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Reyila A, Gao X, Yu J, Nie Y. Insight into the role of DNA methylation in prognosis and treatment response prediction of gastrointestinal cancers. Epigenomics 2025; 17:475-488. [PMID: 40084815 PMCID: PMC12026041 DOI: 10.1080/17501911.2025.2476380] [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: 09/19/2024] [Accepted: 03/04/2025] [Indexed: 03/16/2025] Open
Abstract
Gastrointestinal (GI) cancers impose a significant disease burden, underscoring the critical importance of accurate prognosis prediction and treatment response evaluation. DNA methylation, one of the most extensively studied epigenetic modifications, has gained prominence due to its reliable measurement across various sample types. Numerous studies have reported that DNA methylation was linked to the diagnosis, prognosis and treatment response in malignancies, including GI cancers. While its diagnostic role in GI cancers has been comprehensively reviewed. Recent research has increasingly highlighted its potential in prognosis prediction and treatment response evaluation. However, no existing reviews have exclusively focused on these two aspects. In this review, we retrieved relevant studies and included 230 of them in our discussion, thereby providing an overview of the clinical applicability of aberrant DNA methylation in these two fields among patients with esophageal, gastric, colorectal, pancreatic cancers, and hepatocellular carcinomas. Additionally, we discuss the limitations of the current literature and propose directions for future research. Specifically, we emphasize the need for standardized DNA methylation methodologies and advocate for the integration of gene panels, rather than single genes, to address tumor heterogeneity more effectively.
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Affiliation(s)
- Abudurousuli Reyila
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical University, Xi’an, Shaanxi, China
- National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Xianchun Gao
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical University, Xi’an, Shaanxi, China
- National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Jun Yu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical University, Xi’an, Shaanxi, China
- National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Yongzhan Nie
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical University, Xi’an, Shaanxi, China
- National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, Shaanxi, China
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Lanka G, Banerjee S, Adhikari N, Ghosh B. Fragment-based discovery of new potential DNMT1 inhibitors integrating multiple pharmacophore modeling, 3D-QSAR, virtual screening, molecular docking, ADME, and molecular dynamics simulation approaches. Mol Divers 2025; 29:117-137. [PMID: 38637479 DOI: 10.1007/s11030-024-10837-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 03/05/2024] [Indexed: 04/20/2024]
Abstract
DNA methyl transferases (DNMTs) are one of the crucial epigenetic modulators associated with a wide variety of cancer conditions. Among the DNMT isoforms, DNMT1 is correlated with bladder, pancreatic, and breast cancer, as well as acute myeloid leukemia and esophagus squamous cell carcinoma. Therefore, the inhibition of DNMT1 could be an attractive target for combating cancers and other metabolic disorders. The disadvantages of the existing nucleoside and non-nucleoside DNMT1 inhibitors are the main motive for the discovery of novel promising inhibitors. Here, pharmacophore modeling, 3D-QSAR, and e-pharmacophore modeling of DNMT1 inhibitors were performed for the large fragment database screening. The resulting fragments with high dock scores were combined into molecules. The current study revealed several constitutional pharmacophoric features that can be essential for selective DNMT1 inhibition. The fragment docking and virtual screening identified 10 final hit molecules that exhibited good binding affinities in terms of docking score, binding free energies, and acceptable ADME properties. Also, the modified lead molecules (GL1b and GL2b) designed in this study showed effective binding with DNMT1 confirmed by their docking scores, binding free energies, 3D-QSAR predicted activities and acceptable drug-like properties. The MD simulation studies also suggested that leads (GL1b and GL2b) formed stable complexes with DNMT1. Therefore, the findings of this study can provide effective information for the development/identification of novel DNMT1 inhibitors as effective anticancer agents.
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Affiliation(s)
- Goverdhan Lanka
- Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani Hyderabad Campus, Shamirpet, Hyderabad, 500078, India
- Computer Aided Drug Design Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani Hyderabad Campus, Shamirpet, Hyderabad, 500078, India
| | - Suvankar Banerjee
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, P. O. Box 17020, Kolkata, West Bengal, 700032, India
| | - Nilanjan Adhikari
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, P. O. Box 17020, Kolkata, West Bengal, 700032, India
| | - Balaram Ghosh
- Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani Hyderabad Campus, Shamirpet, Hyderabad, 500078, India.
- Computer Aided Drug Design Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani Hyderabad Campus, Shamirpet, Hyderabad, 500078, India.
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3
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Yao W, Shang L, Wang Y, Xu L, Bai Y, Feng M, Jia X, Wu S. DNMT1-driven methylation of RORA facilitates esophageal squamous cell carcinoma progression under hypoxia through SLC2A3. J Transl Med 2024; 22:1167. [PMID: 39741267 DOI: 10.1186/s12967-024-05960-8] [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: 07/22/2024] [Accepted: 12/11/2024] [Indexed: 01/02/2025] Open
Abstract
BACKGROUND The RAR-related orphan receptor alpha (RORA), a circadian clock molecule, is highly associated with anti-oncogenes. In this paper, we defined the precise action and mechanistic basis of RORA in ESCC development under hypoxia. METHODS Expression analysis was conducted by RT-qPCR, western blotting, immunofluorescence (IF), and immunohistochemistry (IHC) assays. The functions of RORA were assessed by detecting its regulatory effects on cell viability, motility, invasion, and tumor growth. DNA pull-down assay and proteomic analysis were employed to identify proteins bound to the RORA promoter. The promoter methylation level of RORA was detected by DNA pyrosequencing. RNA-seq analysis was performed to explore the downstream mechanisms of RORA, and the transcriptional regulation of RORA on SLC2A3 was verified by ChIP-qPCR and dual-luciferase reporter assay. Glycolysis was assessed by detecting the consumption of glucose and the production of lactic acid and ATP. RESULTS In vitro, RORA was shown to suppress ESCC cell viability, motility, and invasion under hypoxic condition. In vivo, increased RORA expression in mouse xenografts impeded tumor growth. DNMT1 was identified to widely exist in the RORA promoter, increasing DNA methylation and reducing RORA expression in hypoxia-induced KYSE150 ESCC cells. Mechanistically, RORA was found to inactivate the transcription of glucose transporter protein SLC2A3 by interacting with its promoter F1 region. Furthermore, rescue experiments revealed that RORA-mediated suppressive effects on ESCC cell migration and invasion were largely based on its negative regulation of SLC2A3 and glycolysis. CONCLUSION DNMT1-driven methylation of RORA promotes ESCC progression largely through affecting SLC2A3 transcription and glycolysis. These findings turn RORA into potential target of anti-cancer therapeutic agents.
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Affiliation(s)
- Wenjian Yao
- Department of Thoracic Surgery, School of Clinical Medicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Henan University, No.7, Wei Wu Road, Jinshui District, Zhengzhou, Henan, 450003, China
| | - Linlin Shang
- Department of Thoracic Surgery, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, No.7, Wei Wu Road, Jinshui District, Zhengzhou, Henan, 450003, China
| | - Yinghao Wang
- Department of Thoracic Surgery, Henan University People's Hospital, Henan Provincial People's Hospital, No.7, Wei Wu Road, Jinshui District, Zhengzhou, Henan, 450003, China
| | - Lei Xu
- Department of Thoracic Surgery, School of Clinical Medicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Henan University, No.7, Wei Wu Road, Jinshui District, Zhengzhou, Henan, 450003, China
| | - Yu Bai
- Department of Pathology, Xinxiang Medical University, No.601 Jinsui Avenue, Hongqi District, Xinxiang, Henan, 453003, China
| | - Mingyu Feng
- Department of Education, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Xicheng District, Beijing, 100053, China
| | - Xiangbo Jia
- Department of Thoracic Surgery, School of Clinical Medicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Henan University, No.7, Wei Wu Road, Jinshui District, Zhengzhou, Henan, 450003, China.
| | - Sen Wu
- Department of Thoracic Surgery, School of Clinical Medicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Henan University, No.7, Wei Wu Road, Jinshui District, Zhengzhou, Henan, 450003, China.
