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Tian J, Li Y, Tong Y, Zhang Y, Zhao T, Kang Y, Bi Q. Uridine-cytidine kinase 2 is correlated with immune, DNA damage repair and promotion of cancer stemness in pan-cancer. Front Oncol 2025; 15:1503300. [PMID: 39931080 PMCID: PMC11807824 DOI: 10.3389/fonc.2025.1503300] [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: 09/28/2024] [Accepted: 01/03/2025] [Indexed: 02/13/2025] Open
Abstract
Background UCK2 (Uridine-Cytidine Kinase 2) is a promising prognostic marker for malignant tumors, but its association with immune infiltration and cancer stemness in pan-cancer remains to be fully understood. we find that gene UCK2 is closed related to RNA stemness scores (RNAss) and DNA stemness scores (DNAss), which is measured the tumor stemness. We also discover an association between UCK2 expression and immune cells by CIBERSORT algorithm, ESTIMATE algorithm and ssGSEA algorithm, especially, related to T cell, monocytes, mast cells, and macrophages. This study aims to shed light on the role and possible mechanism of UCK2 in pan-cancer. Methods We used the R programming language for pan-cancer bulk sequencing data analysis, which were obtained from the University of California, Santa Cruz (UCSC) datasets. UCSC database is a very useful for explore data from TCGA and other cancer genomics datasets, The data we explored at the UCK2 transcriptome level came from TCGA data in the UCSC database. We explored differential UCK2 expression between tumor and normal samples. Immunohistochemistry (IHC) was utilized to validate the expression of UCK2 in different types cancers using tumor tissue chips. The correlations of UCK2 with prognosis, genetic instability, DNA repair, cancer stem cell characteristics, and immune cell infiltration were investigated. Furthermore, single-cell datasets, acquired from the Gene Expression Omnibus (GEO) database, were used to validate the relationship between UCK2 and immune cells. GEO is a famous public genomics database supporting freely disseminates microarray data. Finally, we analyzed the correlation between UCK2 and drug sensitivity. Results UCK2 expression was observed to be high in most cancers and was remarkably related to the prognosis of pan-cancers. We found that the increased UCK2 expression was associated with higher genetic instability. Additionally, positive relationships were observed between UCK2 expression and mismatch repair genes, homologous recombination repair genes, and cancer stemness across different cancer types. There were significant correlations between UCK2 and T cells, monocytes, mast cells, and macrophages. Moreover, as expected, the immune checkpoint human leucocyte antigen (HLA) was found to be negatively related to UCK2. Similarly, UCK2 was also observed to have a negative association with major histocompatibility complex (MHC) genes. We noted that UCK2 had significant correlations with the sensitivity to various anti-cancer drug. Conclusion We have observed that UCK2 plays pivotal roles in prognosis and tumor immunity, and it is associated with DNA repair and cancer stemness. The UCK2 gene exhibits a strong correlation with the immune checkpoints HLA. This study highlights its potential impact on drug sensitivity.
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Affiliation(s)
- Jinlong Tian
- Graduate School of Bengbu Medical University, Bengbu, Anhui, China
| | - Yanlei Li
- Graduate School of Bengbu Medical University, Bengbu, Anhui, China
| | - Yu Tong
- Sports Medicine Center, Department of Orthopedics, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
| | - Yuan Zhang
- Department of Rheumatology and Immunology, The Second Affiliated Hospital of Zhejiang University of Traditional Chinese Medicine, Hangzhou, China
| | - Tingxiao Zhao
- Sports Medicine Center, Department of Orthopedics, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
| | - Yao Kang
- Sports Medicine Center, Department of Orthopedics, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
| | - Qing Bi
- Graduate School of Bengbu Medical University, Bengbu, Anhui, China
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Fiorentino F, Fabbrizi E, Raucci A, Noce B, Fioravanti R, Valente S, Paolini C, De Maria R, Steinkühler C, Gallinari P, Rotili D, Mai A. Uracil- and Pyridine-Containing HDAC Inhibitors Displayed Cytotoxicity in Colorectal and Glioblastoma Cancer Stem Cells. ChemMedChem 2024; 19:e202300655. [PMID: 38529661 DOI: 10.1002/cmdc.202300655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 03/01/2024] [Accepted: 03/25/2024] [Indexed: 03/27/2024]
Abstract
Cancer stem cells (CSCs) are a niche of highly tumorigenic cells featuring self-renewal, activation of pluripotency genes, multidrug resistance, and ability to cause cancer relapse. Seven HDACi (1-7), showing either hydroxamate or 2'-aminoanilide function, were tested in colorectal cancer (CRC) and glioblastoma multiforme (GBM) CSCs to determine their effects on cell proliferation, H3 acetylation levels and in-cell HDAC activity. Two uracil-based hydroxamates, 5 and 6, which differ in substitution at C5 and C6 positions of the pyrimidine ring, exhibited the greatest cytotoxicity in GBM (5) and CRC (6) CSCs, followed by the pyridine-hydroxamate 2, with 2- to 6-fold higher potency than the positive control SAHA. Finally, increased H3 acetylation as well as HDAC inhibition directly in cells by selected 2'-aminoanilide 4 and hydroxamate 5 confirmed target engagement. Further investigation will be conducted into the broad-spectrum anticancer properties of the most potent derivatives and their effects in combination with approved, conventional anticancer drugs.
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Affiliation(s)
- Francesco Fiorentino
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo, Moro n. 5, 00185, Rome, Italy
| | - Emanuele Fabbrizi
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo, Moro n. 5, 00185, Rome, Italy
| | - Alessia Raucci
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo, Moro n. 5, 00185, Rome, Italy
| | - Beatrice Noce
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo, Moro n. 5, 00185, Rome, Italy
| | - Rossella Fioravanti
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo, Moro n. 5, 00185, Rome, Italy
| | - Sergio Valente
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo, Moro n. 5, 00185, Rome, Italy
| | - Chantal Paolini
- IRBM S.p.A., Via Pontina km 30.600, 00071, Pomezia, Rome, Italy
| | - Ruggero De Maria
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168, Rome, Italy
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168, Rome, Italy
| | - Christian Steinkühler
- Research and Development, Italfarmaco Group, Via dei Lavoratori 54, 20092, Cinisello Balsamo, Italy
| | - Paola Gallinari
- Exiris S.r.l., Tecnopolo Castel, Romano, Via Castel Romano 100, 00128, Rome, Italy
| | - Dante Rotili
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo, Moro n. 5, 00185, Rome, Italy
| | - Antonello Mai
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo, Moro n. 5, 00185, Rome, Italy
- Pasteur Institute, Cenci-Bolognetti Foundation, Sapienza University of Rome, P. de Aldo Moro n. 5, 00185, Rome, Italy
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Zhao Q, Zong H, Zhu P, Su C, Tang W, Chen Z, Jin S. Crosstalk between colorectal CSCs and immune cells in tumorigenesis, and strategies for targeting colorectal CSCs. Exp Hematol Oncol 2024; 13:6. [PMID: 38254219 PMCID: PMC10802076 DOI: 10.1186/s40164-024-00474-x] [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: 09/28/2023] [Accepted: 01/06/2024] [Indexed: 01/24/2024] Open
Abstract
Cancer immunotherapy has emerged as a promising strategy in the treatment of colorectal cancer, and relapse after tumor immunotherapy has attracted increasing attention. Cancer stem cells (CSCs), a small subset of tumor cells with self-renewal and differentiation capacities, are resistant to traditional therapies such as radiotherapy and chemotherapy. Recently, CSCs have been proven to be the cells driving tumor relapse after immunotherapy. However, the mutual interactions between CSCs and cancer niche immune cells are largely uncharacterized. In this review, we focus on colorectal CSCs, CSC-immune cell interactions and CSC-based immunotherapy. Colorectal CSCs are characterized by robust expression of surface markers such as CD44, CD133 and Lgr5; hyperactivation of stemness-related signaling pathways, such as the Wnt/β-catenin, Hippo/Yap1, Jak/Stat and Notch pathways; and disordered epigenetic modifications, including DNA methylation, histone modification, chromatin remodeling, and noncoding RNA action. Moreover, colorectal CSCs express abnormal levels of immune-related genes such as MHC and immune checkpoint molecules and mutually interact with cancer niche cells in multiple tumorigenesis-related processes, including tumor initiation, maintenance, metastasis and drug resistance. To date, many therapies targeting CSCs have been evaluated, including monoclonal antibodies, antibody‒drug conjugates, bispecific antibodies, tumor vaccines adoptive cell therapy, and small molecule inhibitors. With the development of CSC-/niche-targeting technology, as well as the integration of multidisciplinary studies, novel therapies that eliminate CSCs and reverse their immunosuppressive microenvironment are expected to be developed for the treatment of solid tumors, including colorectal cancer.
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Affiliation(s)
- Qi Zhao
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Hong Zong
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Pingping Zhu
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Chang Su
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Wenxue Tang
- The Research and Application Center of Precision Medicine, The Second Affiliated Hospital of Zhengzhou University, No. 2 Jing‑ba Road, Zhengzhou, 450014, China.
| | - Zhenzhen Chen
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China.
| | - Shuiling Jin
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
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Olsson M, Larsson P, Johansson J, Sah VR, Parris TZ. Cancer stem cells are prevalent in the basal-like 2 and mesenchymal triple-negative breast cancer subtypes in vitro. Front Cell Dev Biol 2023; 11:1237673. [PMID: 37771376 PMCID: PMC10523387 DOI: 10.3389/fcell.2023.1237673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 08/14/2023] [Indexed: 09/30/2023] Open
Abstract
Background: Triple-negative breast cancer (TNBC) is an aggressive subtype with the most unfavorable clinical outcomes, in part due to tumor heterogeneity, treatment resistance, and tumor relapse. The TNBC subtypes [basal-like 1 (BL1), basal-like 2 (BL2), mesenchymal (M), and luminal androgen receptor (LAR)] are biologically and clinically distinct entities that respond differently to local and systemic therapies. Therefore, we need to have a better understanding of cancer stemness relating to drug-resistant populations in the TNBC subtypes. Methods: Breast cancer stem cell (BCSC) distribution was investigated using an integrated flow cytometry approach with the ALDEFLUOR™ assay (ALDH) and CD24/CD44 antibodies. In total, 27 commercially available cell lines derived from normal and malignant mammary tissue were characterized into differentiated tumor cells and/or BCSC subpopulations (ALDH-CD44+CD24-/low enriched mesenchymal-like BCSCs, ALDH+non-CD44+CD24-/low enriched epithelial-like BCSCs, and highly purified ALDH+CD44+CD24-/low BCSCs). Results: BCSCs were not only enriched in estrogen receptor (ER) negative (mean, 49.6% versus 6.9% in ER+) and TNBC cell lines (51.3% versus 2.1% in Luminal A), but certain BCSC subpopulations (e.g., enriched mesenchymal-like BCSCs) were also significantly more common in the M (64.0% versus 6.2% in BL1; 64.0% versus 0% in LAR) and BL2 (77.4% versus 6.2% in BL1; 77.4% versus 0% in LAR; 77.4% versus 10.4% in TNBC UNS) TNBC subtypes. In contrast, ALDH status alone was not indicative of ER status or BC subtype. Conclusion: Taken together, these findings demonstrate the enrichment of potentially treatment-resistant BCSC subpopulations in the M and BL2 triple-negative breast cancer subtypes.
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Affiliation(s)
- Maxim Olsson
- Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden
| | - Peter Larsson
- Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Junko Johansson
- Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Vasu R. Sah
- Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Toshima Z. Parris
- Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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Bhavnagari H, Raval A, Shah F. Deciphering Potential Role of Hippo Signaling Pathway in Breast Cancer: A Comprehensive Review. Curr Pharm Des 2023; 29:3505-3518. [PMID: 38141194 DOI: 10.2174/0113816128274418231215054210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 11/16/2023] [Accepted: 11/23/2023] [Indexed: 12/25/2023]
Abstract
Breast cancer is a heterogeneous disease and a leading malignancy around the world. It is a vital cause of untimely mortality among women. Drug resistance is the major challenge for effective cancer therapeutics. In contrast, cancer stem cells (CSCs) are one of the reasons for drug resistance, tumor progression, and metastasis. The small population of CSCs present in each tumor has the ability of self-renewal, differentiation, and tumorigenicity. CSCs are often identified and enriched using a variety of cell surface markers (CD44, CD24, CD133, ABCG2, CD49f, LGR5, SSEA-3, CD70) that exert their functions by different regulatory networks, i.e., Notch, Wnt/β-catenin, hedgehog (Hh), and Hippo signaling pathways. Particularly the Hippo signaling pathway is the emerging and very less explored cancer stem cell pathway. Here, in this review, the Hippo signaling molecules are elaborated with respect to their ability of stemness as epigenetic modulators and how these molecules can be targeted for better cancer treatment and to overcome drug resistance.
