91779-48974 Iran
| | - Morteza Zahedi
- Graduate Program in Physiology, Department of Basic Sciences, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Hooman Mosannen Mozaffari
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Gastroenterology and Hepatology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hadi Bagheri Hosseini
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Gastroenterology and Hepatology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Kamran Ghaffarzadegan
- Pathology Department, Education and Research Department, Razavi Hospital, Mashhad, Iran
| | - Ladan Goshayeshi
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hesam Dehghani
- Stem Cell Biology and Regenerative Medicine Research Group, Research Institute of Biotechnology, Ferdowsi University of Mashhad, Azadi Square, Mashhad, 91779-48974 Iran
- Division of Biotechnology, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran
- Department of Basic Sciences, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran
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Zhang X, Zhang R, Yu J. New Understanding of the Relevant Role of LINE-1 Retrotransposition in Human Disease and Immune Modulation. Front Cell Dev Biol 2020; 8:657. [PMID: 32850797 PMCID: PMC7426637 DOI: 10.3389/fcell.2020.00657] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 07/01/2020] [Indexed: 12/21/2022] Open
Abstract
Long interspersed nuclear element-1 (LINE-1) retrotransposition is a major hallmark of cancer accompanied by global chromosomal instability, genomic instability, and genetic heterogeneity and has become one indicator for the occurrence, development, and poor prognosis of many diseases. LINE-1 also modulates the immune system and affects the immune microenvironment in a variety of ways. Aberrant expression of LINE-1 retrotransposon can provide strong stimuli for an innate immune response, activate the immune system, and induce autoimmunity and inflammation. Therefore, inhibition the activity of LINE-1 has become a potential treatment strategy for various diseases. In this review, we discussed the components and regulatory mechanisms involved with LINE-1, its correlations with disease and immunity, and multiple inhibitors of LINE-1, providing a new understanding of LINE-1.
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Affiliation(s)
- Xiao Zhang
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Rui Zhang
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Jinpu Yu
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
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Zeggar HR, How-Kit A, Daunay A, Bettaieb I, Sahbatou M, Rahal K, Adouni O, Gammoudi A, Douik H, Deleuze JF, Kharrat M. Tumor DNA hypomethylation of LINE-1 is associated with low tumor grade of breast cancer in Tunisian patients. Oncol Lett 2020; 20:1999-2006. [PMID: 32724446 PMCID: PMC7377197 DOI: 10.3892/ol.2020.11745] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Accepted: 05/19/2020] [Indexed: 12/24/2022] Open
Abstract
DNA hypomethylation of long interspersed repetitive DNA retrotransposon (LINE-1) and Alu repeats elements of short interspersed elements family (SINEs) is an early event in carcinogenesis that causes transcriptional activation and leads to chromosomal instability. In the current study, DNA methylation levels of LINE-1 and Alu repeats were analyzed in tumoral tissues of invasive breast cancer in a Tunisian cohort and its association with the clinicopathological features of patients was defined. DNA methylation of LINE-1 and Alu repeats were analyzed using pyrosequencing in 61 invasive breast cancers. Median values observed for DNA methylation of LINE-1 and Alu repeats were considered as the cut-off (59.81 and 18.49%, respectively). The results of the current study demonstrated a positive correlation between DNA methylation levels of LINE-1 and Alu repeats (rho=0.284; P<0.03). DNA hypomethylation of LINE-1 was also indicated to be associated with low grade (P=0.023). To the best of our knowledge, the current study is the first study regarding DNA methylation of LINE-1 and Alu repeats element in breast cancer of the Tunisian population. The results of the current study suggest that, since hypomethylation of LINE-1 is associated with low grade, it could be used as a biomarker for prognosis for patients with breast cancer.