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Lee SW, Frankston CM, Kim J. Epigenome editing in cancer: Advances and challenges for potential therapeutic options. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2023; 383:191-230. [PMID: 38359969 DOI: 10.1016/bs.ircmb.2023.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/17/2024]
Abstract
Cancers are diseases caused by genetic and non-genetic environmental factors. Epigenetic alterations, some attributed to non-genetic factors, can lead to cancer development. Epigenetic changes can occur in tumor suppressors or oncogenes, or they may contribute to global cell state changes, making cells abnormal. Recent advances in gene editing technology show potential for cancer treatment. Herein, we will discuss our current knowledge of epigenetic alterations occurring in cancer and epigenetic editing technologies that can be applied to developing therapeutic options.
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Affiliation(s)
- Seung-Won Lee
- Cancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United States; Department of Molecular and Medical Genetics, School of Medicine, Oregon Health & Science University, Portland, OR, United States
| | - Connor Mitchell Frankston
- Cancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United States; Biomedical Engineering Graduate Program, Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, OR, United States
| | - Jungsun Kim
- Cancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United States; Department of Molecular and Medical Genetics, School of Medicine, Oregon Health & Science University, Portland, OR, United States; Cancer Biology Research Program, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United States.
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Maksimova VP, Usalka OG, Makus YV, Popova VG, Trapeznikova ES, Khayrieva GI, Sagitova GR, Zhidkova EM, Prus AY, Yakubovskaya MG, Kirsanov KI. Aberrations of DNA methylation in cancer. ADVANCES IN MOLECULAR ONCOLOGY 2022. [DOI: 10.17650/2313-805x-2022-9-4-24-40] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
DNA methylation is a chromatin modification that plays an important role in the epigenetic regulation of gene expression. Changes in DNA methylation patterns are characteristic of many malignant neoplasms. DNA methylation is occurred by DNA methyltransferases (DNMTs), while demethylation is mediated by TET family proteins. Mutations and changes in the expression profile of these enzymes lead to DNA hypo- and hypermethylation and have a strong impact on carcinogenesis. In this review, we considered the key aspects of the mechanisms of regulation of DNA methylation and demethylation, and also analyzed the role of DNA methyltransferases and TET family proteins in the pathogenesis of various malignant neoplasms.During the preparation of the review, we used the following biomedical literature information bases: Scopus (504), PubMed (553), Web of Science (1568), eLibrary (190). To obtain full-text documents, the electronic resources of PubMed Central (PMC), Science Direct, Research Gate, CyberLeninka were used. To analyze the mutational profile of epigenetic regulatory enzymes, we used the cBioportal portal (https://www.cbioportal.org / ), data from The AACR Project GENIE Consortium (https://www.mycancergenome.org / ), COSMIC, Clinvar, and The Cancer Genome Atlas (TCGA).
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Affiliation(s)
- V. P. Maksimova
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
| | - O. G. Usalka
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia; Sechenov First Moscow State Medical University, Ministry of Health of Russia
| | - Yu. V. Makus
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia; Peoples’ Friendship University of Russia
| | - V. G. Popova
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia; Mendeleev University of Chemical Technology of Russia
| | - E. S. Trapeznikova
- Sechenov First Moscow State Medical University, Ministry of Health of Russia
| | - G. I. Khayrieva
- Sechenov First Moscow State Medical University, Ministry of Health of Russia
| | - G. R. Sagitova
- Sechenov First Moscow State Medical University, Ministry of Health of Russia
| | - E. M. Zhidkova
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
| | - A. Yu. Prus
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia; MIREA – Russian Technological University
| | - M. G. Yakubovskaya
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
| | - K. I. Kirsanov
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia; Peoples’ Friendship University of Russia
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Saikia M, Bhattacharyya DK, Kalita JK. CBDCEM: An effective centrality based differential co-expression method for critical gene finding. GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2022.101688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
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Yang SC, Wang WY, Zhou JJ, Wu L, Zhang MJ, Yang QC, Deng WW, Sun ZJ. Inhibition of DNMT1 potentiates antitumor immunity in oral squamous cell carcinoma. Int Immunopharmacol 2022; 111:109113. [PMID: 35944462 DOI: 10.1016/j.intimp.2022.109113] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/13/2022] [Accepted: 07/27/2022] [Indexed: 11/05/2022]
Abstract
Epigenetic alterations, including DNA methylation, play crucial roles in the tumor. Epigenetic drugs like DNA methyltransferase-1 (DNMT1) inhibitors have been exhibited positive effects in cancer treatment. However, the role of DNMT1 in oral squamous cell carcinoma (OSCC) is less clearly described. What is more, the effects on the immune microenvironment of DNMT1 have not become appreciated. In this research, we determine the expression levels of DNMT1 and the association of prognosis by analyzing human OSCC tissue microarrays. Two different types of immunocompetent mouse OSCC models were established to explore the effects of DNMT1 inhibitor on the tumor microenvironment(TME). We identified DNMT1 was highly expressed both in human and mouse OSCC tissues. The expression levels of DNMT1 was also correlated with the immunosuppressive molecules and tumor-promoter such as VISTA, PD-L1, B7-H4, and PAK2, indicating a worse prognosis. Of particular concern is that DNMT1 inhibition improved TME and delayed tumor growth by decreasing myeloid-derived suppressor cells (MDSCs) and increasing tumor-infiltrating T cells. Our data suggests that DNMT1 play a key role in OSCC and has a possible immunotherapeutic marker treatment.
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Affiliation(s)
- Shao-Chen Yang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, 430079 Wuhan, China
| | - Wu-Yin Wang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, 430079 Wuhan, China
| | - Jun-Jie Zhou
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, 430079 Wuhan, China
| | - Lei Wu
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, 430079 Wuhan, China
| | - Meng-Jie Zhang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, 430079 Wuhan, China
| | - Qi-Chao Yang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, 430079 Wuhan, China
| | - Wei-Wei Deng
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, 430079 Wuhan, China; Department of Oral Maxillofacial-Head Neck Oncology, School & Hospital of Stomatology, Wuhan University, 430079 Wuhan, China.
| | - Zhi-Jun Sun
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, 430079 Wuhan, China; Department of Oral Maxillofacial-Head Neck Oncology, School & Hospital of Stomatology, Wuhan University, 430079 Wuhan, China.
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Li G, Roy B, Huang X, Mu Y, Yuan J, Xia Y, Song Y, Peng Z. High expression of N-type calcium channel indicates a favorable prognosis in gliomas. Medicine (Baltimore) 2022; 101:e29782. [PMID: 35777045 PMCID: PMC9239611 DOI: 10.1097/md.0000000000029782] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
For the diagnosis and prognosis of glioma, the development of prognostic biomarkers is critical. The N-type calcium channel, whose predominant subunit is encoded by calcium voltage-gated channel subunit alpha1 B (CACNA1B), is mostly found in the nervous system and is closely associated with neurosensory functions. However, the link between the expression of CACNA1B and glioma remains unknown. We used ONCOMINE to explore the differences in CACNA1B expression among different cancers. We then conducted survival analysis and COX analysis using TCGA_LGG and TCGA_GBM datasets, which were divided into CACNA1Bhigh and CACNA1Blow based on the median. We examined the differences in other favorable prognostic markers or clinical characteristics between CACNA1Bhigh and CACNA1Blow using t tests. Differentially expressed genes were identified, and KEGG pathway enrichment was performed. We compared the expression of methyltransferases and analyzed the differentially methylated regions. Immunohistochemistry results were retrieved from the Human Protein Atlas database for validation purposes. CACNA1B was expressed at lower levels in gliomas, and, for the first time, we found that high expression of CACNA1B in gliomas predicts a good prognosis. Other favorable prognostic markers, such as isocitrate dehydrogenase mutation, 1p/19q codeletion, and O6-methylguanine-DNA methyltransferase promoter methylation, were increased in tandem with high expression of CACNA1B. Differentially expressed genes were enriched in multiple pathways related to cancer progression and aberrant epigenetic alterations were significantly associated with CACNA1B. High expression of N-type calcium channels indicates a favorable prognosis for gliomas. This study provides a better understanding of the link between gliomas and N-type calcium channels and may offer guidance for the future treatment of gliomas.
