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1
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Jeong SJ, Lee KH, Cho JY. Comparative epigenomics to clinical trials in human breast cancer and canine mammary tumor. Anim Cells Syst (Seoul) 2025; 29:12-30. [PMID: 40115961 PMCID: PMC11924266 DOI: 10.1080/19768354.2025.2477024] [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: 01/17/2025] [Revised: 02/09/2025] [Accepted: 02/12/2025] [Indexed: 03/23/2025] Open
Abstract
Epigenetics and epigenomics are captivating fields of molecular biology, dedicated to the exploration of heritable alterations in gene expression and cellular phenotypes, which transpire devoid of any discernible modifications to the fundamental DNA sequence. This intricate regulatory apparatus encompasses multiple mechanisms, prominently featuring DNA methylation, histone modifications, and the involvement of non-coding RNA molecules in pivotal roles. To achieve a comprehensive grasp of these diverse mechanisms, it is imperative to conduct research employing animal models as proxies for human studies. Since experimental animal models like mice and rats struggle to replicate the diverse environmental conditions experienced by humans, this review focuses on comparing common epigenetic alterations in naturally occurring tumors in canine models, which share the human environment, with those in humans. Through this, we emphasize the importance of an epigenetic regulation in the comparative medical approach to a deeper understanding of cancers and further development of cancer treatments. Additionally, we elucidate epigenetic modifications pertinent to specific developmental stages, the ageing process, and the progression of various diseases.
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Affiliation(s)
- Su-Jin Jeong
- Department of Biochemistry, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 PLUS Program for Creative Veterinary Science, Seoul National University, Seoul, Republic of Korea
- Comparative Medicine Disease Research Center, Seoul National University, Seoul, Republic of Korea
| | - Kang-Hoon Lee
- Department of Biochemistry, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 PLUS Program for Creative Veterinary Science, Seoul National University, Seoul, Republic of Korea
- Comparative Medicine Disease Research Center, Seoul National University, Seoul, Republic of Korea
| | - Je-Yoel Cho
- Department of Biochemistry, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 PLUS Program for Creative Veterinary Science, Seoul National University, Seoul, Republic of Korea
- Comparative Medicine Disease Research Center, Seoul National University, Seoul, Republic of Korea
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2
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Zhang P, Zhang Z, Wang Y, Du W, Song X, Lai W, Wang H, Zhu B, Xiong J. A CRISPR-Cas9 screen reveals genetic determinants of the cellular response to decitabine. EMBO Rep 2025; 26:1528-1565. [PMID: 39930152 PMCID: PMC11933316 DOI: 10.1038/s44319-025-00385-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Revised: 01/27/2025] [Accepted: 01/28/2025] [Indexed: 03/26/2025] Open
Abstract
Decitabine (DAC), a well-recognized DNA hypomethylating agent, has been applied to treat acute myeloid leukemia. However, clinic investigations revealed that DNA methylation reduction does not correlate with a clinical response, and relapse is prevalent. To gain a better understanding of its anti-tumor mechanism, we perform a temporally resolved CRISPR-Cas9 screen to identify factors governing the DAC response. We show that DNA damage generated by DNMT-DNA adducts and 5-aza-dUTP misincorporation through the dCMP deaminase DCTD act as drivers of DAC-induced acute cytotoxicity. The DNA damage that arises during the next S phase is dependent on DNA replication, unveiling a trans-cell cycle effect of DAC on genome stability. By exploring candidates for synthetic lethality, we unexpectedly uncover that KDM1A promotes survival after DAC treatment through interactions with ZMYM3 and CoREST, independent of its demethylase activity or regulation of viral mimicry. These findings emphasize the importance of DNA repair pathways in DAC response and provide potential biomarkers.
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Affiliation(s)
- Pinqi Zhang
- State Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Zhuqiang Zhang
- State Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Yiyi Wang
- State Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Wenlong Du
- State Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Xingrui Song
- The State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China
| | - Weiyi Lai
- The State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China
| | - Hailin Wang
- The State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China
| | - Bing Zhu
- State Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China.
- New Cornerstone Science Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Jun Xiong
- State Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
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Garb BF, Mohebbi E, Lawas M, Xia S, Maag G, Ahn PH, D’Silva NJ, Rozek LS, Sartor MA. Risk Stratification in HPV-Associated Oropharyngeal Cancer: Limitations of Current Approaches and the Search for Better Solutions. Cancers (Basel) 2025; 17:357. [PMID: 39941727 PMCID: PMC11816258 DOI: 10.3390/cancers17030357] [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: 12/23/2024] [Revised: 01/06/2025] [Accepted: 01/10/2025] [Indexed: 02/16/2025] Open
Abstract
The rising incidence of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) necessitates advancements in risk stratification to optimize treatment outcomes and improve the quality of life for patients. Despite its favorable prognosis compared to HPV-negative OPSCC, current clinical staging and biomarkers, such as p16 status, are limited in their ability to distinguish between high- and low-risk patients within HPV-associated OPSCC. This limitation results in the overtreatment of low-risk patients, exposing them to unnecessary toxicity, and the undertreatment of high-risk patients who require more aggressive interventions. This review critically evaluates current stratification methods, including clinical assessments, de-escalation trials, and candidate molecular biomarkers for risk stratification. Emerging approaches such as immune markers, viral genomic integration patterns, and other molecular markers offer promising avenues for enhanced prognostic accuracy. By integrating advanced risk stratification methods, tailored treatment approaches may one day be developed to balance oncologic efficacy with reduced treatment-related morbidity. This review underscores the need for continued research into predictive biomarkers and adaptive treatment strategies to better address the diverse risk profiles of HPV-associated OPSCC patients.