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Affiliation(s)
- Hayet Radia Zeggar
- University of Tunis El Manar, Faculty of Medicine of Tunis, LR99ES10 Human Genetics Laboratory, 1007 Tunis, Tunisia
| | - Alexandre How-Kit
- Laboratoire de Génomique, Fondation Jean Dausset-CEPH, Centre d'Etude du Polymorphisme Humain, 75010 Paris, France
| | - Antoine Daunay
- Laboratoire de Génomique, Fondation Jean Dausset-CEPH, Centre d'Etude du Polymorphisme Humain, 75010 Paris, France
| | - Ilhem Bettaieb
- Department of Immunohistocytology, Salah Azaïz Cancer Institute, 1006 Tunis, Tunisia
| | - Mourad Sahbatou
- Laboratoire de Biostatistique, Fondation Jean Dausset-CEPH, Centre d'Etude du Polymorphisme Humain, 75010 Paris, France
| | - Khaled Rahal
- Service de Chirurgie Carcinologique, Institut Salah Azaiz de Tunis, 1006 Tunis, Tunisia
| | - Olfa Adouni
- Department of Immunohistocytology, Salah Azaïz Cancer Institute, 1006 Tunis, Tunisia
| | - Amor Gammoudi
- Department of Immunohistocytology, Salah Azaïz Cancer Institute, 1006 Tunis, Tunisia
| | - Hayet Douik
- University of Tunis El Manar, Faculty of Medicine of Tunis, LR99ES10 Human Genetics Laboratory, 1007 Tunis, Tunisia
| | - Jean-François Deleuze
- Laboratoire de Génomique, Fondation Jean Dausset-CEPH, Centre d'Etude du Polymorphisme Humain, 75010 Paris, France
- Centre National de Recherche en Génomique Humaine, CEA, Le Commissariat à l'énergie atomique et aux énergies alternatives-Institut François Jacob, 92265 Evry, France
| | - Maher Kharrat
- University of Tunis El Manar, Faculty of Medicine of Tunis, LR99ES10 Human Genetics Laboratory, 1007 Tunis, Tunisia
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Ogawa D, Hayashi H, Kitamura F, Uemura N, Miyata T, Okabe H, Imai K, Yamasita Y, Kubo S, Baba H. Multiple cholangiocarcinomas in the intrahepatic and extrahepatic biliary tree due to dichloromethane exposure: a case report. Surg Case Rep 2020; 6:79. [PMID: 32318894 PMCID: PMC7174514 DOI: 10.1186/s40792-020-00842-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Accepted: 04/13/2020] [Indexed: 12/24/2022] Open
Abstract
Background An outbreak of cholangiocarcinoma in Japan has led to widespread concern among workers in printing plants. In March 2013, the Japanese Ministry of Health, Labour and Welfare, confirmed a causal relationship between cholangiocarcinoma and long-term exposure to dichloromethane (DCM) and 1,2-dichloropropane (DCP), which were widely used in printing plants. We herein report a rare case of successful radical resection of multiple cholangiocarcinomas in the intrahepatic and extrahepatic bile ducts caused by past exposure to DCM. Case presentation A 54-year-old man developed brown urine 22 years after his last exposure to DCP and DCM. He had an 11-year history of working at a printing plant from the age of 21 to 31 years and dealt with organic solvents during his employment. Enhanced computed tomography revealed a thickened distal bile duct wall with upstream biliary dilatation and multiple intrahepatic cholangiocarcinomas located in liver segments III, VI, and VIII. Biopsy of the distal bile duct wall revealed adenocarcinoma, and a diagnosis of distal cholangiocarcinoma was made. Tumor marker levels were within the reference range (carcinoembryonic antigen, 3.3 ng/mL; carbohydrate antigen 19-9, 25.4 U/mL; SPAN-1, 13 U/mL; and DUPAN-2, 33 U/mL). The multiple intrahepatic and extrahepatic bile duct cancers were treated by subtotal stomach-preserving pancreatoduodenectomy and partial hepatectomy of segments III, VI, and VIII. Pathological examination of the surgical specimens revealed multiple cholangiocarcinomas with well-differentiated adenocarcinoma in the biliary tree. The patient was still alive without recurrence 17 months after the operation. Conclusions We experienced a rare case of multiple cholangiocarcinomas in the intrahepatic and extrahepatic bile ducts that developed 22 years after the patient’s last exposure to DCP and DCM. Long-term and careful follow-up is required for workers with an occupational history of exposure to organic solvents because of the risk of development of cholangiocarcinoma.