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Affiliation(s)
- Guibin Li
- Guangzhou KingMed Transformative Medicine Institute, Guangzhou, China
- *Correspondence: Guibin Li, Guangzhou KingMed Transformative Medicine Institute, No. 10 Luoxuan 3rd Road, International Biotech Island, Guangzhou 510320, Guangdong Province, China (e-mail: )
| | | | - Xiaoqiang Huang
- KingMed Center for Clinical Laboratory Co. Ltd., Guangzhou, China
| | - Yafei Mu
- Guangzhou KingMed Transformative Medicine Institute, Guangzhou, China
| | - Jiecheng Yuan
- KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, China
| | - Yang Xia
- Second Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Yue Song
- Second Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Ziyue Peng
- Second Affiliated Hospital, Harbin Medical University, Harbin, China
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Parker WB, Thottassery JV. 5-Aza-4'-thio-2'-deoxycytidine, a New Orally Bioavailable Nontoxic "Best-in-Class": DNA Methyltransferase 1-Depleting Agent in Clinical Development. J Pharmacol Exp Ther 2021; 379:211-222. [PMID: 34503994 PMCID: PMC9164309 DOI: 10.1124/jpet.121.000758] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 09/01/2021] [Indexed: 11/22/2022] Open
Abstract
DNA methyltransferase (DNMT) 1 is an enzyme that functions as a maintenance methyltransferase during DNA replication, and depletion of this enzyme from cells is considered to be a rational goal in DNA methylation-dependent disorders. Two DNMT1-depleting agents 5-aza-2'-deoxycytidine (aza-dCyd, decitabine) and 5-aza-cytidine (aza-Cyd, azacitidine) are currently used for the treatment of myelodysplastic syndromes and acute myeloid leukemia and have also been investigated for nononcology indications, such as sickle cell disease. However, these agents have several off-target activities leading to significant toxicities that limit dosing and duration of treatment. Development of more selective inhibitors of DNMT1 could therefore afford treatment of long durations at effective doses. We have discovered that 5-aza-4'-thio-2'-deoxycytidine (aza-T-dCyd) is as effective as aza-dCyd in depleting DNMT1 in mouse tumor models but with markedly low toxicity. In this review we describe the preclinical studies that led to the development of aza-T-dCyd as a superior DNMT1-depleting agent with respect to aza-dCyd and will describe its pharmacology, metabolism, and mechanism of action. In an effort to understand why aza-T-dCyd is a more selective DNMT1 depleting agent than aza-dCyd, we will also compare and contrast the activities of these two agents. SIGNIFICANCE STATEMENT: Aza-T-dCyd is a potent DNMT1-depleting agent. Although similar in structure to decitabine (aza-dCyd), its metabolism and mechanism of action is different than that of aza-dCyd, resulting in less off-target activity and less toxicity. The larger therapeutic index of aza-T-dCyd (DNMT1 depletion vs. toxicity) in mice suggests that it would be a better clinical candidate to selectively deplete DNMT1 from target cells and determine whether or not depletion of DNMT1 is an effective target for various diseases.
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Affiliation(s)
- William B Parker
- PNP Therapeutics, Birmingham, Alabama (W.B.P.); and UDG Healthcare, Smartanalyst - Ashfield Division, New York, New York (J.V.T.)
| | - Jaideep V Thottassery
- PNP Therapeutics, Birmingham, Alabama (W.B.P.); and UDG Healthcare, Smartanalyst - Ashfield Division, New York, New York (J.V.T.)
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Burkitt K, Saloura V. Epigenetic Modifiers as Novel Therapeutic Targets and a Systematic Review of Clinical Studies Investigating Epigenetic Inhibitors in Head and Neck Cancer. Cancers (Basel) 2021; 13:cancers13205241. [PMID: 34680389 PMCID: PMC8534083 DOI: 10.3390/cancers13205241] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 10/05/2021] [Accepted: 10/09/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Head and neck cancer is the sixth most common malignancy worldwide and it affects approximately 50,000 patients annually in the United States. Current treatments are suboptimal and induce significant long-term toxicities that permanently affect quality of life. Novel therapeutic approaches are thus urgently needed to increase the survival and quality of life of these patients. Epigenetic modifications have been recognized as potential therapeutic targets in various cancer types, including head and neck cancer. The objective of this review is to provide a brief overview of the function of important epigenetic modifiers in head and neck cancer, and to discuss the results of past and ongoing clinical trials evaluating epigenetic interventions targeting these epigenetic modifiers in head and neck cancer patients. The field of epigenetic therapy in head and neck cancer is still nascent; however, it holds significant promise. Although more specific epigenetic drugs are being developed, we envision the rational design of clinical trials that will target a select group of head and neck cancer patients with epigenetic vulnerabilities that can be targeted in combination with immunotherapy, chemotherapy and/or radiotherapy, rendering higher and durable responses while minimizing chronic complications for patients with head and neck cancer. Abstract The survival rate of head and neck squamous cell carcinoma patients with the current standard of care therapy is suboptimal and is associated with long-term side effects. Novel therapeutics that will improve survival rates while minimizing treatment-related side effects are the focus of active investigation. Epigenetic modifications have been recognized as potential therapeutic targets in various cancer types, including head and neck cancer. This review summarizes the current knowledge on the function of important epigenetic modifiers in head and neck cancer, their clinical implications and discusses results of clinical trials evaluating epigenetic interventions in past and ongoing clinical trials as monotherapy or combination therapy with either chemotherapy, radiotherapy or immunotherapy. Understanding the function of epigenetic modifiers in both preclinical and clinical settings will provide insight into a more rational design of clinical trials using epigenetic interventions and the patient subgroups that may benefit from such interventions.
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Affiliation(s)
- Kyunghee Burkitt
- Head and Neck Medical Oncology, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
- Correspondence: (K.B.); (V.S.)
| | - Vassiliki Saloura
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
- Correspondence: (K.B.); (V.S.)