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Affiliation(s)
- Hunayna Bhavnagari
- Molecular Diagnostic and Research Lab-3, Department of Cancer Biology, The Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India
| | - Apexa Raval
- Molecular Diagnostic and Research Lab-3, Department of Cancer Biology, The Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India
| | - Franky Shah
- Molecular Diagnostic and Research Lab-3, Department of Cancer Biology, The Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India
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6
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Targeting emerging cancer hallmarks by transition metal complexes: Epigenetic reprogramming and epitherapies. Part II. Coord Chem Rev 2023. [DOI: 10.1016/j.ccr.2022.214899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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Huang B, Lang X, Li X. The role of IL-6/JAK2/STAT3 signaling pathway in cancers. Front Oncol 2022; 12:1023177. [PMID: 36591515 PMCID: PMC9800921 DOI: 10.3389/fonc.2022.1023177] [Citation(s) in RCA: 183] [Impact Index Per Article: 61.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 12/06/2022] [Indexed: 12/23/2022] Open
Abstract
Interleukin-6 (IL-6) is a pleiotropic cytokine involved in immune regulation. It can activate janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) signaling pathway. As one of the important signal transduction pathways in cells, JAK2/STAT3 signaling pathway plays a critical role in cell proliferation and differentiation by affecting the activation state of downstream effector molecules. The activation of JAK2/STAT3 signaling pathway is involved in tumorigenesis and development. It contributes to the formation of tumor inflammatory microenvironment and is closely related to the occurrence and development of many human tumors. This article focuses on the relationship between IL-6/JAK2/STAT3 signaling pathway and liver cancer, breast cancer, colorectal cancer, gastric cancer, lung cancer, pancreatic cancer and ovarian cancer, hoping to provide references for the research of cancer treatment targeting key molecules in IL-6/JAK2/STAT3 signaling pathway.
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Affiliation(s)
- Bei Huang
- Operational Management Office, West China Second University Hospital, Sichuan University, Chengdu, China,Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
| | - Xiaoling Lang
- Operational Management Office, West China Second University Hospital, Sichuan University, Chengdu, China,Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China,*Correspondence: Xiaoling Lang, ; Xihong Li,
| | - Xihong Li
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China,Emergency Department, West China Second University Hospital, Sichuan University, Chengdu, China,*Correspondence: Xiaoling Lang, ; Xihong Li,
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Sun G, Zheng W, Tan P, Zhou J, Tang W, Cao H, Liu L, Shi X, Li Z, Zhang W. Comprehensive Analysis of VCAN Expression Profiles and Prognostic Values in HCC. Front Genet 2022; 13:900306. [PMID: 35812745 PMCID: PMC9263583 DOI: 10.3389/fgene.2022.900306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Accepted: 05/13/2022] [Indexed: 12/24/2022] Open
Abstract
Background: Hepatocellular carcinoma (HCC) is the world’s most common cause of cancer death. Therefore, more molecular mechanisms need to be clarified to meet the urgent need to develop new detection and treatment strategies. Methods: We used TCGAportal, Kaplan–Meier Plotter, the Cistrome DB Toolkit Database, MExpress, GEPIA2, and other databases to discuss the expression profiles, possible biological function, and potential prognostic value of versican (VCAN) in HCC. We conducted cell experiments such as Transwell migration and invasion assays, wound healing assay, and CCK8 experiment to explore the function of VCAN in HCC. Result: We selected three HCC transcriptome databases GSE124535, GSE136247, and GSE144269 and analyzed the overexpressed genes contained in them. The overlapping genes were found by the Venn map, and two interacting network modules were found by Mcode. Module 1 was mainly related to mitosis and cell cycle, and module 2 was mainly related to EMT, angiogenesis, glycolysis, and so on. We found that the seed gene in module 2 is VCAN. Data from TCGAportal showed that compared with normal tissues, the expression of VCAN was up-regulated in HCC tissues. The patients with high expression of VCAN had shorter distant recurrence-free survival and overall survival. Multiple possible VCAN interactions had also been identified. These results revealed that the level of VCAN was higher in the subtypes of HCC with higher malignant degree and was connected to the poor prognosis. In addition, the treatment of VCAN with DNA methyltransferase inhibitors and transcription factor inhibitors may improve the prognosis of patients with HCC. Conclusion: Our findings systematically elucidated the expression profile and different prognostic values of VCAN in HCC, which may provide new therapeutic targets and potential prognostic biomarkers for HCC patients.
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Affiliation(s)
- Guangshun Sun
- Department of General Surgery, Nanjing First Hospital, The Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, China
| | - Wubin Zheng
- Department of General Surgery, Nanjing First Hospital, The Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, China
| | - Pengyu Tan
- Department of Food Science and Engineering, Nanjing Xiaozhuang University, Nanjing, China
| | - Jin Zhou
- Department of General Surgery, Nanjing First Hospital, The Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, China
| | - Weiwei Tang
- Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
| | - Hongyong Cao
- Department of General Surgery, Nanjing First Hospital, The Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, China
- *Correspondence: Hongyong Cao, ; Li Liu, ; Xuesong Shi, ; Zhouxiao Li, ; Wenling Zhang,
| | - Li Liu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
- *Correspondence: Hongyong Cao, ; Li Liu, ; Xuesong Shi, ; Zhouxiao Li, ; Wenling Zhang,
| | - Xuesong Shi
- Department of General Surgery, Nanjing First Hospital, The Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, China
- *Correspondence: Hongyong Cao, ; Li Liu, ; Xuesong Shi, ; Zhouxiao Li, ; Wenling Zhang,
| | - Zhouxiao Li
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Hongyong Cao, ; Li Liu, ; Xuesong Shi, ; Zhouxiao Li, ; Wenling Zhang,
| | - Wenling Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- *Correspondence: Hongyong Cao, ; Li Liu, ; Xuesong Shi, ; Zhouxiao Li, ; Wenling Zhang,
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Xing XL, Liu Y, Liu J, Zhou H, Zhang H, Zuo Q, Bu P, Duan T, Zhou Y, Xiao Z. Comprehensive Analysis of Ferroptosis- and Immune-Related Signatures to Improve the Prognosis and Diagnosis of Kidney Renal Clear Cell Carcinoma. Front Immunol 2022; 13:851312. [PMID: 35619698 PMCID: PMC9128788 DOI: 10.3389/fimmu.2022.851312] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Accepted: 04/12/2022] [Indexed: 12/31/2022] Open
Abstract
Background Almost 40% of patients with kidney renal clear cell carcinoma (KIRC) with advanced cancers eventually develop to metastases, and their 5-year survival rates are approximately 10%. Aberrant DNA methylations are significantly associated with the development of KIRC. The aim of our present study was to identify suitable ferroptosis- and immune-related (FI) biomarkers correlated with aberrant methylations to improve the prognosis and diagnosis of KIRC. Methods ChAMP and DESeq2 in R (3.6.2) were used to screen the differentially expressed methylation probes and differentially expressed genes, respectively. Univariate and multivariate Cox regression were used to identify the overall survival (OS)-related biomarkers. Results We finally identified five FI biomarkers (CCR4, CMTM3, IFITM1, MX2, and NR3C2) that were independently correlated with the OS of KIRC. The area under the curve value of the receiver operating characteristic value of prognosis model was 0.74, 0.68, and 0.72 in the training, validation, and entire cohorts, respectively. The sensitivity and specificity of the diagnosis model were 0.8698 and 0.9722, respectively. In addition, the prognosis model was also significantly correlated with several immune cells and factors. Conclusion Our present study suggested that these five FI-DEGs (CCR4, CMTM3, IFITM1, MX2, and NR3C2) could be used as prognosis and diagnosis biomarkers for patients with KIRC, but further cross-validation clinical studies are still needed to confirm them.
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Affiliation(s)
- Xiao-Liang Xing
- Department of General Medicine, University of South China affiliated Changsha Central Hospital, Changsha, China
- School of Public Health and Laboratory Medicine, Hunan University of Medicine, Huaihua, China
| | - Yan Liu
- Department of General Medicine, University of South China affiliated Changsha Central Hospital, Changsha, China
| | - Jiheng Liu
- Department of Emergency, First Hospital of Changsha, Changsha, China
| | - Huanfa Zhou
- Department of General Medicine, University of South China affiliated Changsha Central Hospital, Changsha, China
| | - Huirong Zhang
- Department of General Medicine, University of South China affiliated Changsha Central Hospital, Changsha, China
| | - Qi Zuo
- Department of Emergency, First Hospital of Changsha, Changsha, China
| | - Ping Bu
- Department of General Medicine, University of South China affiliated Changsha Central Hospital, Changsha, China
| | - Tong Duan
- Department of Emergency, First Hospital of Changsha, Changsha, China
| | - Yan Zhou
- Department of Emergency, First Hospital of Changsha, Changsha, China
| | - Zhiquan Xiao
- Department of General Medicine, University of South China affiliated Changsha Central Hospital, Changsha, China
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He J, Fu H, Li C, Deng Z, Chang H. Association between Vitamin B 12 and Risk of Gastric Cancer: A Systematic Review and Meta-Analysis of Epidemiological Studies. Nutr Cancer 2022; 74:3263-3273. [PMID: 35538710 DOI: 10.1080/01635581.2022.2074062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Epidemiological studies focusing on the association between vitamin B12 and gastric cancer risk reported inconsistent findings. We conducted a systematic review and meta-analysis to assess the relationship. PubMed (Medline), Web of science and EMBASE databases were systematically searched. A total of nine studies involving 3,494 cases of with gastric cancer and 611,638 participants were included. The result showed that there is no significant association between vitamin B12 intake and the risk of gastric cancer (OR = 0.88, 95% CI: 0.69-1.12, P = 0.303). Nevertheless, high intake of vitamin B12 might decrease the risk of gastric cancer in Helicobacter pylori (Hp)-negative people (OR = 0.83, 95% CI: 0.62-0.99, P = 0.044), but increase the cancer risk in Hp-positive populations (OR = 1.66, 95% CI: 1.27-2.16, P = 10-4). Additionally, further analysis indicated that excessive vitamin B12 might increase the risk of non-cardia gastric cancer (OR = 1.15, 95% CI: 1.01-1.33, P = 0.006). A negative association between vitamin B12 intake and gastric cancer risk was found in nonsmokers (OR = 0.83, 95% CI: 0.71-0.96, P = 0.012) but not in smokers (OR = 1.08, 95% CI: 0.71-1.47, P = 0.619). In conclusion, although we found no convincing evidence that vitamin B12 intake is associated with the risk of gastric cancer, it is important to maintain the relative stability of vitamin B12 for people with Hp infection.
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Affiliation(s)
- Jianbo He
- College of Food Science, Southwest University, Chongqing, China
| | - Hongjuan Fu
- College of Food Science, Southwest University, Chongqing, China
| | - Cancan Li
- College of Food Science, Southwest University, Chongqing, China
| | - Zhihui Deng
- College of Food Science, Southwest University, Chongqing, China
| | - Hui Chang
- College of Food Science, Southwest University, Chongqing, China
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11
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Kumar VE, Nambiar R, De Souza C, Nguyen A, Chien J, Lam KS. Targeting Epigenetic Modifiers of Tumor Plasticity and Cancer Stem Cell Behavior. Cells 2022; 11:cells11091403. [PMID: 35563709 PMCID: PMC9102449 DOI: 10.3390/cells11091403] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 04/11/2022] [Accepted: 04/15/2022] [Indexed: 02/01/2023] Open
Abstract
Tumor heterogeneity poses one of the greatest challenges to a successful treatment of cancer. Tumor cell populations consist of different subpopulations that have distinct phenotypic and genotypic profiles. Such variability poses a challenge in successfully targeting all tumor subpopulations at the same time. Relapse after treatment has been previously explained using the cancer stem cell model and the clonal evolution model. Cancer stem cells are an important subpopulation of tumor cells that regulate tumor plasticity and determine therapeutic resistance. Tumor plasticity is controlled by genetic and epigenetic changes of crucial genes involved in cancer cell survival, growth and metastasis. Targeting epigenetic modulators associated with cancer stem cell survival can unlock a promising therapeutic approach in completely eradicating cancer. Here, we review various factors governing epigenetic dysregulation of cancer stem cells ranging from the role of epigenetic mediators such as histone and DNA methyltransferases, histone deacetylases, histone methyltransferases to various signaling pathways associated with cancer stem cell regulation. We also discuss current treatment regimens targeting these factors and other promising inhibitors in clinical trials.