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Affiliation(s)
- Daisuke Ogawa
- Department of Gastroenterological Surgery, Graduate School of Life Sciences Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Hiromitsu Hayashi
- Department of Gastroenterological Surgery, Graduate School of Life Sciences Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan.
| | - Fumimasa Kitamura
- Department of Gastroenterological Surgery, Graduate School of Life Sciences Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Norio Uemura
- Department of Gastroenterological Surgery, Graduate School of Life Sciences Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Tatsunori Miyata
- Department of Gastroenterological Surgery, Graduate School of Life Sciences Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Hirohisa Okabe
- Department of Gastroenterological Surgery, Graduate School of Life Sciences Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Katsunori Imai
- Department of Gastroenterological Surgery, Graduate School of Life Sciences Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Yoichi Yamasita
- Department of Gastroenterological Surgery, Graduate School of Life Sciences Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Shoji Kubo
- Department of Hepato-Biliary-Pancreatic Surgery, Osaka City University, Osaka, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Life Sciences Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
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Jung G, Hernández-Illán E, Moreira L, Balaguer F, Goel A. Epigenetics of colorectal cancer: biomarker and therapeutic potential. Nat Rev Gastroenterol Hepatol 2020; 17:111-130. [PMID: 31900466 PMCID: PMC7228650 DOI: 10.1038/s41575-019-0230-y] [Citation(s) in RCA: 504] [Impact Index Per Article: 100.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/16/2019] [Indexed: 12/24/2022]
Abstract
Colorectal cancer (CRC), a leading cause of cancer-related death worldwide, evolves as a result of the stepwise accumulation of a series of genetic and epigenetic alterations in the normal colonic epithelium, leading to the development of colorectal adenomas and invasive adenocarcinomas. Although genetic alterations have a major role in a subset of CRCs, the pathophysiological contribution of epigenetic aberrations in this malignancy has attracted considerable attention. Data from the past couple of decades has unequivocally illustrated that epigenetic marks are important molecular hallmarks of cancer, as they occur very early in disease pathogenesis, involve virtually all key cancer-associated pathways and, most importantly, can be exploited as clinically relevant disease biomarkers for diagnosis, prognostication and prediction of treatment response. In this Review, we summarize the current knowledge on the best-studied epigenetic modifications in CRC, including DNA methylation and histone modifications, as well as the role of non-coding RNAs as epigenetic regulators. We focus on the emerging potential for the bench-to-bedside translation of some of these epigenetic alterations into clinical practice and discuss the burgeoning evidence supporting the potential of emerging epigenetic therapies in CRC as we usher in the era of precision medicine.
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Affiliation(s)
- Gerhard Jung
- Gastroenterology Department, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Eva Hernández-Illán
- Gastroenterology Department, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Leticia Moreira
- Gastroenterology Department, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Francesc Balaguer
- Gastroenterology Department, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain.
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain.
| | - Ajay Goel
- Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, USA.
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
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Drongitis D, Aniello F, Fucci L, Donizetti A. Roles of Transposable Elements in the Different Layers of Gene Expression Regulation. Int J Mol Sci 2019; 20:ijms20225755. [PMID: 31731828 PMCID: PMC6888579 DOI: 10.3390/ijms20225755] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 11/12/2019] [Accepted: 11/14/2019] [Indexed: 02/03/2023] Open
Abstract
The biology of transposable elements (TEs) is a fascinating and complex field of investigation. TEs represent a substantial fraction of many eukaryotic genomes and can influence many aspects of DNA function that range from the evolution of genetic information to duplication, stability, and gene expression. Their ability to move inside the genome has been largely recognized as a double-edged sword, as both useful and deleterious effects can result. A fundamental role has been played by the evolution of the molecular processes needed to properly control the expression of TEs. Today, we are far removed from the original reductive vision of TEs as “junk DNA”, and are more convinced that TEs represent an essential element in the regulation of gene expression. In this review, we summarize some of the more recent findings, mainly in the animal kingdom, concerning the active roles that TEs play at every level of gene expression regulation, including chromatin modification, splicing, and protein translation.