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Bruine de Bruin L, Clausen MJAM, Slagter-Menkema L, de Bock GH, Langendijk JA, van der Vegt B, van der Laan BFAM, Schuuring E. High DNMT1 Is Associated With Worse Local Control in Early-Stage Laryngeal Squamous Cell Carcinoma. Laryngoscope 2021; 132:801-805. [PMID: 34427325 PMCID: PMC9290472 DOI: 10.1002/lary.29833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 08/08/2021] [Accepted: 08/10/2021] [Indexed: 11/16/2022]
Abstract
Objectives/Hypothesis Early‐stage laryngeal squamous cell carcinoma (LSCC) has yielded local control rates of 75% after radiotherapy. DNA methylation, in which DNA methyltransferases play an important role, has influence on tumorigenesis. In this study, we investigated the association between the expression of DNA methyltransferase 1 (DNMT1) and local control in early‐stage LSCC treated with radiotherapy. Study Design Retrospective cohort study. Methods We analyzed a well‐defined homogeneous series of 125 LSCC patients treated with radiotherapy with curative intent. The association of immunohistochemical expression of DNMT1 with local control was evaluated using Cox proportional hazard regression models. Results With a median follow‐up of 58 months, 29 local recurrences (23%) were observed. On univariate analysis, worse local control was associated with high DNMT1 expression (hazard ratio [HR] 2.57, 95% confidence interval [CI] 1.10–6.01). Also, higher T‐stage (HR 2.48, 95% CI 1.06–5.80) and positive N‐status (HR 2.62, 95% CI 1.06–6.47) were associated with worse local control. Multivariate Cox regression demonstrated that high DNMT1 (HR 2.81; 95% CI 1.20–6.58) was independently associated with worse local control. Conclusions We found an association between high DNMT1 expression and worse local control in a homogeneous well‐defined cohort of early‐stage LSCC patients treated with definitive radiotherapy. The association between DNA methylation status as determined by DNMT1 expression and local control suggests that DNMT1 acts as a potential prognostic tumor marker in treatment decision‐making in early‐stage laryngeal carcinoma. Level of evidence NA Laryngoscope, 132:801–805, 2022
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Affiliation(s)
- Leonie Bruine de Bruin
- Department of Otorhinolaryngology/Head and Neck Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Martijn J A M Clausen
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Lorian Slagter-Menkema
- Department of Otorhinolaryngology/Head and Neck Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Gertruida H de Bock
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Johannes A Langendijk
- Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Bert van der Vegt
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Bernard F A M van der Laan
- Department of Otorhinolaryngology/Head and Neck Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Ed Schuuring
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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12
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Mohammadzadeh N, Mosaffa F, Khadivi E, Jahangiri R, Jamialahmadi K. Increased Expression of DNA Methyltransferase 1 and 3B Correlates with Tumor Grade in Laryngeal Squamous Cell Carcinoma. PHARMACEUTICAL SCIENCES 2020. [DOI: 10.34172/ps.2020.86] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Background: DNA methyltransferase (DNMT) enzymes, encoded by DNMT1, DNMT3A andDNMT3B genes, play a major role in the development of cancers through aberrant promotermethylation. Due to little information about the biological and clinical significance of expressionchanges of these genes in Laryngeal Squamous Cell carcinoma (LSCC), the current study wasdesigned to evaluate the contribution of DNMTs expression as potential diagnostic biomarkersin progression of LSCC. Methods: DNMT1, DNMT3A and DNMT3B expressions in tumoral and normal tissues fromthirty-three LSCC patients were evaluated by relative comparative real-time PCR, prior toany therapeutic intervention. Relationship between genes expression and clinicopathologicalfeatures were also analyzed. Results: The mRNA expression levels of all three DNMTs (DNMT1, DNMT3A and DNMT3B)were significantly elevated in LSCC tumor specimens compared to that of non-tumor tissues(P<0.0001, P=0.011 and P<0.0001, respectively). The expression of DNMT1 and DNMT3Bwas strongly associated with histopathological tumor grade. Moreover, the mRNA expressionlevels of DNMT3A were significantly correlated with laryngopharyngeal reflux. No significantrelationships existed with other clinicopathological parameters. Conclusion: Data showed that the expression levels of DNMT1, DNMT3A and DNMT3Bmarkedly increased in LSCC tissues. DNMT1 and DNMT3B were mainly overexpressed in highgrade LSCC tumors, therefore, they may have a role in LSCC progression. It seems that thesegenes may serve as diagnostic biomarkers in development of LSCC.
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Affiliation(s)
- Nooshin Mohammadzadeh
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fatemeh Mosaffa
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ehsan Khadivi
- Sinus and Surgical Endoscopic Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Rosa Jahangiri
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Khadijeh Jamialahmadi
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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13
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Liao L, Yao Z, Fang W, He Q, Xu WW, Li B. Epigenetics in Esophageal Cancer: From Mechanisms to Therapeutics. SMALL METHODS 2020; 4:2000391. [DOI: 10.1002/smtd.202000391] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Indexed: 02/05/2023]
Affiliation(s)
- Long Liao
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes Institute of Life and Health Engineering College of Life Science and Technology Jinan University Guangzhou 510632 China
| | - Zi‐Ting Yao
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes Institute of Life and Health Engineering College of Life Science and Technology Jinan University Guangzhou 510632 China
| | - Wang‐Kai Fang
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area Department of Biochemistry and Molecular Biology Shantou University Medical College Shantou 515041 China
| | - Qing‐Yu He
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes Institute of Life and Health Engineering College of Life Science and Technology Jinan University Guangzhou 510632 China
| | - Wen Wen Xu
- MOE Key Laboratory of Tumor Molecular Biology and Guangdong Provincial Key Laboratory of Bioengineering Medicine National Engineering Research Center of Genetic Medicine Institute of Biomedicine College of Life Science and Technology Jinan University Guangzhou 510632 China
| | - Bin Li
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes Institute of Life and Health Engineering College of Life Science and Technology Jinan University Guangzhou 510632 China
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14
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Epigenetic Alterations in Oesophageal Cancer: Expression and Role of the Involved Enzymes. Int J Mol Sci 2020; 21:ijms21103522. [PMID: 32429269 PMCID: PMC7278932 DOI: 10.3390/ijms21103522] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 05/12/2020] [Accepted: 05/13/2020] [Indexed: 12/25/2022] Open
Abstract
Oesophageal cancer is a life-threatening disease, accounting for high mortality rates. The poor prognosis of this malignancy is mostly due to late diagnosis and lack of effective therapies for advanced disease. Epigenetic alterations may constitute novel and attractive therapeutic targets, owing to their ubiquity in cancer and their reversible nature. Herein, we offer an overview of the most important studies which compared differences in expression of enzymes that mediate epigenetic alterations between oesophageal cancer and normal mucosa, as well as in vitro data addressing the role of these genes/proteins in oesophageal cancer. Furthermore, The Cancer Genome Atlas database was interrogated for the correlation between expression of these epigenetic markers and standard clinicopathological features. We concluded that most epigenetic players studied thus far are overexpressed in tumours compared to normal tissue. Furthermore, functional assays suggest an oncogenic role for most of those enzymes, supporting their potential as therapeutic targets in oesophageal cancer.
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15
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Shahkarami S, Zoghi S, Rezaei N. The Role of DNA Methylation in Cancer. CANCER IMMUNOLOGY 2020:491-511. [DOI: 10.1007/978-3-030-30845-2_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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16
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Wang R, Liu X. Epigenetic regulation of prostate cancer. Genes Dis 2019; 7:606-613. [PMID: 33335960 PMCID: PMC7729106 DOI: 10.1016/j.gendis.2019.10.018] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 10/16/2019] [Accepted: 10/30/2019] [Indexed: 12/21/2022] Open
Abstract
Prostate cancer is (PCa) the second leading cause of cancer death in males in the United State, with 174,650 new cases and 31,620 deaths estimated in 2019. It has been documented that epigenetic deregulation such as histone modification and DNA methylation contributes to PCa initiation and progression. EZH2 (enhancer of zeste homolog 2), the catalytic subunit of the Polycomb Repressive Complex (PRC2) responsible for H3K27me3 and gene repression, has been identified as a promising target in PCa. In addition, overexpression of other epigenetic regulators such as DNA methyltransferases (DNMT) is also observed in PCa. These epigenetic regulators undergo extensive post-translational modifications, in particular, phosphorylation. AKT, CDKs, PLK1, PKA, ATR and DNA-PK are the established kinases responsible for phosphorylation of various epigenetic regulators.