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Affiliation(s)
- Vigneshwari Easwar Kumar
- Department of Biochemistry and Molecular Medicine, UC Davis Medical Center, Sacramento, CA 95817, USA; (V.E.K.); (R.N.); (C.D.S.); (A.N.); (K.S.L.)
| | - Roshni Nambiar
- Department of Biochemistry and Molecular Medicine, UC Davis Medical Center, Sacramento, CA 95817, USA; (V.E.K.); (R.N.); (C.D.S.); (A.N.); (K.S.L.)
| | - Cristabelle De Souza
- Department of Biochemistry and Molecular Medicine, UC Davis Medical Center, Sacramento, CA 95817, USA; (V.E.K.); (R.N.); (C.D.S.); (A.N.); (K.S.L.)
- Department of Stem Cell Research and Regenerative Medicine, School of Medicine, Stanford University, Stanford, CA 94305, USA
| | - Audrey Nguyen
- Department of Biochemistry and Molecular Medicine, UC Davis Medical Center, Sacramento, CA 95817, USA; (V.E.K.); (R.N.); (C.D.S.); (A.N.); (K.S.L.)
| | - Jeremy Chien
- Department of Biochemistry and Molecular Medicine, UC Davis Medical Center, Sacramento, CA 95817, USA; (V.E.K.); (R.N.); (C.D.S.); (A.N.); (K.S.L.)
- Department of Obstetrics and Gynecology, UC Davis Medical Center, Sacramento, CA 95817, USA
- Correspondence:
| | - Kit S. Lam
- Department of Biochemistry and Molecular Medicine, UC Davis Medical Center, Sacramento, CA 95817, USA; (V.E.K.); (R.N.); (C.D.S.); (A.N.); (K.S.L.)
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12
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Mazloumi Z, Farahzadi R, Rafat A, Asl KD, Karimipour M, Montazer M, Movassaghpour AA, Dehnad A, Charoudeh HN. Effect of aberrant DNA methylation on cancer stem cell properties. Exp Mol Pathol 2022; 125:104757. [PMID: 35339454 DOI: 10.1016/j.yexmp.2022.104757] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 03/09/2022] [Accepted: 03/19/2022] [Indexed: 12/21/2022]
Abstract
DNA methylation, as an epigenetic mechanism, occurs by adding a methyl group of cytosines in position 5 by DNA methyltransferases and has essential roles in cellular function, especially in the transcriptional regulation of embryonic and adult stem cells. Hypomethylation and hypermethylation cause either the expression or inhibition of genes, and there is a tight balance between regulating the activation or repression of genes in normal cellular activity. Abnormal methylation is well-known hallmark of cancer development and progression and can switch normal stem cells into cancer stem cells. Cancer Stem Cells (CSCs) are minor populations of tumor cells that exhibit unique properties such as self-regeneration, resistance to chemotherapy, and high ability of metastasis. The purpose of this paper is to show how aberrant DNA methylation accumulation affects self-renewal, differentiation, multidrug-resistant, and metastasis processes in cancer stem cells.
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Affiliation(s)
- Zeinab Mazloumi
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran; Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Raheleh Farahzadi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Rafat
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Khadijeh Dizaji Asl
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Karimipour
- Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Majid Montazer
- Department of Cardiovascular Surgery, Imam Reza Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Alireza Dehnad
- Department of Bacterial Disease Research, Razi Vaccine and Serum Research Institute, AREEO, Tabriz, Iran
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Liu H, Zhang Z, Song L, Gao J, Liu Y. Lipid metabolism of cancer stem cells (Review). Oncol Lett 2022; 23:119. [PMID: 35261633 PMCID: PMC8855159 DOI: 10.3892/ol.2022.13239] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 12/07/2021] [Indexed: 11/21/2022] Open
Abstract
Cancer stem cells (CSCs), also termed cancer-initiating cells, are a special subset of cells with high self-replicating and self-renewing abilities that can differentiate into various cell types under certain conditions. A number of studies have demonstrated that CSCs have distinct metabolic properties. The reprogramming of energy metabolism enables CSCs to meet the needs of self-renewal and stemness maintenance. Increasing evidence supports the view that alterations in lipid metabolism, including an increase in fatty acid (FA) uptake, de novo lipogenesis, formation of lipid droplets and mitochondrial FA oxidation, are involved in CSC regulation. In the present review, the metabolic characteristics of CSCs, particularly in lipid metabolism, were summarized. In addition, the potential mechanisms of CSC lipid metabolism in treatment resistance were discussed. Given their significance in cancer biology, targeting CSC metabolism may serve an important role in future cancer treatment.
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Affiliation(s)
- Huihui Liu
- Department of Medical Imaging, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, P.R. China
| | - Zhengyang Zhang
- Department of Medical Imaging, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, P.R. China
| | - Lian Song
- Department of Medical Imaging, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, P.R. China
| | - Jie Gao
- Department of Medical Imaging, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, P.R. China
| | - Yanfang Liu
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
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14
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Impact of Advanced Glycation End products (AGEs) and its receptor (RAGE) on cancer metabolic signaling pathways and its progression. Glycoconj J 2022; 38:717-734. [PMID: 35064413 DOI: 10.1007/s10719-021-10031-x] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/26/2021] [Accepted: 11/30/2021] [Indexed: 02/07/2023]
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15
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Mensah IK, Norvil AB, AlAbdi L, McGovern S, Petell CJ, He M, Gowher H. Misregulation of the expression and activity of DNA methyltransferases in cancer. NAR Cancer 2021; 3:zcab045. [PMID: 34870206 PMCID: PMC8634572 DOI: 10.1093/narcan/zcab045] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 10/29/2021] [Accepted: 11/10/2021] [Indexed: 12/15/2022] Open
Abstract
In mammals, DNA methyltransferases DNMT1 and DNMT3's (A, B and L) deposit and maintain DNA methylation in dividing and nondividing cells. Although these enzymes have an unremarkable DNA sequence specificity (CpG), their regional specificity is regulated by interactions with various protein factors, chromatin modifiers, and post-translational modifications of histones. Changes in the DNMT expression or interacting partners affect DNA methylation patterns. Consequently, the acquired gene expression may increase the proliferative potential of cells, often concomitant with loss of cell identity as found in cancer. Aberrant DNA methylation, including hypermethylation and hypomethylation at various genomic regions, therefore, is a hallmark of most cancers. Additionally, somatic mutations in DNMTs that affect catalytic activity were mapped in Acute Myeloid Leukemia cancer cells. Despite being very effective in some cancers, the clinically approved DNMT inhibitors lack specificity, which could result in a wide range of deleterious effects. Elucidating distinct molecular mechanisms of DNMTs will facilitate the discovery of alternative cancer therapeutic targets. This review is focused on: (i) the structure and characteristics of DNMTs, (ii) the prevalence of mutations and abnormal expression of DNMTs in cancer, (iii) factors that mediate their abnormal expression and (iv) the effect of anomalous DNMT-complexes in cancer.
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Affiliation(s)
- Isaiah K Mensah
- Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA
| | | | - Lama AlAbdi
- Department of Zoology, Collage of Science, King Saud University, Riyadh, Saudi Arabia
| | - Sarah McGovern
- Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA
| | | | - Ming He
- Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA
| | - Humaira Gowher
- Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA
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16
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Liu Z, Ren Y, Meng L, Li L, Beatson R, Deng J, Zhang T, Liu J, Han X. Epigenetic Signaling of Cancer Stem Cells During Inflammation. Front Cell Dev Biol 2021; 9:772211. [PMID: 34722553 PMCID: PMC8554148 DOI: 10.3389/fcell.2021.772211] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 09/21/2021] [Indexed: 12/12/2022] Open
Abstract
Malignant tumors pose a great challenge to human health, which has led to many studies increasingly elucidating the tumorigenic process. Cancer Stem Cells (CSCs) have profound impacts on tumorigenesis and development of drug resistance. Recently, there has been increased interest in the relationship between inflammation and CSCs but the mechanism underlying this relationship has not been fully elucidated. Inflammatory cytokines produced during chronic inflammation activate signaling pathways that regulate the generation of CSCs through epigenetic mechanisms. In this review, we focus on the effects of inflammation on cancer stem cells, particularly the role of signaling pathways such as NF-κB pathway, STAT3 pathway and Smad pathway involved in regulating epigenetic changes. We hope to provide a novel perspective for improving strategies for tumor treatment.
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Affiliation(s)
- Zaoqu Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Interventional Institute of Zhengzhou University, Zhengzhou, China.,Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, China
| | - Yuqing Ren
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Lingfang Meng
- Department of Ultrasound, Zhengzhou Sixth People's Hospital, Henan Infectious Disease Hospital, Zhengzhou, China
| | - Lifeng Li
- Internet Medical and System Applications of National Engineering Laboratory, Zhengzhou, China
| | - Richard Beatson
- School of Cancer and Pharmaceutical Sciences, King's College London, London, United Kingdom
| | - Jinhai Deng
- Richard Dimbleby Laboratory of Cancer Research, School of Cancer and Pharmaceutical Sciences, King's College London, London, United Kingdom
| | - Tengfei Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Junqi Liu
- Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xinwei Han
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Interventional Institute of Zhengzhou University, Zhengzhou, China.,Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, China
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17
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French R, Pauklin S. Epigenetic regulation of cancer stem cell formation and maintenance. Int J Cancer 2021; 148:2884-2897. [PMID: 33197277 PMCID: PMC8246550 DOI: 10.1002/ijc.33398] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 10/23/2020] [Accepted: 11/11/2020] [Indexed: 12/12/2022]
Abstract
Cancerous tumours contain a rare subset of cells with stem-like properties that are termed cancer stem cells (CSCs). CSCs are defined by their ability to divide both symmetrically and asymmetrically, to initiate new tumour growth and to tolerate the foreign niches required for metastatic dissemination. Accumulating evidence suggests that tumours arise from cells with stem-like properties, the generation of CSCs is therefore likely to be an initiatory event in carcinogenesis. Furthermore, CSCs in established tumours exist in a dynamic and plastic state, with nonstem tumour cells thought to be capable of de-differentiation to CSCs. The regulation of the CSC state both during tumour initiation and within established tumours is a desirable therapeutic target and is mediated by epigenetic factors. In this review, we will explore the epigenetic parallels between induced pluripotency and the generation of CSCs, and discuss how the epigenetic regulation of CSCs opens up novel opportunities for therapeutic intervention.
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Affiliation(s)
- Rhiannon French
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal SciencesUniversity of OxfordOxfordUK
| | - Siim Pauklin
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal SciencesUniversity of OxfordOxfordUK
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18
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Xia X, Wu WKK, Wong SH, Liu D, Kwong TNY, Nakatsu G, Yan PS, Chuang YM, Chan MWY, Coker OO, Chen Z, Yeoh YK, Zhao L, Wang X, Cheng WY, Chan MTV, Chan PKS, Sung JJY, Wang MH, Yu J. Bacteria pathogens drive host colonic epithelial cell promoter hypermethylation of tumor suppressor genes in colorectal cancer. MICROBIOME 2020; 8:108. [PMID: 32678024 PMCID: PMC7367367 DOI: 10.1186/s40168-020-00847-4] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 04/26/2020] [Indexed: 05/09/2023]
Abstract
BACKGROUND Altered microbiome composition and aberrant promoter hypermethylation of tumor suppressor genes (TSGs) are two important hallmarks of colorectal cancer (CRC). Here we performed concurrent 16S rRNA gene sequencing and methyl-CpG binding domain-based capture sequencing in 33 tissue biopsies (5 normal colonic mucosa tissues, 4 pairs of adenoma and adenoma-adjacent tissues, and 10 pairs of CRC and CRC-adjacent tissues) to identify significant associations between TSG promoter hypermethylation and CRC-associated bacteria, followed by functional validation of the methylation-associated bacteria. RESULTS Fusobacterium nucleatum and Hungatella hathewayi were identified as the top two methylation-regulating bacteria. Targeted analysis on bona fide TSGs revealed that H. hathewayi and Streptococcus spp. significantly correlated with CDX2 and MLH1 promoter hypermethylation, respectively. Mechanistic validation with cell-line and animal models revealed that F. nucleatum and H. hathewayi upregulated DNA methyltransferase. H. hathewayi inoculation also promoted colonic epithelial cell proliferation in germ-free and conventional mice. CONCLUSION Our integrative analysis revealed previously unknown epigenetic regulation of TSGs in host cells through inducing DNA methyltransferase by F. nucleatum and H. hathewayi, and established the latter as CRC-promoting bacteria. Video abstract.