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Affiliation(s)
- Denise Drongitis
- Institute of Genetics and Biophysics “Adriano Buzzati Traverso”, Consiglio Nazionale delle Ricerche, 80131 Naples, Italy;
| | - Francesco Aniello
- Department of Biology, University of Naples Federico II, 80126 Naples, Italy; (F.A.); (L.F.)
| | - Laura Fucci
- Department of Biology, University of Naples Federico II, 80126 Naples, Italy; (F.A.); (L.F.)
| | - Aldo Donizetti
- Department of Biology, University of Naples Federico II, 80126 Naples, Italy; (F.A.); (L.F.)
- Correspondence:
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Awada Z, Nasr R, Akika R, Cahais V, Cuenin C, Zhivagui M, Herceg Z, Ghantous A, Zgheib NK. DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics 2019; 11:138. [PMID: 31601247 PMCID: PMC6785895 DOI: 10.1186/s13148-019-0725-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 08/12/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Bisphenol A (BPA), an estrogen-like endocrine disruptor used in plastics, has been associated with development and promotion of breast cancer, so plastic manufacturers shifted towards less-studied analogs, BPF and BPS. Studying the associated DNA methylome-wide mechanisms of these derivatives is timely, particularly in comparison with BPA. METHODS We assessed proliferation, cell cycle, and migration of breast cancer cells (estrogen receptor (ER)-positive: MCF-7 and ER-negative: MDA-MB-231) treated with BPF and BPS ± estrogen receptor inhibitor (ERI) in comparison to BPA ± ERI. RNA expression and activity of DNA (de)methylation enzymes and LINE-1 methylation were quantified. DNA methylome-wide analysis was evaluated in bisphenol-exposed cells and compared to clinical breast cancer data. RESULTS The three bisphenols caused ER-dependent increased proliferation and migration of MCF-7 but not MDA-MB-231 cells, with BPS being 10 times less potent than BPA and BPF. Although they have similar chemical structures, the three bisphenols induced differential DNA methylation alterations at several genomic clusters of or single CpG sites, with the majority of these being ER-dependent. At equipotent doses, BPA had the strongest effect on the methylome, followed by BPS then BPF. No pathways were enriched for BPF while BPA- and BPS-induced methylome alterations were enriched in focal adhesion, cGMP-PKG, and cancer pathways, which were also dysregulated in methylome-wide alterations comparing ER-positive breast cancer samples to adjacent normal tissues. CONCLUSIONS The three bisphenols have important epigenetic effects in breast cell lines, with those of BPA and BPS overlapping with cancer-related pathways in clinical breast cancer models. Hence, further investigation of their safety is warranted.
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Affiliation(s)
- Z Awada
- Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Riad El-Solh, Beirut, 1107-2020, Lebanon
| | - R Nasr
- Anatomy, Cell Biology and Physiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - R Akika
- Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Riad El-Solh, Beirut, 1107-2020, Lebanon
| | - V Cahais
- Epigenetics group, International Agency for Research on Cancer, Cours Albert Thomas, 69372, Lyon, France
| | - C Cuenin
- Epigenetics group, International Agency for Research on Cancer, Cours Albert Thomas, 69372, Lyon, France
| | - M Zhivagui
- Epigenetics group, International Agency for Research on Cancer, Cours Albert Thomas, 69372, Lyon, France
| | - Z Herceg
- Epigenetics group, International Agency for Research on Cancer, Cours Albert Thomas, 69372, Lyon, France
| | - A Ghantous
- Epigenetics group, International Agency for Research on Cancer, Cours Albert Thomas, 69372, Lyon, France.
| | - N K Zgheib
- Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Riad El-Solh, Beirut, 1107-2020, Lebanon.