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Affiliation(s)
- Ruixin Wang
- Department of Biochemistry, Purdue University, West Lafayette, IN, 47907, USA.,Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, 40536, USA
| | - Xiaoqi Liu
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, 40536, USA.,Markey Cancer Center, University of Kentucky, Lexington, KY, 40536, USA
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17
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Lu S, Xu F, Hu W, Niu Z, Cai H, Chen Y, Tu Q, Zhang Y, Chen W, Liu W, Tang S, Zhang Z. SCD1 methylation in subcutaneous adipose tissue associated with menopausal age. Climacteric 2019; 22:395-402. [PMID: 30777456 DOI: 10.1080/13697137.2019.1571028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Affiliation(s)
- S. Lu
- Department of Obstetrics and Gynecology, Hangzhou Women’s Hospital (Hangzhou Maternity and Child Health Care Hospital), Hangzhou, China
| | - F. Xu
- Department of Gastroenterology, Hangzhou Third People's Hospital, Hangzhou, China
| | - W. Hu
- Department of Obstetrics and Gynecology, Hangzhou Women’s Hospital (Hangzhou Maternity and Child Health Care Hospital), Hangzhou, China
| | - Z. Niu
- Department of Obstetrics and Gynecology, The Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou, China
| | - H. Cai
- Department of Obstetrics and Gynecology, The Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou, China
| | - Y. Chen
- Laboratory of Gene Diagnosis, The Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou, China
| | - Q. Tu
- Laboratory of Gene Diagnosis, The Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou, China
| | - Y. Zhang
- Department of Obstetrics and Gynecology, Hangzhou Women’s Hospital (Hangzhou Maternity and Child Health Care Hospital), Hangzhou, China
| | - W. Chen
- Department of Obstetrics and Gynecology, The Second People's Hospital of Tonglu, Hangzhou, China
| | - W. Liu
- Department of Obstetrics and Gynecology, Hangzhou Women’s Hospital (Hangzhou Maternity and Child Health Care Hospital), Hangzhou, China
| | - S. Tang
- Department of Obstetrics and Gynecology, Hangzhou Women’s Hospital (Hangzhou Maternity and Child Health Care Hospital), Hangzhou, China
| | - Z. Zhang
- Department of Obstetrics and Gynecology, Hangzhou Women’s Hospital (Hangzhou Maternity and Child Health Care Hospital), Hangzhou, China
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18
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Schizas D, Mastoraki A, Naar L, Spartalis E, Tsilimigras DI, Karachaliou GS, Bagias G, Moris D. Concept of histone deacetylases in cancer: Reflections on esophageal carcinogenesis and treatment. World J Gastroenterol 2018; 24:4635-4642. [PMID: 30416311 PMCID: PMC6224471 DOI: 10.3748/wjg.v24.i41.4635] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 09/02/2018] [Accepted: 10/05/2018] [Indexed: 02/06/2023] Open
Abstract
Esophageal cancer (EC) presents a high mortality rate, mainly due to its aggressive nature. Squamous cell carcinoma is the most common histological type worldwide, though, a continuous increase in esophageal adenocarcinomas has been noted in the past decades. Common risk factors associated with EC include smoking, alcohol consumption, gastroesophageal reflux disease, Barrett's esophagus and obesity. In an effort to overcome chemotherapy resistance in oncology, it was discovered that histone acetylation/deacetylation equilibrium is altered in carcinogenesis, leading to changes in chromatin structure and altering expression of genes important in the cell cycle, differentiation and apoptosis. Based on this knowledge, histone acetylation was addressed as a potential novel chemotherapy drug target to repress cancer cell proliferation. There are four classes of histone deacetylases (HDACs) inhibitors with a variety of different mechanisms of actions that render them possible anti-cancer drugs. They arrest the cell cycle, inhibit differentiation and angiogenesis and induce apoptosis. They do not necessarily act on histone proteins, since they can also exert indirect anti-cancer effects, by modifying various cellular proteins. In addition, HDACs have also been associated with increased chemotherapy resistance. Based on the literature, HDACs have been associated with EC, with surveys revealing that increased expression of certain HDACs correlates with advanced TNM stages, tumor grade, metastatic potential and decreased 5-year overall and disease-free survival. The aim of this survey is to elucidate the molecular identity and mechanism of action of HDAC inhibitors as well as verify their potential utility as anti-cancer agents in esophageal cancer.
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Affiliation(s)
- Dimitrios Schizas
- 1st Department of Surgery, Laikon General Hospital, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Aikaterini Mastoraki
- 1st Department of Surgery, Laikon General Hospital, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Leon Naar
- 4th Department of Surgery, Attikon University Hospital, National and Kapodistrian University of Athens, Athens 12462, Greece
| | - Eleftherios Spartalis
- Laboratory of Experimental Surgery and Surgical Research, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Diamantis I Tsilimigras
- 1st Department of Surgery, Laikon General Hospital, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Georgia-Sofia Karachaliou
- Laboratory of Experimental Surgery and Surgical Research, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - George Bagias
- Department of General, Visceral and Transplant Surgery, University Hospital Essen, Essen 45141, Germany
| | - Dimitrios Moris
- Department of Surgery, Duke University Medical Center, Durham, NC 27710, United States
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19
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Nagata H, Kozaki KI, Muramatsu T, Hiramoto H, Tanimoto K, Fujiwara N, Imoto S, Ichikawa D, Otsuji E, Miyano S, Kawano T, Inazawa J. Genome-wide screening of DNA methylation associated with lymph node metastasis in esophageal squamous cell carcinoma. Oncotarget 2018; 8:37740-37750. [PMID: 28465481 PMCID: PMC5514945 DOI: 10.18632/oncotarget.17147] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Accepted: 03/28/2017] [Indexed: 12/18/2022] Open
Abstract
Lymph node metastasis (LNM) of esophageal squamous cell carcinoma (ESCC) is well-known to be an early event associated with poor prognosis in patients with ESCC. Recently, tumor-specific aberrant DNA methylation of CpG islands around the promoter regions of tumor-related genes has been investigated as a possible biomarker for use in early diagnosis and prediction of prognosis. However, there are few DNA methylation markers able to predict the presence of LNM in ESCC. To identify DNA methylation markers associated with LNM of ESCC, we performed a genome-wide screening of DNA methylation status in a discovery cohort of 67 primary ESCC tissues and their paired normal esophageal tissues using the Illumina Infinium HumanMethylation450 BeadChip. In this screening, we focused on differentially methylated regions (DMRs) that were associated with LNM of ESCC, as prime candidates for DNA methylation markers. We extracted three genes, HOXB2, SLC15A3, and SEPT9, as candidates predicting LNM of ESCC, using pyrosequencing and several statistical analyses in the discovery cohort. We confirmed that HOXB2 and SEPT9 were highly methylated in LNM-positive tumors in 59 ESCC validation samples. These results suggested that HOXB2 and SEPT9 may be useful epigenetic biomarkers for the prediction of the presence of LNM in ESCC.
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Affiliation(s)
- Hiroaki Nagata
- Department of Molecular Cytogenetics, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.,Department of Digestive Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan
| | - Ken-Ichi Kozaki
- Department of Molecular Cytogenetics, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.,Hard Tissue Genome Research Center, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.,Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kita-ku, Okayama, Japan
| | - Tomoki Muramatsu
- Department of Molecular Cytogenetics, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hidekazu Hiramoto
- Department of Molecular Cytogenetics, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.,Department of Digestive Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan
| | - Kousuke Tanimoto
- Genome Laboratory, Graduate School of Medicine, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
| | - Naoto Fujiwara
- Department of Molecular Cytogenetics, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.,Department of Esophageal and General Surgery, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
| | - Seiya Imoto
- Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Daisuke Ichikawa
- Department of Digestive Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan
| | - Eigo Otsuji
- Department of Digestive Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan
| | - Satoru Miyano
- Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Tatsuyuki Kawano
- Department of Esophageal and General Surgery, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
| | - Johji Inazawa
- Department of Molecular Cytogenetics, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.,Hard Tissue Genome Research Center, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.,Bioresource Research Center, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
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20
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Yoon JH, You BH, Park CH, Kim YJ, Nam JW, Lee SK. The long noncoding RNA LUCAT1 promotes tumorigenesis by controlling ubiquitination and stability of DNA methyltransferase 1 in esophageal squamous cell carcinoma. Cancer Lett 2018; 417:47-57. [PMID: 29247823 DOI: 10.1016/j.canlet.2017.12.016] [Citation(s) in RCA: 109] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Revised: 12/11/2017] [Accepted: 12/11/2017] [Indexed: 12/21/2022]
Abstract
Available targeted therapies for esophageal squamous cell carcinoma (ESCC) are limited; thus, further genetic and epigenetic studies are needed. Recently, many long noncoding RNAs (lncRNAs) have been reported to be involved in various cancers. Here, we investigated whether the lncRNA LUCAT1 was related to the carcinogenesis of ESCC based on previous studies in lung cancer. LUCAT1 was significantly upregulated in ESCC cell lines and cancer tissue compared with normal cells and adjacent normal tissues. LUCAT1 knockdown reduced cell proliferation, induced apoptosis, and upregulated tumor-suppressor genes by reducing DNA methylation in KYSE-30 cells. Moreover, LUCAT1 siRNA reduced DNA methyltransferase 1 (DNMT1) protein levels without affecting transcription. Patients with high LUCAT1 expression had significantly lower survival rates than patients with low LUCAT1 expression. Our results thus suggest that LUCAT1 regulates the stability of DNMT1 and inhibits the expression of tumor suppressors through DNA methylation, leading to the formation and metastasis of ESCC. We identified LUCAT1 as a potential target for drug development and as a biomarker for ESCC.