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Affiliation(s)
- Xiaoxuan Xia
- Division of Biostatistics, Centre for Clinical Research and Biostatistics, JC School of Public Health and Primary Care, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
| | - William Ka Kei Wu
- Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
| | - Sunny Hei Wong
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
- State Key Laboratory of Digestive Diseases, Institute of Digestive Diseases, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
| | - Dabin Liu
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
- State Key Laboratory of Digestive Diseases, Institute of Digestive Diseases, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
| | - Thomas Ngai Yeung Kwong
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
- State Key Laboratory of Digestive Diseases, Institute of Digestive Diseases, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
| | - Geicho Nakatsu
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
- State Key Laboratory of Digestive Diseases, Institute of Digestive Diseases, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
| | - Pearlly S Yan
- Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
| | - Yu-Ming Chuang
- Department of Biomedical Sciences, National Chung Cheng University, Chia-Yi, Taiwan, Republic of China
| | - Michael Wing-Yan Chan
- Department of Biomedical Sciences, National Chung Cheng University, Chia-Yi, Taiwan, Republic of China
| | - Olabisi Oluwabukola Coker
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
- State Key Laboratory of Digestive Diseases, Institute of Digestive Diseases, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
| | - Zigui Chen
- Department of Microbiology, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
| | - Yun Kit Yeoh
- Department of Microbiology, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
| | - Liuyang Zhao
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
- State Key Laboratory of Digestive Diseases, Institute of Digestive Diseases, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
| | - Xiansong Wang
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
- State Key Laboratory of Digestive Diseases, Institute of Digestive Diseases, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
| | - Wing Yin Cheng
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
- State Key Laboratory of Digestive Diseases, Institute of Digestive Diseases, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
| | - Matthew Tak Vai Chan
- Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
| | - Paul Kay Sheung Chan
- Department of Microbiology, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
| | - Joseph Jao Yiu Sung
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
- State Key Laboratory of Digestive Diseases, Institute of Digestive Diseases, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
| | - Maggie Haitian Wang
- Division of Biostatistics, Centre for Clinical Research and Biostatistics, JC School of Public Health and Primary Care, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China.
| | - Jun Yu
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China.
- State Key Laboratory of Digestive Diseases, Institute of Digestive Diseases, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China.
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China.
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Wuputra K, Ku CC, Wu DC, Lin YC, Saito S, Yokoyama KK. Prevention of tumor risk associated with the reprogramming of human pluripotent stem cells. J Exp Clin Cancer Res 2020; 39:100. [PMID: 32493501 PMCID: PMC7268627 DOI: 10.1186/s13046-020-01584-0] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Accepted: 04/22/2020] [Indexed: 02/07/2023] Open
Abstract
Human pluripotent embryonic stem cells have two special features: self-renewal and pluripotency. It is important to understand the properties of pluripotent stem cells and reprogrammed stem cells. One of the major problems is the risk of reprogrammed stem cells developing into tumors. To understand the process of differentiation through which stem cells develop into cancer cells, investigators have attempted to identify the key factors that generate tumors in humans. The most effective method for the prevention of tumorigenesis is the exclusion of cancer cells during cell reprogramming. The risk of cancer formation is dependent on mutations of oncogenes and tumor suppressor genes during the conversion of stem cells to cancer cells and on the environmental effects of pluripotent stem cells. Dissecting the processes of epigenetic regulation and chromatin regulation may be helpful for achieving correct cell reprogramming without inducing tumor formation and for developing new drugs for cancer treatment. This review focuses on the risk of tumor formation by human pluripotent stem cells, and on the possible treatment options if it occurs. Potential new techniques that target epigenetic processes and chromatin regulation provide opportunities for human cancer modeling and clinical applications of regenerative medicine.
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Affiliation(s)
- Kenly Wuputra
- Graduate Institute of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Rd., San-Ming District, Kaohsiung, 807, Taiwan
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan
| | - Chia-Chen Ku
- Graduate Institute of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Rd., San-Ming District, Kaohsiung, 807, Taiwan
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan
| | - Deng-Chyang Wu
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan
| | - Ying-Chu Lin
- School of Dentistry, School of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
| | - Shigeo Saito
- Waseda University Research Institute for Science and Engineering, Shinjuku, Tokyo, 162-8480, Japan.
- Saito Laboratory of Cell Technology Institute, Yaita, Tochigi, 329-1571, Japan.
| | - Kazunari K Yokoyama
- Graduate Institute of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Rd., San-Ming District, Kaohsiung, 807, Taiwan.
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan.
- Waseda University Research Institute for Science and Engineering, Shinjuku, Tokyo, 162-8480, Japan.
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20
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Pan D, Su M, Huang G, Luo P, Zhang T, Fu L, Wei J, Wang S, Sun G. MTHFR C677T genetic polymorphism in combination with serum vitamin B 2, B 12 and aberrant DNA methylation of P16 and P53 genes in esophageal squamous cell carcinoma and esophageal precancerous lesions: a case-control study. Cancer Cell Int 2019; 19:288. [PMID: 31754346 PMCID: PMC6852963 DOI: 10.1186/s12935-019-1012-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Accepted: 11/01/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The study aimed to explore the associations between the interactions of serum vitamin B2 or B12 levels, aberrant DNA methylation of p16 or p53 and MTHFR C677T polymorphism and the risks of esophageal squamous cell carcinoma (ESCC) and esophageal precancerous lesion (EPL). METHODS 200 ESCC cases, 200 EPL cases and 200 normal controls were matched by age (± 2 years) and gender. Serum vitamin B2 and B12 levels, MTHFR C677T genetic polymorphisms and the methylation status of genes were assessed. Chi square test, one-way analysis of variance and binary logistic regression were performed. RESULTS The lowest quartile of both serum vitamin B2 and B12 with TT genotype showed significant increased EPL risk (OR = 4.91, 95% CI 1.31-18.35; OR = 6.88, 95% CI 1.10-42.80). The highest quartile of both serum vitamin B2 and B12 with CC genotype showed significant decreased ESCC risk (OR = 0.16, 95% CI 0.04-0.60; OR = 0.10, 95% CI 0.02-0.46). The ORs of p16 methylation for genotype CT and TT were 1.98 (95% CI 1.01-3.89) and 17.79 (95% CI 2.26-140.22) in EPL, 4.86 (95% CI 2.48-9.50) and 20.40 (95% CI 2.53-164.81) in ESCC, respectively. Similarly, p53 methylation with genotype TT was associated with increased EPL and ESCC risks (OR = 13.28, 95% CI 1.67-105.70; OR = 15.24, 95% CI 1.90-122.62). CONCLUSIONS The MTHFR C677T genotype and serum vitamin B2 or B12 levels may interact in ways which associated with the EPL and ESCC risks. The gene-gene interaction suggested that aberrant DNA methyaltion of either p16 or p53 combined with T alleles of MTHFR was associated with increased risks of both EPL and ESCC.
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Affiliation(s)
- Da Pan
- Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, and Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing, 210009 People’s Republic of China
| | - Ming Su
- Huai’an District Center for Disease Control and Prevention, Huai’an, 223200 People’s Republic of China
| | - Guiling Huang
- Jiangsu Vocational College of Medicine, Yancheng, 224005 People’s Republic of China
| | - Pengfei Luo
- Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, 210009 People’s Republic of China
| | - Ting Zhang
- Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, and Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing, 210009 People’s Republic of China
| | - Lingmeng Fu
- Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, and Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing, 210009 People’s Republic of China
| | - Jie Wei
- Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, and Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing, 210009 People’s Republic of China
| | - Shaokang Wang
- Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, and Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing, 210009 People’s Republic of China
| | - Guiju Sun
- Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, and Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing, 210009 People’s Republic of China
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21
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Wang Z, Yang C. Metal carcinogen exposure induces cancer stem cell-like property through epigenetic reprograming: A novel mechanism of metal carcinogenesis. Semin Cancer Biol 2019; 57:95-104. [PMID: 30641125 PMCID: PMC6625953 DOI: 10.1016/j.semcancer.2019.01.002] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2018] [Revised: 01/08/2019] [Accepted: 01/10/2019] [Indexed: 12/13/2022]
Abstract
Arsenic, cadmium, nickel and hexavalent chromium are among the most common environmental pollutants and potent carcinogens. Chronic exposure to these metals causes various types of cancer in humans, representing a significant environmental health issue. Although under active investigation, the mechanisms of metal carcinogenesis have not been clearly defined. One common feature of these metal carcinogens is that they are all able to cause various epigenetic dysregulations, which are believed to play important roles in their carcinogenicity. However, how metal carcinogen-caused epigenetic dysregulation contributes to metal carcinogenesis remains largely unknown. The evolution of cancer stem cell (CSC) theory has opened exciting new avenues for studying the mechanism of metal carcinogenesis. Increasing evidence indicates that chronic metal carcinogen exposure produces CSC-like cells through dysregulated epigenetic mechanisms. This review will first provide some brief introductions about CSC, epigenetics and epigenetic regulation of CSCs; then summarize progresses in recent studies on metal carcinogen-induced CSC-like property through epigenetic reprograming as a novel mechanism of metal carcinogenesis. Some perspectives for future studies in this field are also presented.
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Affiliation(s)
- Zhishan Wang
- Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY, United States.
| | - Chengfeng Yang
- Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY, United States; Center for Research on Environment Disease, College of Medicine, University of Kentucky, Lexington, KY, United States.
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22
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Chen Y, Feng H, Zhang H, Li X. High expression of DNA methyltransferase 1 in Kazakh esophageal epithelial cells may promote malignant transformation induced by N-methyl-N′-nitro-N-nitrosoguanidine. Hum Exp Toxicol 2019; 38:1060-1068. [DOI: 10.1177/0960327119851254] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
We examined the role of DNA methyltransferase 1 (DNMT1) in N-methyl- N′-nitro- N-nitrosoguanidine (MNNG)–induced malignant transformation of Kazakh esophageal epithelial (EE) cells to better understand the pathogenesis of esophageal cancer (EC). The 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide method and colony formation assays were performed to determine the MNNG dose for malignant transformation. Colony formation assays showed the effects of different frequencies of MNNG exposure and different cell passages on malignant transformation. A nude mouse tumor experiment indicated the malignancy of Kazakh EE cells expressing high DNMT1 levels and of transformed cells. The result shows that when the dose, frequency, and time of MNNG exposure increased, cell morphology became irregular, cell-contact suppression disappeared, and cell tolerance and growth rate increased. Colony formation occurred in the Kazakh-DNMT1 group after 14 transfections and 27 passages. Significant differences in DNMT1 mRNA and protein levels were observed in different types of cells and tumor tissues ( F = 140.644, p < 0.001; F = 105.545, p < 0.001). Our study demonstrated that DNMT1 could promote MNNG to induce malignant transformation of EE cells, and this study will help understand EC better in order to develop appropriate treatment strategies.
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Affiliation(s)
- Y Chen
- The Medical School of Jiaxing University, Jiaxing, China
- Department of Health Toxicology, College of Public Health, Xinjiang Medical University, Urumqi, China
| | - H Feng
- The Medical School of Jiaxing University, Jiaxing, China
| | - H Zhang
- Department of Health Toxicology, College of Public Health, Xinjiang Medical University, Urumqi, China
| | - X Li
- Department of Health Toxicology, College of Public Health, Xinjiang Medical University, Urumqi, China
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23
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Golub D, Iyengar N, Dogra S, Wong T, Bready D, Tang K, Modrek AS, Placantonakis DG. Mutant Isocitrate Dehydrogenase Inhibitors as Targeted Cancer Therapeutics. Front Oncol 2019; 9:417. [PMID: 31165048 PMCID: PMC6534082 DOI: 10.3389/fonc.2019.00417] [Citation(s) in RCA: 178] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2019] [Accepted: 05/02/2019] [Indexed: 12/15/2022] Open
Abstract
The identification of heterozygous neomorphic isocitrate dehydrogenase (IDH) mutations across multiple cancer types including both solid and hematologic malignancies has revolutionized our understanding of oncogenesis in these malignancies and the potential for targeted therapeutics using small molecule inhibitors. The neomorphic mutation in IDH generates an oncometabolite product, 2-hydroxyglutarate (2HG), which has been linked to the disruption of metabolic and epigenetic mechanisms responsible for cellular differentiation and is likely an early and critical contributor to oncogenesis. In the past 2 years, two mutant IDH (mutIDH) inhibitors, Enasidenib (AG-221), and Ivosidenib (AG-120), have been FDA-approved for IDH-mutant relapsed or refractory acute myeloid leukemia (AML) based on phase 1 safety and efficacy data and continue to be studied in trials in hematologic malignancies, as well as in glioma, cholangiocarcinoma, and chondrosarcoma. In this review, we will summarize the molecular pathways and oncogenic consequences associated with mutIDH with a particular emphasis on glioma and AML, and systematically review the development and preclinical testing of mutIDH inhibitors. Existing clinical data in both hematologic and solid tumors will likewise be reviewed followed by a discussion on the potential limitations of mutIDH inhibitor monotherapy and potential routes for treatment optimization using combination therapy.