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Tumor Long-interspersed Nucleotide Element-1 Methylation Level and Immune Response to Esophageal Cancer. Ann Surg 2019; 272:1025-1034. [DOI: 10.1097/sla.0000000000003264] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Sahnane N, Ottini G, Turri-Zanoni M, Furlan D, Battaglia P, Karligkiotis A, Albeni C, Cerutti R, Mura E, Chiaravalli AM, Castelnuovo P, Sessa F, Facco C. Comprehensive analysis of HPV infection, EGFR exon 20 mutations and LINE1 hypomethylation as risk factors for malignant transformation of sinonasal-inverted papilloma to squamous cell carcinoma. Int J Cancer 2018; 144:1313-1320. [PMID: 30411788 DOI: 10.1002/ijc.31971] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 10/10/2018] [Accepted: 10/22/2018] [Indexed: 12/11/2022]
Abstract
Different risk factors are suspected to be involved in malignant transformation of sinonasal papillomas and include HPV infection, tobacco smoking, occupational exposure, EGFR/KRAS mutations and DNA methylation alterations. In our study, 25 inverted sinonasal papillomas (ISPs), 5 oncocytic sinonasal papillomas (OSP) and 35 squamous cell carcinomas (SCCs) from 54 patients were genotyped for 10 genes involved in EGFR signalling. HPV-DNA detection was performed by in-situ hybridisation and LINE-1 methylation was quantitatively determined by bisulphite-pyrosequencing. High-risk HPV was observed only in 13% of ISP-associated SCC and in 8% of de novo-SCC patients. EGFR mutations occurred in 72% of ISPs, 30% of ISP-associated SCCs and 17% of de novo-SCCs. At 5-year follow-up, SCC arose in only 30% (6/20) of patients with EGFR-mutated ISPs compared to 76% (13/17) of patients with EGFR-wild-type ISP (p = 0.0044). LINE-1 hypomethylation significantly increased from papilloma/early stage SCC to advanced stage SCC (p = 0.03) and was associated with occupational exposure (p = 0.01) and worse prognosis (p = 0.09). In conclusion, our results suggest that a small subset of these tumours could be related to HPV infection; EGFR mutations characterise those ISPs with a lower risk of developing into SCC; LINE-1 hypomethylation is associated with occupational exposure and could identify more aggressive nasal SCC.
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Affiliation(s)
- Nora Sahnane
- Unit of Pathology, Department of Medicine and Surgery, University of Insubria and ASST Sette-Laghi, Varese, Italy
| | - Giorgia Ottini
- Unit of Pathology, Department of Medicine and Surgery, University of Insubria and ASST Sette-Laghi, Varese, Italy
| | - Mario Turri-Zanoni
- Division of Otorhinolaryngology, Department of Biotechnology and Life Sciences, University of Insubria and ASST Sette-Laghi, Varese, Italy
| | - Daniela Furlan
- Unit of Pathology, Department of Medicine and Surgery, University of Insubria and ASST Sette-Laghi, Varese, Italy
| | - Paolo Battaglia
- Division of Otorhinolaryngology, Department of Biotechnology and Life Sciences, University of Insubria and ASST Sette-Laghi, Varese, Italy
| | - Apostolos Karligkiotis
- Division of Otorhinolaryngology, Department of Biotechnology and Life Sciences, University of Insubria and ASST Sette-Laghi, Varese, Italy
| | - Chiara Albeni
- Unit of Pathology, Department of Medicine and Surgery, University of Insubria and ASST Sette-Laghi, Varese, Italy
| | - Roberta Cerutti
- Unit of Pathology, Department of Medicine and Surgery, University of Insubria and ASST Sette-Laghi, Varese, Italy
| | - Eleonora Mura
- Division of Otorhinolaryngology, Department of Biotechnology and Life Sciences, University of Insubria and ASST Sette-Laghi, Varese, Italy
| | - Anna Maria Chiaravalli
- Unit of Pathology, Department of Medicine and Surgery, University of Insubria and ASST Sette-Laghi, Varese, Italy
| | - Paolo Castelnuovo
- Division of Otorhinolaryngology, Department of Biotechnology and Life Sciences, University of Insubria and ASST Sette-Laghi, Varese, Italy
| | - Fausto Sessa
- Unit of Pathology, Department of Medicine and Surgery, University of Insubria and ASST Sette-Laghi, Varese, Italy
| | - Carla Facco
- Unit of Pathology, Department of Medicine and Surgery, University of Insubria and ASST Sette-Laghi, Varese, Italy
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