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Affiliation(s)
- Jung-Ho Yoon
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Republic of Korea
| | - Bo-Hyun You
- Department of Life Science, College of Natural Sciences, Hanyang University, Seoul 133791, Republic of Korea
| | - Chan Hyuk Park
- Division of Gastroenterology, Institute of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Severance Hospital, Seoul, Republic of Korea
| | - Yeong Jin Kim
- Division of Gastroenterology, Institute of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Severance Hospital, Seoul, Republic of Korea
| | - Jin-Wu Nam
- Department of Life Science, College of Natural Sciences, Hanyang University, Seoul 133791, Republic of Korea; Research Institute for Convergence of Basic Sciences, Hanyang University, Seoul 133791, Republic of Korea
| | - Sang Kil Lee
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Republic of Korea; Division of Gastroenterology, Institute of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Severance Hospital, Seoul, Republic of Korea.
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21
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Bai J, Zhang X, Liu B, Wang H, Du Z, Song J. Silencing DNA methyltransferase 1 leads to the activation of the esophageal suppressor gene p16 in vitro and in vivo. Oncol Lett 2017; 14:3077-3081. [PMID: 28927055 DOI: 10.3892/ol.2017.6535] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 11/25/2017] [Indexed: 11/06/2022] Open
Abstract
Previous studies have demonstrated that DNA methyltransferase 1 (DNMT1) is required for the maintenance of DNA methylation and epigenetic changes that may lead to the development of esophageal squamous cell carcinoma (ESCC). In order to investigate whether the silencing of DNMT1 protects tumor suppressor genes, including p16, and is able to be used as a potential therapy for human ESCC, short hairpin RNA targeting DNMT1 (shRNA-DNMT1) was synthesized and transfected into the human ESCC lines KYSE150 and KYSE410, which were then injected into the backs of nude mice prior to harvesting. Results from the reverse transcription-quantitative polymerase chain reaction (PCR) and western blotting demonstrated that p16 mRNA expression was increased in the shRNA-DNMT1-transfected ESCC cell lines in vitro and in vivo. Consistent with the immunohistochemistry results, p16 was expressed in tumor tissue from nude mice that had been transplanted with the modified human ESCC lines. It was also observed that p16 methylation was inhibited following transfection with shRNA-DNMT1 as detected using methylation-specific PCR analysis. The results of the present study suggest that silencing DNMT1 serves a protective role through the demethylation and subsequent activation of p16 in vitro and in vivo.
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Affiliation(s)
- Jian Bai
- Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Medical University, Xi'an, Shaanxi 710000, P.R. China
| | - Xue Zhang
- Department of Respiratory Medicine, The First Affiliated Hospital of Xi'an Medical University, Xi'an, Shaanxi 710000, P.R. China
| | - Bangqing Liu
- Department of Thoracic and Cardiovascular Surgery, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi Zhuang 541100, P.R. China
| | - Haiyong Wang
- Department of Thoracic and Cardiovascular Surgery, The Affiliated Hospital of Guilin Medical University, Guilin, Guangxi Zhuang 541001, P.R. China
| | - Zhenzong Du
- Department of Thoracic Surgery, Nanxi Shan Hospital of Guangxi Zhuang Autonomous Region, Guilin, Guangxi Zhuang 541002, P.R. China
| | - Jianfei Song
- Department of Thoracic and Cardiovascular Surgery, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi Zhuang 541100, P.R. China
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22
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Zhang W, Xu J. DNA methyltransferases and their roles in tumorigenesis. Biomark Res 2017; 5:1. [PMID: 28127428 PMCID: PMC5251331 DOI: 10.1186/s40364-017-0081-z] [Citation(s) in RCA: 250] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Accepted: 01/03/2017] [Indexed: 01/13/2023] Open
Abstract
DNA methylation plays an important role in gene expression, chromatin stability, and genetic imprinting. In mammals, DNA methylation patterns are written and regulated by DNA methyltransferases (DNMTs), including DNMT1, DNMT3A and DNMT3B. Recent emerging evidence shows that defects in DNMTs are involved in tumor transformation and progression, thus indicating that epigenetic disruptions caused by DNMT abnormalities are associated with tumorigenesis. Herein, we review the latest findings related to DNMT alterations in cancer cells and discuss the contributions of these effects to oncogenic phenotypes.
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Affiliation(s)
- Wu Zhang
- State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, Rui-Jin Hospital affiliated to Shanghai Jiao-Tong University School of Medicine, 197 Rui Jin Er Road, 200025 Shanghai, China
| | - Jie Xu
- State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, Rui-Jin Hospital affiliated to Shanghai Jiao-Tong University School of Medicine, 197 Rui Jin Er Road, 200025 Shanghai, China
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23
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Supic G, Kozomara R, Zeljic K, Jovic N, Magic Z. Prognostic value of the DNMTs mRNA expression and genetic polymorphisms on the clinical outcome in oral cancer patients. Clin Oral Investig 2017; 21:173-182. [PMID: 26966018 DOI: 10.1007/s00784-016-1772-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Accepted: 02/29/2016] [Indexed: 01/07/2023]
Abstract
OBJECTIVES Although the importance of the epigenetic changes in tumors, including oral squamous cell carcinomas (OSCCs), is now becoming apparent, the mechanisms that trigger or cause aberrant DNA methylation in cancer are still unrevealed. DNA methylation is regulated by a family of enzymes, DNA methyltransferases (DNMTs). DNMT gene expression analysis, as well as genetic polymorphisms, has not been previously evaluated in OSCC. MATERIALS AND METHODS In 65 OSCC patients, SYBR Green real-time PCR method was assessed for relative quantification of DNMT1, DNMT3A, and DNMT3B mRNAs, normalized to TATA-binding protein (TBP) mRNA. The expression levels of all three genes were dichotomized as high or low, with a twofold change of normalized mRNA expression used as the cutoff value. Polymorphisms in DNMT1 (rs2228612) and DNMT3B (rs406193) were analyzed in 99 OSCCs by TaqMan SNPs genotyping assays. RESULTS DNMT1, DNMT3A, and DNMT3B were overexpressed in 36.9, 26, and 23 % of the OSCC patients, respectively. DNMT1 overexpression was significantly associated with the overall survival, p = 0.029, and relapse-free survival of OSCC patients, p = 0.003. Patients with DNMT1 overexpression, as an independent prognostic factor, had a 2.385 times higher risk to relapse than those with lower expression. The DNMT1 A201G gene polymorphism was associated with a reduced overall survival in OSCC patients, p = 0.036. CONCLUSIONS Our results suggest that DNMT1 could play an important role in modulating OSCC patient survival. CLINICAL RELEVANCE DNMT gene expression could be a potential prognostic marker that might lead to an improvement in diagnosis, prognosis, and prospective use of epigenetic-targeted therapy of OSCC.
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Affiliation(s)
- Gordana Supic
- Faculty of Medicine, Military Medical Academy, University of Defense, Belgrade, Serbia.