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Affiliation(s)
- Danielle Golub
- Department of Neurosurgery, New York University School of Medicine, NYU Langone Health, New York, NY, United States.,Clinical and Translational Science Institute, New York University School of Medicine, NYU Langone Health, New York, NY, United States
| | - Nishanth Iyengar
- New York University School of Medicine, NYU Langone Health, New York, NY, United States
| | - Siddhant Dogra
- New York University School of Medicine, NYU Langone Health, New York, NY, United States
| | - Taylor Wong
- Department of Neurosurgery, New York University School of Medicine, NYU Langone Health, New York, NY, United States
| | - Devin Bready
- Department of Neurosurgery, New York University School of Medicine, NYU Langone Health, New York, NY, United States
| | - Karen Tang
- Clinical and Translational Science Institute, New York University School of Medicine, NYU Langone Health, New York, NY, United States.,Division of Hematology/Oncology, Department of Pediatrics, New York University School of Medicine, NYU Langone Health, New York, NY, United States
| | - Aram S Modrek
- Department of Radiation Oncology, New York University School of Medicine, NYU Langone Health, New York, NY, United States
| | - Dimitris G Placantonakis
- Department of Neurosurgery, New York University School of Medicine, NYU Langone Health, New York, NY, United States.,Kimmel Center for Stem Cell Biology, New York University School of Medicine, NYU Langone Health, New York, NY, United States.,Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY, United States.,Brain Tumor Center, New York University School of Medicine, NYU Langone Health, New York, NY, United States.,Neuroscience Institute, New York University School of Medicine, NYU Langone Health, New York, NY, United States
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24
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Norollahi SE, Mansour-Ghanaei F, Joukar F, Ghadarjani S, Mojtahedi K, Gharaei Nejad K, Hemmati H, Gharibpoor F, Khaksar R, Samadani AA. Therapeutic approach of Cancer stem cells (CSCs) in gastric adenocarcinoma; DNA methyltransferases enzymes in cancer targeted therapy. Biomed Pharmacother 2019; 115:108958. [PMID: 31075731 DOI: 10.1016/j.biopha.2019.108958] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 05/03/2019] [Accepted: 05/03/2019] [Indexed: 02/08/2023] Open
Abstract
Cancer stem cells (CSCs) show a remarkable sub class of cancer cells population which have a potential to organize and regulate stemness properties which possess a main particular responsibility for uncontrolled growth in carcinogenesis, production of different cancers in differentiated situation and also resistancy to radiotherapy and chemotherapy. Correspondingly, gastric cancer (GC) as a very serious type in cancer mortality in the world, has received a deep attention in molecular therapy recently. Besides the main characteristics of CSCs like differentiation, epithelial mesenchymal transition, self-renewal and metastasis, they are so effective in expression of stemness genes resistancy in radiotherapy and chemotherapy. In this way, the regulation of epigenetic elements including DNA methylation and the performance of DNA methyltransferase (DNMT) which is a notable epigenetic trait in GC, is of great importance. Inhibitors of DNA methylation are the first epigenetic drugs in cancer therapy. Considerably, recent studies indicate that low doses of DNMT inhibitors have a high potential in sustaining reduced DNA methylation and related with re-expression of silenced genes in tumorigenesis. Importantly, these certain doses have the ability to decrease the carcinogenesis and tumorigenesis in CSC populations within GC. Meaningly, the inhibition of DNMTs are able to reduce the accumulation of tumorigenic ability of GC CSCs. Furthermore, many epigenetic drugs have a great potential in cancer therapy, including histone methyltransferases, lysine demethylases, histone deacetylasesand, bromodomain and extra-terminal domain proteins and DNA methyltransferases inhibitors. In this review article, we try to focus on the therapeutic mechanism of DNMTs alongside with their impact on CSCs in GC.
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Affiliation(s)
- Syedeh Elham Norollahi
- Gastrointestinal and liver diseases research center, Guilan University of Medical Sciences, Rasht, Iran
| | - Fariborz Mansour-Ghanaei
- Gastrointestinal and liver diseases research center, Guilan University of Medical Sciences, Rasht, Iran
| | - Farahnaz Joukar
- Gastrointestinal and liver diseases research center, Guilan University of Medical Sciences, Rasht, Iran
| | - Shervin Ghadarjani
- Department of Neurosurgery, Guilan University of Medical Sciences, Rasht, Iran
| | - Kourosh Mojtahedi
- Gastrointestinal and liver diseases research center, Guilan University of Medical Sciences, Rasht, Iran
| | - Kaveh Gharaei Nejad
- Skin Research Center, Dermatology Department, Guilan University of Medical Sciences, Razi Hospital, Sardare Jangal Street, Rasht, Iran
| | - Hossein Hemmati
- Razi Clinical Research Development Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Faeze Gharibpoor
- Gastrointestinal and liver diseases research center, Guilan University of Medical Sciences, Rasht, Iran
| | - Roya Khaksar
- Gastrointestinal and liver diseases research center, Guilan University of Medical Sciences, Rasht, Iran.
| | - Ali Akbar Samadani
- Gastrointestinal and liver diseases research center, Guilan University of Medical Sciences, Rasht, Iran.
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25
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Qiang Y, Li Q, Xin Y, Fang X, Tian Y, Ma J, Wang J, Wang Q, Zhang R, Wang J, Wang F. Intake of Dietary One-Carbon Metabolism-Related B Vitamins and the Risk of Esophageal Cancer: A Dose-Response Meta-Analysis. Nutrients 2018; 10:835. [PMID: 29954131 PMCID: PMC6073467 DOI: 10.3390/nu10070835] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 06/24/2018] [Accepted: 06/25/2018] [Indexed: 12/14/2022] Open
Abstract
Several B vitamins are essential in the one-carbon metabolism pathway, which is central to DNA methylation, synthesis, and repair. Moreover, an imbalance in this pathway has been linked to certain types of cancers. Here, we performed a meta-analysis in order to investigate the relationship between the intake of four dietary one-carbon metabolism-related B vitamins (B2, B6, folate, and B12) and the risk of esophageal cancer (EC). We searched PubMed, Web of Science, and Embase for relevant studies published through 1 March 2018. The odds ratio (OR) with 95% confidence interval (CI) for the highest versus the lowest level of each dietary B vitamin was then calculated. From 21 articles reporting 26 studies including 6404 EC cases and 504,550 controls, we found an inverse correlation between the consumption of vitamin B6 and folate and the risk of EC; this association was specific to the US, Europe, and Australia, but was not found in Asia. A dose-response analysis revealed that each 100 μg/day increase in folate intake reduced the risk of EC by 12%. Moreover, each 1 mg/day increase in vitamin B6 intake decreased the risk of EC by 16%. Surprisingly, we found that each 1 μg/day increase in vitamin B12 intake increased the risk of esophageal adenocarcinoma by 2%, particularly in the US and Europe, suggesting both geographic and histological differences. Together, our results suggest that an increased intake of one-carbon metabolism-related B vitamins may protect against EC, with the exception of vitamin B12, which should be consumed in moderation.
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Affiliation(s)
- Yuzhen Qiang
- Department of Nutrition, Precision Nutrition Innovation Center, School of Public Health, Zhengzhou University, Zhengzhou 450001, China.
| | - Qianwen Li
- Department of Nutrition, Precision Nutrition Innovation Center, School of Public Health, Zhengzhou University, Zhengzhou 450001, China.
| | - Yongjuan Xin
- Department of Nutrition, Precision Nutrition Innovation Center, School of Public Health, Zhengzhou University, Zhengzhou 450001, China.
| | - Xuexian Fang
- Institute of Nutrition and Food Safety, School of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, China.
| | - Yongmei Tian
- Department of Nutrition, Precision Nutrition Innovation Center, School of Public Health, Zhengzhou University, Zhengzhou 450001, China.
| | - Jifei Ma
- Department of Nutrition, Precision Nutrition Innovation Center, School of Public Health, Zhengzhou University, Zhengzhou 450001, China.
| | - Jianyao Wang
- Department of Nutrition, Precision Nutrition Innovation Center, School of Public Health, Zhengzhou University, Zhengzhou 450001, China.
| | - Qingqing Wang
- Department of Nutrition, Precision Nutrition Innovation Center, School of Public Health, Zhengzhou University, Zhengzhou 450001, China.
| | - Ruochen Zhang
- Department of Nutrition, Precision Nutrition Innovation Center, School of Public Health, Zhengzhou University, Zhengzhou 450001, China.
| | - Junhao Wang
- Department of Nutrition, Precision Nutrition Innovation Center, School of Public Health, Zhengzhou University, Zhengzhou 450001, China.
| | - Fudi Wang
- Department of Nutrition, Precision Nutrition Innovation Center, School of Public Health, Zhengzhou University, Zhengzhou 450001, China.
- Institute of Nutrition and Food Safety, School of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, China.
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26
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Tumorigenic Cell Reprogramming and Cancer Plasticity: Interplay between Signaling, Microenvironment, and Epigenetics. Stem Cells Int 2018; 2018:4598195. [PMID: 29853913 PMCID: PMC5954911 DOI: 10.1155/2018/4598195] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Accepted: 04/01/2018] [Indexed: 02/06/2023] Open
Abstract
Accumulating evidences indicate that many tumors rely on subpopulations of cancer stem cells (CSCs) with the ability to propagate malignant clones indefinitely and to produce an overt cancer. Of importance, CSCs seem to be more resistant to the conventional cytotoxic treatments, driving tumor growth and contributing to relapse. CSCs can originate from normal committed cells which undergo tumor-reprogramming processes and reacquire a stem cell-like phenotype. Increasing evidences also show how tumor homeostasis and progression strongly rely on the capacity of nontumorigenic cancer cells to dedifferentiate to CSCs. Both tumor microenvironment and epigenetic reprogramming drive such dynamic mechanisms, favoring cancer cell plasticity and tumor heterogeneity. Here, we report new developments which led to an advancement in the CSC field, elucidating the concepts of cancer cell of origin and CSC plasticity in solid tumor initiation and maintenance. We further discuss the main signaling pathways which, under the influence of extrinsic environmental factors, play a critical role in the formation and maintenance of CSCs. Moreover, we propose a review of the main epigenetic mechanisms whose deregulation can favor the onset of CSC features both in tumor initiation and tumor maintenance. Finally, we provide an update of the main strategies that could be applied to target CSCs and cancer cell plasticity.
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27
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Li S, Han Z, Zhao N, Zhu B, Zhang Q, Yang X, Sheng D, Hou J, Guo S, Wei L, Zhang L. Inhibition of DNMT suppresses the stemness of colorectal cancer cells through down-regulating Wnt signaling pathway. Cell Signal 2018; 47:79-87. [PMID: 29601907 DOI: 10.1016/j.cellsig.2018.03.014] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Revised: 03/19/2018] [Accepted: 03/25/2018] [Indexed: 12/19/2022]
Abstract
Cancer stem cell (CSC) theory reveals a new insight into the understanding of tumorigenesis and metastasis. Recently, DNA methylation is suggested to be a potential epigenetic mechanism for maintenance of CSCs. What's more, studies have shown that DNA methyltransferase (DNMT) is essential for CSCs and deletion of DNMT can reduce tumorigenesis by limiting CSC pool. Therefore, targeting the epigenetic modifiers especially DNA methylation offers an optional strategy for treating human cancers. In the present study we found that DNMT inhibitor 5-Aza-2'-deoxycytidine (5-AzaDC) markedly reduced colorectal CSC abundance in vitro and suppressed liver metastatic tumor growth in vivo. And 5-AzaDC inhibited the expression of active β-catenin and down-regulated the Wnt signaling pathway. The Wnt inhibitors were frequently inactivated by promoter methylation in colorectal cancer; however analysis of TCGA data base showed that only the expression of SFRP1 was significantly reduced in tumors compared to normal tissues. In addition, restoring of SFRP1 expression inhibited the stem cell-like potential of colorectal cancer cells. Our results indicated that inhibition of DNMT blocked the self-renewal of colorectal CSCs and SFRP1 was essential for the maintenance of colorectal CSCs.
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Affiliation(s)
- Shanxin Li
- Department of Pharmacy, Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Zhipeng Han
- Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
| | - Naping Zhao
- Department of Pharmacy, Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Bing Zhu
- Department of Pharmacy, Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Qianwen Zhang
- Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, China
| | - Xue Yang
- Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
| | - Dandan Sheng
- Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
| | - Jing Hou
- Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shiwei Guo
- Third Department of General Surgery, Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Lixin Wei
- Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.
| | - Li Zhang
- Department of Pharmacy, Changhai Hospital, The Second Military Medical University, Shanghai, China.