- Institute for Medical Research, Military Medical Academy, Crnotravska 17, Belgrade, 11002, Serbia.
| | - Ruzica Kozomara
- Faculty of Medicine, Military Medical Academy, University of Defense, Belgrade, Serbia
- Clinic for Maxillofacial Surgery, Military Medical Academy, Belgrade, Serbia
| | - Katarina Zeljic
- Institute for Medical Research, Military Medical Academy, Crnotravska 17, Belgrade, 11002, Serbia
- Faculty of Biology, University of Belgrade, Belgrade, Serbia
| | - Nebojsa Jovic
- Faculty of Medicine, Military Medical Academy, University of Defense, Belgrade, Serbia
- Clinic for Maxillofacial Surgery, Military Medical Academy, Belgrade, Serbia
| | - Zvonko Magic
- Faculty of Medicine, Military Medical Academy, University of Defense, Belgrade, Serbia
- Institute for Medical Research, Military Medical Academy, Crnotravska 17, Belgrade, 11002, Serbia
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24
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Huang YW, Gu F, Dombkowski A, Wang LS, Stoner GD. Black raspberries demethylate Sfrp4, a WNT pathway antagonist, in rat esophageal squamous cell papilloma. Mol Carcinog 2016; 55:1867-1875. [PMID: 27696538 DOI: 10.1002/mc.22435] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Revised: 10/26/2015] [Accepted: 11/03/2015] [Indexed: 11/10/2022]
Abstract
Aberrant methylation of DNA is a common event in the development of cancers, including squamous cell carcinoma (SCC) of the human esophagus. In the present study, we determined: (a) whether aberrant DNA methylation also occurs in the development of N-nitrosomethylbenzylamine (NMBA)-induced tumorigenesis in the rat esophagus, a model of human esophageal SCC; and (b) if so, whether dietary black raspberries (BRBs) are capable of preventing this aberrant DNA methylation. A diet containing 5% BRBs inhibited the development of NMBA-induced tumors in the rat esophagus. This inhibition was associated with reduced mRNA levels of the DNA methyltransferases, Dnmt1 and Dnmt3b, in both dysplastic lesions and in papillomas of the esophagus. In addition, promoter methylation of Sfrp4, a WNT pathway antagonist, was significantly reduced by the berry diet, and this was associated with decreased nuclear localization of β-CATENIN and reduced expression of c-MYC protein in NMBA-treated esophagi. Decreased promoter methylation of Sfrp4 correlated with decreased expression of Dmnt3b and, ultimately, with increased Sfrp4 mRNA expression. This suggests that epigenetic alterations in NMBA-induced rat esophageal tumorigenesis recapitulate epigenetic events in human esophageal SCC, and that BRBs could be useful in preventing the aberrant DNA methylation involved in the development of human esophageal SCC. © 2015 Wiley Periodicals, Inc.
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Affiliation(s)
- Yi-Wen Huang
- Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, Wisconsin.
| | - Fei Gu
- Department of Pediatrics, Children's Hospital Boston, Boston, Massachusetts
| | - Alan Dombkowski
- Department of Pediatrics, Wayne State University School of Medicine, Detroit, Michigan
| | - Li-Shu Wang
- Department of Medicine, Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Gary D Stoner
- Department of Medicine, Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin
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25
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Response of esophageal cancer cells to epigenetic inhibitors is mediated via altered thioredoxin activity. J Transl Med 2016; 96:307-16. [PMID: 26692290 DOI: 10.1038/labinvest.2015.148] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Revised: 08/14/2015] [Accepted: 09/03/2015] [Indexed: 01/01/2023] Open
Abstract
We previously showed that histone deacetylase inhibitor (HDACi) and 5-azacytidine (AZA) treatment selectively induced cell death of esophageal cancer cells. The mechanisms of cancer selectivity, however, remained unclear. Here we examined whether the cancer selectivity of HDACi/AZA treatment is mediated by the thioredoxin (Trx) system and reactive oxygen species (ROS) in esophageal cancer cells. For this, we first analyzed human tissue specimens of 37 esophageal cancer patients by immunohistochemistry for Trx, Trx-interacting protein (TXNIP) and Trx reductase (TXNRD). This revealed a loss or at least reduction of nuclear Trx in esophageal cancer cells, compared with normal epithelial cells (P<0.001). Although no differences were observed for TXNIP, TXNRD was more frequently expressed in cancer cells (P<0.001). In the two main histotypes of esophageal squamous cell carcinomas (ESCCs, n=19) and esophageal adenomcarcinomas (EAC, n=16), similar Trx, TXNIP and TXNRD expression patterns were observed. Also in vitro, nuclear Trx was only detectable in non-neoplastic Het-1A cells, but not in OE21/ESCC or OE33/EAC cell lines. Moreover, the two cancer cell lines showed an increased Trx activity, being significant for OE21 (P=0.0237). After treatment with HDACi and/or AZA, ROS were exclusively increased in both cancer cell lines (P=0.048-0.017), with parallel decrease of Trx activity. This was variably accompanied by increased TXNIP levels upon AZA, MS-275 or MS-275/AZA treatment for 6 or 24 h in OE21, but not in Het-1A or OE33 cells. In summary, this study evaluated Trx and its associated proteins TXNIP and TXNRD for the first time in esophageal cancers. The analyses revealed an altered subcellular localization of Trx and strong upregulation of TXNRD in esophageal cancer cells. Moreover, HDACi and AZA disrupted Trx function and induced accumulation of ROS with subsequent apoptosis in esophageal cancer cells exclusively. Trx function is hence an important cellular mediator conferring non-neoplastic cell resistance for HDACi and/or AZA.
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26
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Ahrens TD, Timme S, Hoeppner J, Ostendorp J, Hembach S, Follo M, Hopt UT, Werner M, Busch H, Boerries M, Lassmann S. Selective inhibition of esophageal cancer cells by combination of HDAC inhibitors and Azacytidine. Epigenetics 2016; 10:431-45. [PMID: 25923331 DOI: 10.1080/15592294.2015.1039216] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Esophageal cancers are highly aggressive tumors with poor prognosis despite some recent advances in surgical and radiochemotherapy treatment options. This study addressed the feasibility of drugs targeting epigenetic modifiers in esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) cells. We tested inhibition of histone deacetylases (HDACs) by SAHA, MS-275, and FK228, inhibition of DNA methyltransferases by Azacytidine (AZA) and Decitabine (DAC), and the effect of combination treatment using both types of drugs. The drug targets, HDAC1/2/3 and DNMT1, were expressed in normal esophageal epithelium and tumor cells of ESCC or EAC tissue specimens, as well as in non-neoplastic esophageal epithelial (Het-1A), ESCC (OE21, Kyse-270, Kyse-410), and EAC (OE33, SK-GT-4) cell lines. In vitro, HDAC activity, histone acetylation, and p21 expression were similarly affected in non-neoplastic, ESCC, and EAC cell lines post inhibitor treatment. Combined MS-275/AZA treatment, however, selectively targeted esophageal cancer cell lines by inducing DNA damage, cell viability loss, and apoptosis, and by decreasing cell migration. Non-neoplastic Het-1A cells were protected against HDACi (MS-275)/AZA treatment. RNA transcriptome analyses post MS-275 and/or AZA treatment identified novel regulated candidate genes (up: BCL6, Hes2; down: FAIM, MLKL), which were specifically associated with the treatment responses of esophageal cancer cells. In summary, combined HDACi/AZA treatment is efficient and selective for the targeting of esophageal cancer cells, despite similar target expression of normal and esophageal cancer epithelium, in vitro and in human esophageal carcinomas. The precise mechanisms of action of treatment responses involve novel candidate genes regulated by HDACi/AZA in esophageal cancer cells. Together, targeting of epigenetic modifiers in esophageal cancers may represent a potential future therapeutic approach.
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Key Words
- 5mC, 5-methylcytidine
- AZA, Azacytidine
- DAC, Decitabine
- DNMT, DNA (cytosine-5)-methyltransferase
- EAC, esophageal adenocarcinoma
- ESCC, esophageal squamous cell carcinoma
- FAIM, Fas apoptotic inhibitory molecule
- GEJ, gastro-esophageal junction
- H3Ac, histone H3 acetylation
- H3K4me3, histone H3 trimethylation at lysine 4
- H3K9Ac, histone 3 lysine 9 acetylation
- HDAC, histone deacetylases
- HDACi, HDAC inhibitor
- Hes-2, Hairy and enhancer of split 2
- SAHA, suberoylanilide hydroxamic acid
- TSA, Trichostatin A
- azacytidine/gene pathway regulation
- epigenetics/HDAC inhibitor
- esophageal cancer
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Affiliation(s)
- Theresa D Ahrens
- a Dept. of Pathology; University Medical Center ; Freiburg , Germany
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27
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Ge GZ, Xu TR, Chen C. Tobacco carcinogen NNK-induced lung cancer animal models and associated carcinogenic mechanisms. Acta Biochim Biophys Sin (Shanghai) 2015; 47:477-87. [PMID: 26040315 DOI: 10.1093/abbs/gmv041] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2015] [Accepted: 02/11/2015] [Indexed: 12/18/2022] Open
Abstract
Tobacco usage is a major risk factor in the development, progression, and outcomes for lung cancer. Of the carcinogens associated with lung cancer, tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is among the most potent ones. The oncogenic mechanisms of NNK are not entirely understood, hindering the development of effective strategies for preventing and treating smoking-associated lung cancers. Here, we introduce the NNK-induced lung cancer animal models in different species and its potential mechanisms. Finally, we summarize several chemopreventive agents developed from these animal models.