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28
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Morales-Ruiz T, García-Ortiz MV, Devesa-Guerra I, Raya-Ruiz L, Tejedor JR, Bayón GF, Sierra MI, Fraga MF, Ariza RR, Roldán-Arjona T. DNA methylation reprogramming of human cancer cells by expression of a plant 5-methylcytosine DNA glycosylase. Epigenetics 2018; 13:95-107. [PMID: 29235922 PMCID: PMC5836972 DOI: 10.1080/15592294.2017.1414128] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Revised: 11/24/2017] [Accepted: 11/29/2017] [Indexed: 12/18/2022] Open
Abstract
Patterns of DNA methylation, an important epigenetic modification involved in gene silencing and development, are disrupted in cancer cells. Understanding the functional significance of aberrant methylation in tumors remains challenging, due in part to the lack of suitable tools to actively modify methylation patterns. DNA demethylation caused by mammalian DNA methyltransferase inhibitors is transient and replication-dependent, whereas that induced by TET enzymes involves oxidized 5mC derivatives that perform poorly understood regulatory functions. Unlike animals, plants possess enzymes that directly excise unoxidized 5mC from DNA, allowing restoration of unmethylated C through base excision repair. Here, we show that expression of Arabidopsis 5mC DNA glycosylase DEMETER (DME) in colon cancer cells demethylates and reactivates hypermethylated silenced loci. Interestingly, DME expression causes genome-wide changes that include both DNA methylation losses and gains, and partially restores the methylation pattern observed in normal tissue. Furthermore, such methylome reprogramming is accompanied by altered cell cycle responses and increased sensibility to anti-tumor drugs, decreased ability to form colonospheres, and tumor growth impairment in vivo. Our study shows that it is possible to reprogram a human cancer DNA methylome by expression of a plant DNA demethylase.
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Affiliation(s)
- Teresa Morales-Ruiz
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain
- Department of Genetics, University of Córdoba, Córdoba, Spain
- Reina Sofia University Hospital, Córdoba, Spain
| | - María Victoria García-Ortiz
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain
- Department of Genetics, University of Córdoba, Córdoba, Spain
- Reina Sofia University Hospital, Córdoba, Spain
| | - Iván Devesa-Guerra
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain
- Department of Genetics, University of Córdoba, Córdoba, Spain
- Reina Sofia University Hospital, Córdoba, Spain
| | - Laura Raya-Ruiz
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain
- Department of Genetics, University of Córdoba, Córdoba, Spain
- Reina Sofia University Hospital, Córdoba, Spain
| | - Juan R. Tejedor
- Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), HUCA, Universidad de Oviedo, Oviedo, Spain
| | - Gustavo F. Bayón
- Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), HUCA, Universidad de Oviedo, Oviedo, Spain
| | - Marta I. Sierra
- Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), HUCA, Universidad de Oviedo, Oviedo, Spain
| | - Mario F. Fraga
- Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), HUCA, Universidad de Oviedo, Oviedo, Spain
- Nanomaterials and Nanotechnology Research Center (CINN-CSIC)-Universidad de Oviedo-Principado de Asturias, Spain
| | - Rafael R. Ariza
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain
- Department of Genetics, University of Córdoba, Córdoba, Spain
- Reina Sofia University Hospital, Córdoba, Spain
| | - Teresa Roldán-Arjona
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain
- Department of Genetics, University of Córdoba, Córdoba, Spain
- Reina Sofia University Hospital, Córdoba, Spain
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29
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Teng Y, Yu X, Yuan H, Guo L, Jiang W, Lu SH. DNMT1 ablation suppresses tumorigenesis by inhibiting the self-renewal of esophageal cancer stem cells. Oncotarget 2018; 9:18896-18907. [PMID: 29721170 PMCID: PMC5922364 DOI: 10.18632/oncotarget.24116] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Accepted: 12/01/2017] [Indexed: 12/20/2022] Open
Abstract
Cancer stem cells (CSCs) have been isolated from many tumors and considered as the main reason of cancer recurrence and metastasis. DNA methyltransferase 1 (DNMT1) mediates DNA methylation and plays an important role in CSCs maintenance. However, the function of DNMT1 in CSCs of esophageal squamous cell carcinoma (ESCC) remains unclear. In this study, we examined the role of DNMT1 in regulating self-renewal in CSCs of ESCC. We found a high expression of DNMT1 in both side population (SP) cells and sphere formation cells that represented as substitutes for CSCs in KYSE150 and EC109 ESCC cell lines. We performed the knockdown of DNMT1 using lentivirus-mediated RNA interference (RNAi) methods. We revealed that ablation of DNMT1 resulted in the numbers and self-renewal abilities of CSCs refrained significantly in ESCC cells. As a result of the CSCs inhibition, the malignant phenotypes such as cell proliferation, colony formation, migration and drug resistance abilities were dramatically inhibited in ESCC cells. Treatment of 5-aza-2'-deoxycytidine (5-aza-dC), a DNMT inhibitor, also resulted in the inhibition of CSCs and malignant profiles in ESCC cells. Our findings also provided the first evidence that 5-aza-dC inhibited the colony and sphere formation of CSCs. Thus, our results indicated that DNMT1 was important for the self-renewal maintenance of CSCs in ESCC, and 5-aza-dC could be a potential therapy for the CSCs of ESCC.
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Affiliation(s)
- Ying Teng
- Department of Etiology and Carcinogenesis and State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Xiying Yu
- Department of Etiology and Carcinogenesis and State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Hui Yuan
- Department of Etiology and Carcinogenesis and State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Liping Guo
- Department of Etiology and Carcinogenesis and State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Wei Jiang
- Department of Etiology and Carcinogenesis and State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shih-Hsin Lu
- Department of Etiology and Carcinogenesis and State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China.,Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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30
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Feng HC, Lin JY, Hsu SH, Lan WY, Kuo CS, Tian YF, Sun DP, Huang RFS. Low folate metabolic stress reprograms DNA methylation-activated sonic hedgehog signaling to mediate cancer stem cell-like signatures and invasive tumour stage-specific malignancy of human colorectal cancers. Int J Cancer 2017; 141:2537-2550. [PMID: 28833104 DOI: 10.1002/ijc.31008] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2017] [Accepted: 08/03/2017] [Indexed: 01/10/2023]
Abstract
The mechanistic role of colonic low folate metabolic stress (LFMS) in colorectal cancer (CRC) malignancy development remains unknown. Folate analysis on the 99 paired human CRC tissues localized LFMS to the deep invasive T3/T4 staged tumours with hypo-methylated sonic hedgehog (Shh) promoter region and amplified expressions of Shh ligand and Gli1 effector, which coincided with deregulated expressions of the epithelial-mesenchymal transition (EMT) mediators. Colonic folate levels of CRC were inversely correlated with pluripotent expressions of the SOX2, NANOG and OCT4 markers (p < 0.05). Exposure of human colon adenocarcinoma cells to LFMS microenvironment significantly hypomethylated Shh promoter region, activated Shh signaling, induced transcript and protein expressions of the pluripotent markers, promoted trans-differentiation as EMT by deregulation of Snail mediator and epithelial marker E-cadherin, increased MMP2/MMP9 enzymatic digestion on matrix protein for invasion, and promoted self-renewal capability of anchorage-independent tumor-spheroid formation. LFMS-induced cancer stem cell (CSC) signature and CRC invasion is synergized with inhibition of DNA methylation by 5-Aza-2-deoxycytidine (5AZA) in rewiring EMT genotypes, which can be blockade by the Shh inhibitor (cyclopamine). The in vivo and in vitro data corroboratively identify CSC-like molecular targets specific to the LFMS-predisposed invasive CRC through reprogramming DNA methylation-activated Shh signaling. The study highlights CSC targets specific to LFMS-predisposed invasive CRC in optimizing folate co-chemotherapy to minimize tumour metastasis potential of CRC patients.
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Affiliation(s)
- Hsin-Chun Feng
- Department of Nutritional Science, Fu Jen Catholic University, Taiwan.,Department of Dietetics, National Taiwan University Hospital, Taiwan
| | - Jhuan-Yu Lin
- Department of Nutritional Science, Fu Jen Catholic University, Taiwan
| | - Shu-Han Hsu
- Department of Nutritional Science, Fu Jen Catholic University, Taiwan
| | - Wen-Yu Lan
- Department of Nutritional Science, Fu Jen Catholic University, Taiwan
| | - Chang-Sheng Kuo
- Department of Dietetics, Fu Jen Catholic University Hospital, Fu Jen Catholic University, Taiwan
| | - Yu-Feng Tian
- Division of Surgery, Chi-Mei Medical Center, Tainan, Taiwan
| | - Ding-Ping Sun
- Division of Transplantation Medicine, Chi-Mei Medical Center, Tainan, Taiwan
| | - Rwei-Fen Syu Huang
- Department of Nutritional Science, Fu Jen Catholic University, Taiwan.,Department of Dietetics, Fu Jen Catholic University Hospital, Fu Jen Catholic University, Taiwan
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Abstract
Compelling evidence have demonstrated that bulk tumors can arise from a unique subset of cells commonly termed "cancer stem cells" that has been proposed to be a strong driving force of tumorigenesis and a key mechanism of therapeutic resistance. Recent advances in epigenomics have illuminated key mechanisms by which epigenetic regulation contribute to cancer progression. In this review, we present a discussion of how deregulation of various epigenetic pathways can contribute to cancer initiation and tumorigenesis, particularly with respect to maintenance and survival of cancer stem cells. This information, together with several promising clinical and preclinical trials of epigenetic modulating drugs, offer new possibilities for targeting cancer stem cells as well as improving cancer therapy overall.
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Affiliation(s)
- Tan Boon Toh
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Jhin Jieh Lim
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Edward Kai-Hua Chow
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Centre for Translational Medicine, National University of Singapore, 14 Medical Drive #12-01, Singapore, 117599 Singapore
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Benetatos L, Vartholomatos G. On the potential role of DNMT1 in acute myeloid leukemia and myelodysplastic syndromes: not another mutated epigenetic driver. Ann Hematol 2016; 95:1571-82. [PMID: 26983918 DOI: 10.1007/s00277-016-2636-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Accepted: 03/04/2016] [Indexed: 12/19/2022]
Abstract
DNA methylation is the most common epigenetic modification in the mammalian genome. DNA methylation is governed by the DNA methyltransferases mainly DNMT1, DNMT3A, and DNMT3B. DNMT1 methylates hemimethylated DNA ensuring accurate DNA methylation maintenance. DNMT1 is involved in the proper differentiation of hematopoietic stem cells (HSCs) through the interaction with effector molecules. DNMT1 is deregulated in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) as early as the leukemic stem cell stage. Through the interaction with fundamental transcription factors, non-coding RNAs, fusion oncogenes and by modulating core members of signaling pathways, it can affect leukemic cells biology. DNMT1 action might be also catalytic-independent highlighting a methylation-independent mode of action. In this review, we have gathered some current facts of DNMT1 role in AML and MDS and we also propose some perspectives for future studies.
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Zagorac S, Alcala S, Fernandez Bayon G, Bou Kheir T, Schoenhals M, González-Neira A, Fernandez Fraga M, Aicher A, Heeschen C, Sainz B. DNMT1 Inhibition Reprograms Pancreatic Cancer Stem Cells via Upregulation of the miR-17-92 Cluster. Cancer Res 2016; 76:4546-58. [PMID: 27261509 DOI: 10.1158/0008-5472.can-15-3268] [Citation(s) in RCA: 86] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Accepted: 04/27/2016] [Indexed: 12/23/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) and other carcinomas are hierarchically organized, with cancer stem cells (CSC) residing at the top of the hierarchy, where they drive tumor progression, metastasis, and chemoresistance. As CSC and non-CSC share an identical genetic background, we hypothesize that differences in epigenetics account for the striking functional differences between these two cell populations. Epigenetic mechanisms, such as DNA methylation, play an important role in maintaining pluripotency and regulating the differentiation of stem cells, but the role of DNA methylation in pancreatic CSC is obscure. In this study, we investigated the genome-wide DNA methylation profile of PDAC CSC, and we determined the importance of DNA methyltransferases for CSC maintenance and tumorigenicity. Using high-throughput methylation analysis, we discovered that sorted CSCs have a higher level of DNA methylation, regardless of the heterogeneity or polyclonality of the CSC populations present in the tumors analyzed. Mechanistically, CSC expressed higher DNMT1 levels than non-CSC. Pharmacologic or genetic targeting of DNMT1 in CSCs reduced their self-renewal and in vivo tumorigenic potential, defining DNMT1 as a candidate CSC therapeutic target. The inhibitory effect we observed was mediated in part through epigenetic reactivation of previously silenced miRNAs, in particular the miR-17-92 cluster. Together, our findings indicate that DNA methylation plays an important role in CSC biology and also provide a rationale to develop epigenetic modulators to target CSC plasticity and improve the poor outcome of PDAC patients. Cancer Res; 76(15); 4546-58. ©2016 AACR.