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Affiliation(s)
- Guang-Zhe Ge
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China
| | - Tian-Rui Xu
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China
| | - Ceshi Chen
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China
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28
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Yang H, Zhou T, Wang H, Liu T, Ueda K, Zhan R, Zhao L, Tong Y, Tian X, Zhang T, Jin Y, Han X, Li Z, Zhao Y, Guo X, Xiao W, Fan D, Liu G, Chui D. Lipoprotein lipase deficiency leads to α-synuclein aggregation and ubiquitin C-terminal hydrolase L1 reduction. Neuroscience 2015; 290:1-10. [DOI: 10.1016/j.neuroscience.2014.12.068] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Revised: 12/29/2014] [Accepted: 12/30/2014] [Indexed: 10/24/2022]
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29
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Kailasam A, Mittal SK, Agrawal DK. Epigenetics in the Pathogenesis of Esophageal Adenocarcinoma. Clin Transl Sci 2014; 8:394-402. [PMID: 25388215 DOI: 10.1111/cts.12242] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Epigenetic influences, such as DNA methylation, histone acetylation, and up-regulation/down-regulation of genes by microRNAs, change the genetic makeup of an individual without affecting DNA base-pair sequences. Indeed, epigenetic changes play an integral role in the progression from normal esophageal mucosa to Barrett's esophagus to esophageal adenocarcinoma via dysplasia-metaplasia-neoplasia sequence. Many genes involved in esophageal adenocarcinoma display hypermethylation, leading to their down-regulation. The classes of these genes include cell cycle control, DNA and growth factor repair, tumor suppressors, antimetastasis, Wnt-related genes, and proapoptotic genes. Histone acetylation in the pathophysiology of esophageal diseases has not been thoroughly investigated, and its critical role in the development of esophageal adenocarcinoma is less defined. Many microRNAs have been associated with the development of Barrett's esophagus and esophageal adenocarcinoma. Here, we critically addressed the specific steps most closely influenced by microRNAs in the progression from Barrett's esophagus to esophageal adenocarcinoma. However, microRNAs can target up to hundreds of genes, making it difficult to correlate directly with a given phenotype of the disease. Esophageal adenocarcinoma progressing from premalignant condition of Barrett's esophagus carries an extremely poor prognosis. Risk stratification for patients based on their epigenetic profiles may be useful in providing more targeted and directed treatment to patients.
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Affiliation(s)
- Aparna Kailasam
- School of Medicine, Center for Clinical & Translational Science, Creighton University, Omaha, NE, USA
| | - Sumeet K Mittal
- School of Medicine, Center for Clinical & Translational Science, Creighton University, Omaha, NE, USA
| | - Devendra K Agrawal
- School of Medicine, Center for Clinical & Translational Science, Creighton University, Omaha, NE, USA
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30
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p16 hypermethylation: A biomarker for increased esophageal cancer susceptibility in high incidence region of North East India. Tumour Biol 2014; 36:1627-42. [DOI: 10.1007/s13277-014-2762-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Accepted: 10/22/2014] [Indexed: 10/24/2022] Open
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31
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Interplay among epigenetic alterations and crosstalk between genetic and epigenetic alterations in esophageal squamous cell carcinoma. Esophagus 2014. [DOI: 10.1007/s10388-014-0431-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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32
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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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33
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Sun X, Qiu JJ, Zhu S, Cao B, Sun L, Li S, Li P, Zhang S, Dong S. Oncogenic features of PHF8 histone demethylase in esophageal squamous cell carcinoma. PLoS One 2013; 8:e77353. [PMID: 24146981 PMCID: PMC3795633 DOI: 10.1371/journal.pone.0077353] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2013] [Accepted: 08/30/2013] [Indexed: 12/23/2022] Open
Abstract
Esophageal cancer is the sixth leading cause of cancer-related deaths worldwide. It has been reported that histone demethylases are involved in the carcinogenesis of certain types of tumors. Here, we studied the role of one of the histone lysine demethylases, plant homeodomain finger protein 8 (PHF8), in the carcinogenesis of esophageal squamous cell carcinoma (ESCC). Using short hairpin RNA via lentiviral infection, we established stable ESCC cell lines with constitutive downregulation of PHF8 expression. Knockdown of PHF8 in ESCC cells resulted in inhibition of cell proliferation and an increase of apoptosis. Moreover, there were reductions of both anchorage-dependent and -independent colony formation. In vitro migration and invasion assays showed that knockdown of PHF8 led to a reduction in the number of migratory and invasive cells. Furthermore, downregulation of PHF8 attenuated the tumorigenicity of ESCC cells in vivo. Taken together, our study revealed the oncogenic features of PHF8 in ESCC, suggesting that PHF8 may be a potential diagnostic marker and therapeutic target for ESCC.
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Affiliation(s)
- Xiujing Sun
- Department of Medicine and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, United States of America
- Department of Gastroenterology, Beijing Friendship Hospital Affiliated to Capital Medical University, Beijing, China
| | - Jihui Julia Qiu
- Department of Medicine and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, United States of America
- Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America
| | - Shengtao Zhu
- Department of Gastroenterology, Beijing Friendship Hospital Affiliated to Capital Medical University, Beijing, China
| | - Bangwei Cao
- Department of Oncology, Beijing Friendship Hospital Affiliated to Capital Medical University, Beijing, China
| | - Lin Sun
- Department of Medicine and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, United States of America
| | - Sen Li
- Department of Medicine and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, United States of America
| | - Peng Li
- Department of Gastroenterology, Beijing Friendship Hospital Affiliated to Capital Medical University, Beijing, China
| | - Shutian Zhang
- Department of Gastroenterology, Beijing Friendship Hospital Affiliated to Capital Medical University, Beijing, China
| | - Shuo Dong
- Department of Medicine and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, United States of America
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Wang J, Zhao SL, Li Y, Meng M, Qin CY. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone induces retinoic acid receptor β hypermethylation through DNA methyltransferase 1 accumulation in esophageal squamous epithelial cells. Asian Pac J Cancer Prev 2013; 13:2207-12. [PMID: 22901195 DOI: 10.7314/apjcp.2012.13.5.2207] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Overexpression of DNA methyltransferase 1 (DNMT1) has been detected in many cancers. Tobacco exposure is known to induce genetic and epigenetic changes in the pathogenesis of malignancy. 4-(Methylnitrosamino)- 1-(3-pyridyl)-1-butanone (NNK) is an important carcinogen present in tobacco smoke; however the detailed molecular mechanism of how NNK induces esophageal carcinogenesis is still unclear. We found that DNMT1 was overexpressed in ESCC tissues compared with paired non-cancerous tissues, the overexpression being correlated with smoking status and low expression of RARβ. The latter could be upregulated by NNK treatment in Het-1A cells, and the increased DNMT1 expression level reflected promoter hypermethylation and downregulation of retinoic acid receptor β (RARβ). RNA interference mediated knockdown of DNMT1 resulted in promoter demethylation and upregulation of RARβ in KYSE30 and TE-1 cells. 3-(4,5-Dimethyl-thiazol-2yl)- 2,5-diphenyltetrazolium bromide (MTT) and flow cytometric analysis demonstrated that NNK treatment in Het- 1A cells could enhance cell proliferation and inhibit cell apoptosis in a dose-dependent manner. In conclusion, DNMT1 overexpression is correlated with smoking status and low expression of RARβ in esophageal SCC patients. NNK could induce RARβ promoter hypermethylation through upregulation of DNMT1 in esophageal squamous epithelial cells, finally leading to enhancement of cell proliferation and inhibition of apoptosis.
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Affiliation(s)
- Jing Wang
- Department of Gastroenterology, Provincial Hospital Affiliated to Shandong University, Jinan, China
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