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Affiliation(s)
- Sladjana Zagorac
- Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom. Stem Cells & Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Sonia Alcala
- Stem Cells & Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. Department of Biochemistry, Universidad Autónoma de Madrid, Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, Madrid, Spain
| | - Gustavo Fernandez Bayon
- Cancer Epigenetics Unit, Asturias Central University Hospital, Spanish Council for Scientific Research (CSIC), Oviedo, Spain
| | - Tony Bou Kheir
- Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Matthieu Schoenhals
- Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Anna González-Neira
- Human Genotyping-Cegen Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Mario Fernandez Fraga
- Cancer Epigenetics Unit, Asturias Central University Hospital, Spanish Council for Scientific Research (CSIC), Oviedo, Spain
| | - Alexandra Aicher
- Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom. Stem Cells & Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Christopher Heeschen
- Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom. Stem Cells & Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
| | - Bruno Sainz
- Stem Cells & Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. Department of Biochemistry, Universidad Autónoma de Madrid, Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, Madrid, Spain
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Reppe S, Datta H, Gautvik KM. The Influence of DNA Methylation on Bone Cells. Curr Genomics 2016; 16:384-92. [PMID: 27019613 PMCID: PMC4765525 DOI: 10.2174/1389202916666150817202913] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Revised: 04/19/2015] [Accepted: 06/26/2015] [Indexed: 01/14/2023] Open
Abstract
DNA methylation in eukaryotes invokes heritable alterations of the of the cytosine base in DNA without changing the underlying genomic DNA sequence. DNA methylation may be modified by environmental exposures as well as gene polymorphisms and may be a mechanistic link between environmental risk factors and the development of disease. In this review, we consider the role of DNA methylation in bone cells (osteoclasts/osteoblasts/osteocytes) and their progenitors with special focus on in vitro and ex vivo analyses. The number of studies on DNA methylation in bone cells is still somewhat limited, nevertheless it is getting increasingly clear that this type of the epigenetic changes is a critical regulator of gene expression. DNA methylation is necessary for proper development and function of bone cells and is accompanied by disease characteristic functional alterations as presently reviewed including postmenopausal osteoporosis and mechanical strain.
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Affiliation(s)
- Sjur Reppe
- Oslo University Hospital, Department of Medical Biochemistry, Oslo, Norway; ; Lovisenberg Diakonale Hospital, Oslo, Norway;; University of Oslo, Institute of Basic Medical Sciences, Oslo, Norway
| | - Harish Datta
- Newcastle University, Institute of Cellular Medicine, UK
| | - Kaare M Gautvik
- Lovisenberg Diakonale Hospital, Oslo, Norway;; University of Oslo, Institute of Basic Medical Sciences, Oslo, Norway
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Khan S, Shukla S, Sinha S, Meeran SM. Epigenetic targets in cancer and aging: dietary and therapeutic interventions. Expert Opin Ther Targets 2016; 20:689-703. [PMID: 26667209 DOI: 10.1517/14728222.2016.1132702] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Epigenetic regulation plays a critical role in normal growth and embryonic development by controlling the transcriptional activities of several genes. A growing number of epigenetic changes have been reported in the regulation of key genes involved in cancer and aging. Drugs with epigenetic modulatory activities, mainly histone deacetylase and DNA methyltransferase inhibitors, have received wider attention in aging and cancer research. AREAS COVERED In this review, we summarize the major epigenetic alterations in cancer and aging, with special emphasis on possible therapeutic targets and interventions by dietary as well as bioactive phytochemicals. EXPERT OPINION Some epigenetic-targeting drugs have received FDA approval and many others are undergoing different phases of clinical trials for cancer therapy. In addition to the synthetic compounds, several bioactive phytochemicals and dietary interventions, such as caloric restriction, have been shown to possess epigenetic modulatory activities in multiple cancers. These epigenetic modulators have been shown to delay aging and minimize the risk of cancer both in preclinical as well as clinical models. Therefore, knowledge of bioactive phytochemicals along with dietary interventions can be utilized for cancer prevention and therapy both alone and with existing drugs to achieve optimum efficacy.
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Affiliation(s)
- Sajid Khan
- a Division of Endocrinology , CSIR-Central Drug Research Institute , Lucknow , India
| | - Samriddhi Shukla
- a Division of Endocrinology , CSIR-Central Drug Research Institute , Lucknow , India
| | - Sonam Sinha
- a Division of Endocrinology , CSIR-Central Drug Research Institute , Lucknow , India
| | - Syed Musthapa Meeran
- a Division of Endocrinology , CSIR-Central Drug Research Institute , Lucknow , India
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Opdenaker LM, Modarai SR, Boman BM. The Proportion of ALDEFLUOR-Positive Cancer Stem Cells Changes with Cell Culture Density Due to the Expression of Different ALDH Isoforms. ACTA ACUST UNITED AC 2015; 2:87-95. [PMID: 28280782 PMCID: PMC5340268 DOI: 10.17140/csmmoj-2-113] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
A significant number of discrepancies exist within the literature regarding ALDEFLUOR-positive stem cell populations in cell lines. We hypothesized that these inconsistencies resulted from differences in culture conditions, particularly cell density. We cultured several colon cancer cell lines (N=8) at high and low densities and found a significant decrease in ALDEFLUOR-positive cell populations at high density. However, we found no changes in the CD166-positive stem cell population, self-renewal, or cell cycle distribution of cells cultured at different densities. Interestingly, when we sorted both ALDEFLUOR positive and negative populations from the different density cultures, we identified a significant number of Aldehyde dehydrogenase (ALDH) isoforms whose expression was decreased in ALDEFLUOR-positive stem cells cultured at high density. This novel finding suggests that multiple ALDH isoforms contribute to ALDEFLUOR activity in colon cancer stem cells and decreases in ALDEFLUOR-positive stem cells at high cell density are due to decreased expression of multiple ALDH isoforms. Thus, designing therapeutics to target ALDEFLUOR-positive cancer stem cells may require inhibition of multiple ALDH isoforms.
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Affiliation(s)
- Lynn M Opdenaker
- Department of Biological Sciences, University of Delaware, 118 Wolf Hall, Newark, DE 19716, USA; Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, 4701 Ogletown-Stanton Rd, Newark, DE 19713, USA
| | - Shirin R Modarai
- Department of Biological Sciences, University of Delaware, 118 Wolf Hall, Newark, DE 19716, USA; Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, 4701 Ogletown-Stanton Rd, Newark, DE 19713, USA
| | - Bruce M Boman
- Department of Biological Sciences, University of Delaware, 118 Wolf Hall, Newark, DE 19716, USA; Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, 4701 Ogletown-Stanton Rd, Newark, DE 19713, USA
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Hadjimichael C, Chanoumidou K, Papadopoulou N, Arampatzi P, Papamatheakis J, Kretsovali A. Common stemness regulators of embryonic and cancer stem cells. World J Stem Cells 2015; 7:1150-1184. [PMID: 26516408 PMCID: PMC4620423 DOI: 10.4252/wjsc.v7.i9.1150] [Citation(s) in RCA: 136] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Revised: 05/30/2015] [Accepted: 10/08/2015] [Indexed: 02/06/2023] Open
Abstract
Pluripotency of embryonic stem cells (ESCs) and induced pluripotent stem cells is regulated by a well characterized gene transcription circuitry. The circuitry is assembled by ESC specific transcription factors, signal transducing molecules and epigenetic regulators. Growing understanding of stem-like cells, albeit of more complex phenotypes, present in tumors (cancer stem cells), provides a common conceptual and research framework for basic and applied stem cell biology. In this review, we highlight current results on biomarkers, gene signatures, signaling pathways and epigenetic regulators that are common in embryonic and cancer stem cells. We discuss their role in determining the cell phenotype and finally, their potential use to design next generation biological and pharmaceutical approaches for regenerative medicine and cancer therapies.
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Abstract
Colorectal cancer stem cells (CSCs) were initially considered to be a subset of undifferentiated tumor cells with well-defined phenotypic and molecular markers. However, emerging evidence indicates instead that colorectal CSCs are heterogeneous subsets of tumor cells that are continuously reshaped by the dynamic interactions between genetic, epigenetic, and immune factors in the tumor microenvironment. Thus, the colorectal CSC phenotypes and responsiveness to therapy may not only be a tumor cell-intrinsic feature, but also depend on tumor-extrinsic microenvironmental factors. Furthermore, emerging evidence also implicates colorectal CSCs in potential immune evasion. Therefore, understanding how colorectal CSC-intrinsic mechanisms cooperate with the extrinsic microenvironmental factors to dynamically shape colorectal CSC resistance to chemotherapy and immunotherapy holds great promise for development of targeted CSC therapies of advanced human CRC.
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Farias N, Ho N, Butler S, Delaney L, Morrison J, Shahrzad S, Coomber BL. The effects of folic acid on global DNA methylation and colonosphere formation in colon cancer cell lines. J Nutr Biochem 2015; 26:818-26. [PMID: 25804133 DOI: 10.1016/j.jnutbio.2015.02.002] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Revised: 02/18/2015] [Accepted: 02/20/2015] [Indexed: 02/07/2023]
Abstract
Folate and its synthetic form, folic acid (FA), are essential vitamins for the regeneration of S-adenosyl methionine molecules, thereby maintaining adequate cellular methylation. The deregulation of DNA methylation is a contributing factor to carcinogenesis, as alterations in genetic methylation may contribute to stem cell reprogramming and dedifferentiation processes that lead to a cancer stem cell (CSC) phenotype. Here, we investigate the potential effects of FA exposure on DNA methylation and colonosphere formation in cultured human colorectal cancer (CRC) cell lines. We show for the first time that HCT116, LS174T, and SW480 cells grown without adequate FA demonstrate significantly impaired colonosphere forming ability with limited changes in CD133, CD166, and EpCAM surface expression. These differences were accompanied by concomitant changes to DNA methyltransferase (DNMT) enzyme expression and DNA methylation levels, which varied depending on cell line. Taken together, these results demonstrate an interaction between FA metabolism and CSC phenotype in vitro and help elucidate a connection between supplemental FA intake and CRC development.
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Affiliation(s)
- Nathan Farias
- Department of Biomedical Sciences, University of Guelph, Guelph, ON, Canada N1G 2W1.
| | - Nelson Ho
- Department of Biomedical Sciences, University of Guelph, Guelph, ON, Canada N1G 2W1.
| | - Stacey Butler
- Department of Biomedical Sciences, University of Guelph, Guelph, ON, Canada N1G 2W1.
| | - Leanne Delaney
- Department of Biomedical Sciences, University of Guelph, Guelph, ON, Canada N1G 2W1.
| | - Jodi Morrison
- Department of Biomedical Sciences, University of Guelph, Guelph, ON, Canada N1G 2W1.
| | | | - Brenda L Coomber
- Department of Biomedical Sciences, University of Guelph, Guelph, ON, Canada N1G 2W1.
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40
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Wongtrakoongate P. Epigenetic therapy of cancer stem and progenitor cells by targeting DNA methylation machineries. World J Stem Cells 2015; 7:137-148. [PMID: 25621113 PMCID: PMC4300924 DOI: 10.4252/wjsc.v7.i1.137] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Revised: 10/01/2014] [Accepted: 10/29/2014] [Indexed: 02/06/2023] Open
Abstract
Recent advances in stem cell biology have shed light on how normal stem and progenitor cells can evolve to acquire malignant characteristics during tumorigenesis. The cancer counterparts of normal stem and progenitor cells might be occurred through alterations of stem cell fates including an increase in self-renewal capability and a decrease in differentiation and/or apoptosis. This oncogenic evolution of cancer stem and progenitor cells, which often associates with aggressive phenotypes of the tumorigenic cells, is controlled in part by dysregulated epigenetic mechanisms including aberrant DNA methylation leading to abnormal epigenetic memory. Epigenetic therapy by targeting DNA methyltransferases (DNMT) 1, DNMT3A and DNMT3B via 5-Azacytidine (Aza) and 5-Aza-2’-deoxycytidine (Aza-dC) has proved to be successful toward treatment of hematologic neoplasms especially for patients with myelodysplastic syndrome. In this review, I summarize the current knowledge of mechanisms underlying the inhibition of DNA methylation by Aza and Aza-dC, and of their apoptotic- and differentiation-inducing effects on cancer stem and progenitor cells in leukemia, medulloblastoma, glioblastoma, neuroblastoma, prostate cancer, pancreatic cancer and testicular germ cell tumors. Since cancer stem and progenitor cells are implicated in cancer aggressiveness such as tumor formation, progression, metastasis and recurrence, I propose that effective therapeutic strategies might be achieved through eradication of cancer stem and progenitor cells by targeting the DNA methylation machineries to interfere their “malignant memory”.
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Savio AJ, Bapat B. Beyond the island: epigenetic biomarkers of colorectal and prostate cancer. Methods Mol Biol 2015; 1238:103-24. [PMID: 25421657 DOI: 10.1007/978-1-4939-1804-1_6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Epigenetic dysregulation is a common feature across all cancer types. Epigenetic mechanisms, from DNA methylation to histone modifications, allow for a vast number of cellular phenotypes to be created from the same genetic material. Just as certain genetic changes play a key role in tumor initiation and progression, epigenetic changes may also set the course of tumor development and be required for malignant transformation. The most frequently studied epigenetic changes investigated thus far are global genomic DNA hypomethylation along with specific hypermethylation, predominantly at promoter CpG islands of tumor suppressor genes. In addition to DNA methylation changes at CpG islands, there is an abundance of other epigenetic alterations occurring within cancer cells including DNA methylation alterations outside of CpG islands, non-CpG methylation, changes in cytosine oxidative species (hydroxymethylcytosine, formylcytosine, carboxylcytosine) levels, and histone modifications. This chapter examines epigenetic alterations beyond the island, and summarizes recent findings in DNA-based epigenetic regulation of the two most commonly diagnosed cancers in the Western world: colorectal cancer and prostate cancer.
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Affiliation(s)
- Andrea J Savio
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
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Liu CC, Lin JH, Hsu TW, Su K, Li AFY, Hsu HS, Hung SC. IL-6 enriched lung cancer stem-like cell population by inhibition of cell cycle regulators via DNMT1 upregulation. Int J Cancer 2014; 136:547-59. [PMID: 24947242 DOI: 10.1002/ijc.29033] [Citation(s) in RCA: 92] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Accepted: 06/13/2014] [Indexed: 12/22/2022]
Abstract
Tumors are influenced by a microenvironment rich in inflammatory cytokines, growth factors and chemokines, which may promote tumor growth. Interleukin-6 (IL-6) is a multifunctional cytokine and known as a regulator of immune and inflammation responses. IL-6 has also been reported to be associated with tumor progression and chemoresistance in different types of cancers. In our study, we demonstrated that IL-6 enriches the properties of lung cancer stem-like cells in A549 lung cancer cells cultured in spheroid medium. IL-6 also promotes sphere formation and stem-like properties of A549 cells by enhancing cell proliferation. Methylation-specific polymerase chain reaction (PCR) was performed and revealed that IL-6 increased methylation of p53 and p21 in A549 cancer cells. Western blot analysis and quantitative real-time PCR demonstrated that IL-6 increased the expression of DNA methyltransferase 1 (DNMT1) in A549 cells cultured in spheroid medium, but not the expression of DNMT3a or DNMT3b. Knockdown of DNMT1 eliminated IL-6-mediated hypermethylation of cell cycle regulators and enrichment of lung cancer stem-like properties. In conclusion, our study, for the first time, shows that the IL-6/JAK2/STAT3 pathway upregulates DNMT1 and enhances cancer initiation and lung cancer stem cell (CSC) proliferation by downregulation of p53 and p21 resulting from DNA hypermethylation. Upon blockage of the IL-6/JAK2/STAT3 pathway and inhibition of DNMT1, the proliferation of lung CSCs was reduced and their formation of spheres and ability to initiate tumor growth were decreased. These data suggest that targeting of the IL-6/JAK2/STAT3 signaling pathway and DNMT1 may become important strategies for treating lung cancer.
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Affiliation(s)
- Chen-Chi Liu
- Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Department of Emergency, Taipei Veterans General Hospital, Taipei, Taiwan
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Subramaniam D, Thombre R, Dhar A, Anant S. DNA methyltransferases: a novel target for prevention and therapy. Front Oncol 2014; 4:80. [PMID: 24822169 PMCID: PMC4013461 DOI: 10.3389/fonc.2014.00080] [Citation(s) in RCA: 331] [Impact Index Per Article: 30.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2013] [Accepted: 03/31/2014] [Indexed: 12/14/2022] Open
Abstract
Cancer is the second leading cause of death in US. Despite the emergence of new, targeted agents, and the use of various therapeutic combinations, none of the available treatment options are curative in patients with advanced cancer. Epigenetic alterations are increasingly recognized as valuable targets for the development of cancer therapies. DNA methylation at the 5-position of cytosine, catalyzed by DNA methyltransferases (DNMTs), is the predominant epigenetic modification in mammals. DNMT1, the major enzyme responsible for maintenance of the DNA methylation pattern is located at the replication fork and methylates newly biosynthesized DNA. DNMT2 or TRDMT1, the smallest mammalian DNMT is believed to participate in the recognition of DNA damage, DNA recombination, and mutation repair. It is composed solely of the C-terminal domain, and does not possess the regulatory N-terminal region. The levels of DNMTs, especially those of DNMT3B, DNMT3A, and DNMT3L, are often increased in various cancer tissues and cell lines, which may partially account for the hypermethylation of promoter CpG-rich regions of tumor suppressor genes in a variety of malignancies. Moreover, it has been shown to function in self-renewal and maintenance of colon cancer stem cells and need to be studied in several cancers. Inhibition of DNMTs has demonstrated reduction in tumor formation in part through the increased expression of tumor suppressor genes. Hence, DNMTs can potentially be used as anti-cancer targets. Dietary phytochemicals also inhibit DNMTs and cancer stem cells; this represents a promising approach for the prevention and treatment of many cancers.
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Affiliation(s)
- Dharmalingam Subramaniam
- Department of Molecular and Integrative Physiology, The University of Kansas Medical Center , Kansas City, KS , USA ; The University of Kansas Cancer Center , Kansas City, KS , USA
| | - Ravi Thombre
- Department of Molecular and Integrative Physiology, The University of Kansas Medical Center , Kansas City, KS , USA
| | - Animesh Dhar
- The University of Kansas Cancer Center , Kansas City, KS , USA ; Department of Cancer Biology, The University of Kansas Medical Center , Kansas City, KS , USA
| | - Shrikant Anant
- Department of Molecular and Integrative Physiology, The University of Kansas Medical Center , Kansas City, KS , USA ; The University of Kansas Cancer Center , Kansas City, KS , USA ; Department of Cancer Biology, The University of Kansas Medical Center , Kansas City, KS , USA
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Serra RW, Fang M, Park SM, Hutchinson L, Green MR. A KRAS-directed transcriptional silencing pathway that mediates the CpG island methylator phenotype. eLife 2014; 3:e02313. [PMID: 24623306 PMCID: PMC3949416 DOI: 10.7554/elife.02313] [Citation(s) in RCA: 130] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Approximately 70% of KRAS-positive colorectal cancers (CRCs) have a CpG island methylator phenotype (CIMP) characterized by aberrant DNA hypermethylation and transcriptional silencing of many genes. The factors involved in, and the mechanistic basis of, CIMP is not understood. Among the CIMP genes are the tumor suppressors p14ARF, p15INK4B, and p16INK4A, encoded by the INK4-ARF locus. In this study, we perform an RNA interference screen and identify ZNF304, a zinc-finger DNA-binding protein, as the pivotal factor required for INK4-ARF silencing and CIMP in CRCs containing activated KRAS. In KRAS-positive human CRC cell lines and tumors, ZNF304 is bound at the promoters of INK4-ARF and other CIMP genes. Promoter-bound ZNF304 recruits a corepressor complex that includes the DNA methyltransferase DNMT1, resulting in DNA hypermethylation and transcriptional silencing. KRAS promotes silencing through upregulation of ZNF304, which drives DNA binding. Finally, we show that ZNF304 also directs transcriptional silencing of INK4-ARF in human embryonic stem cells. DOI:http://dx.doi.org/10.7554/eLife.02313.001 Colorectal cancer, which affects the large intestine, is a leading cause of cancer deaths worldwide, ranking fourth after cancers of the lung, stomach, and liver. Like these other cancers, this disease is caused by mutations to genes that allow cells to multiply in an out of control manner. Mutations that change the gene encoding a protein called KRAS are found in many different types of cancer. Moreover, about 70% of colorectal cancers with a KRAS mutation also have an excess of small chemical marks on other genes, some of which are known to suppress the growth of tumors. These marks ‘switch off’ these genes, and although the identities of the enzymes that typically leave these marks on DNA are known, the link between these enzymes and the KRAS protein is unknown. Now Serra, Fang et al. have identified a protein, called ZNF304, that is required by KRAS to switch off a large number of genes, including multiple tumor suppressors. In the absence of ZNF304, these tumor suppressor genes remained switched on in cancer cells with the KRAS mutation, so the growth of the tumor was slowed down. ZNF304 is a protein that binds to stretches of DNA, including regions of DNA at the start of several tumor suppressor genes, and it recruits the enzymes that add the chemical marks that switch off these genes. Serra, Fang et al. found that the levels of ZNF304 protein were elevated in colorectal cancer cells with the mutated KRAS, and showed that this was due to the combined activities of two other proteins that prevented ZNF304 from being broken down in the cell. Mutant KRAS caused an increase in the levels of these two proteins, which in turn caused the elevated ZNF304 levels and the excessive marking of the DNA in the tumor suppressor genes. Furthermore, some of these same tumor suppressor genes are switched off in the earliest cells in a human embryo—which have the potential to become any of 200 or so cell types in the human body. In these embryonic stem cells, Serra, Fang et al. showed that ZNF304, but not KRAS, was also involved in keeping these genes switched off until the stem cells started changing into specific types of cells. Since they are a crucial part of the pathway linking a cancer-causing mutation to increased tumor growth, the proteins identified by Serra, Fang et al. could represent promising targets for the development of new anti-cancer drugs. DOI:http://dx.doi.org/10.7554/eLife.02313.002
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Affiliation(s)
- Ryan W Serra
- Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
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Cheng C, Huang C, Ma TT, Bian EB, He Y, Zhang L, Li J. SOCS1 hypermethylation mediated by DNMT1 is associated with lipopolysaccharide-induced inflammatory cytokines in macrophages. Toxicol Lett 2014; 225:488-97. [PMID: 24440346 DOI: 10.1016/j.toxlet.2013.12.023] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2013] [Revised: 12/28/2013] [Accepted: 12/31/2013] [Indexed: 12/12/2022]
Abstract
Macrophages activation which releases the pro-inflammatory cytokines is an essential event in the process of inflammation. SOCS1 has been shown to act as a negative regulator of cytokine signals and plays a key role in the suppression of tissue injury and inflammatory diseases. DNA methylation mediated by specific DNA methyltransferases1 (DNMT1) which contributes to the epigenetic silencing of multiple genes. SOCS1 promoter hypermethylation is by far the best categorized epigenetic change in tumors. Our study with a view to investigate whether the loss of SOCS1 due to SOCS1 promoter methylation was involved in the course of inflammatory cytokines released from lipopolysaccharide (LPS)-stimulated macrophages. Here, we found that treatment of LPS-induced RAW264.7 macrophage cells with the DNA methylation inhibitor 5-aza-2'-deoxycytidine (5-azadC) reduced aberrant promoter hypermethylation of SOCS1 and prevented the loss of the expression of SOCS1 in macrophages which secret inflammatory cytokines. Knockdown of DNMT1 gene not only attenuated the SOCS1 gene promoter methylation but also up-regulated the expression of SOCS1 in activated RAW264.7 cells. Furthermore, silencing of DNMT1 prevented the activation of JAK2/STAT3 pathway in LPS-induced RAW264.7 cells. These studies demonstrated that DNMT1-mediated SOCS1 hypermethylation caused the loss of SOCS1 expression results in negative regulation of activation of the JAK2/STAT3 pathway, and enhanced the release of LPS-induced pro-inflammatory cytokines such as TNF-α and IL-6 in macrophages.
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Affiliation(s)
- Chang Cheng
- School of Pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China.
| | - Cheng Huang
- School of Pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Tao-Tao Ma
- School of Pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Er-Bao Bian
- School of Pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Yong He
- School of Pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Lei Zhang
- School of Pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Jun Li
- School of Pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China.
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Ao J, Xiao WD. Progresses in research of miR-148a in digestive system cancers. Shijie Huaren Xiaohua Zazhi 2014; 22:4938. [DOI: 10.11569/wcjd.v22.i32.4938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Torigoe T, Hirohashi Y, Yasuda K, Sato N. Constitutive expression and activation of stress response genes in cancer stem-like cells/tumour initiating cells: Potent targets for cancer stem cell therapy. Int J Hyperthermia 2013; 29:436-41. [DOI: 10.3109/02656736.2013.814809] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
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