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Affiliation(s)
- Bailey Fabiny Garb
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA; (B.F.G.)
| | - Elham Mohebbi
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA (L.S.R.)
| | - Maria Lawas
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA; (B.F.G.)
| | - Shaomiao Xia
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA; (B.F.G.)
| | - Garett Maag
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA; (B.F.G.)
| | - Peter H. Ahn
- Department of Radiation Oncology, MedStar Georgetown University Hospital, Washington, DC 20007, USA
| | - Nisha J. D’Silva
- Department of Periodontics and Oral Medicine, University of Michigan, Ann Arbor, MI 48019, USA;
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
| | - Laura S. Rozek
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA (L.S.R.)
| | - Maureen A. Sartor
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA; (B.F.G.)
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
- Biostatistics Department, University of Michigan, Ann Arbor, MI 48109, USA
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4
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Hsieh HH, Kuo MZ, Chen IA, Lin CJ, Hsu V, HuangFu WC, Wu TY. Epigenetic Modifications as Novel Therapeutic Strategies of Cancer Chemoprevention by Phytochemicals. Pharm Res 2025; 42:69-78. [PMID: 39775615 DOI: 10.1007/s11095-024-03810-2] [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: 09/23/2024] [Accepted: 12/17/2024] [Indexed: 01/11/2025]
Abstract
PURPOSE Epigenetic modifications, such as aberrant DNA methylation, histone alterations, non-coding RNA remodeling, and modulation of transcription factors, are pivotal in the pathogenesis of diverse malignancies. Reactive oxygen species (ROS) have the capacity to impact these epigenetic mechanisms, including DNA methylation, throughout the different stages of cancer development. Therefore, the aim of this review is to address the impact of. METHODS Published papers were searched in Pubmed and Google Scholar databases using the keywords "epigenetic", or "DNA methylation", or "phytochemicals", or "chemoprevention" to prepare this review. RESULTS There is mounting evidence indicating that diminishing ROS accumulation within cells can regulate the function of DNA methyltransferases (DNMTs). Moreover, activation of the cellular defense system can impede and potentially reverse the progression of tumors in cancerous cells. As a result, ROS scavengers, antioxidants, and demethylating agents have emerged as potential therapeutic approaches for specific types of cancer. Additionally, dietary phytochemicals present in fruits, vegetables, and herbs, which have been utilized for centuries, exhibit the capability to modulate transcription factors, decrease inflammation, deliver antioxidant benefits, induce cell-cycle arrest, and stimulate apoptosis. CONCLUSION These phytochemicals can also renew and reprogram the expression of genes that suppress cancer. Thus, prolonged exposure to phytochemicals at low doses represents an innovative therapeutic tactic for the prevention of cancer.
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Affiliation(s)
- Hui-Hsia Hsieh
- Department of Pharmacy, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung City, Taiwan
- School of Pharmacy, China Medical University, Taichung City, Taiwan
| | - Min-Zhan Kuo
- Institute of Molecular Medicine and Shanghai Key Laboratory for Nucleic Acid Chemistry and Nanomedicine, State Key Laboratory of Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - I-An Chen
- Department of English, National Taichung University of Education, Taichung City, Taiwan
| | - Chien-Ju Lin
- School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung City, Taiwan
| | - Victor Hsu
- Bergen County Academies, Hackensack, NJ, USA
| | - Wei-Chun HuangFu
- Graduate Institute of Cancer Biology and Drug Development, College of Medical Science and Technology, Taipei Medical University, Taipei City, Taiwan.
| | - Tien-Yuan Wu
- School of Pharmacy, Taipei Medical University, Taipei City, Taiwan.
- Department of Pharmacy, Wan Fang Hospital, Taipei Medical University, Taipei City, Taiwan.
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5
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Shen S, Zhuang H. Homoharringtonine in the treatment of acute myeloid leukemia: A review. Medicine (Baltimore) 2024; 103:e40380. [PMID: 39496012 PMCID: PMC11537654 DOI: 10.1097/md.0000000000040380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Accepted: 10/16/2024] [Indexed: 11/06/2024] Open
Abstract
Acute myeloid leukemia (AML) is a hematological malignancy characterized by the accumulation of immature myeloid precursor cells. Over half of AML patients fail to achieve long-term disease-free survival under existing therapy, and the overall prognosis is poor, necessitating the urgent development of novel therapeutic approaches. The plant alkaloid homoharringtonine (HHT), which has anticancer properties, was first identified more than 40 years ago. It works in a novel method of action that prevents the early elongation phase of protein synthesis. HHT has been widely utilized in the treatment of AML, with strong therapeutic effects, few toxic side effects, and the ability to enhance AML patients' prognoses. In AML, HHT can induce cell apoptosis through multiple pathways, exerting synergistic antitumor effects, according to clinical and pharmacological research. About its modes of action, some findings have been made recently. This paper reviews the development of research on the mechanisms of HHT in treating AML to offer insights for further research and clinical therapy.
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Affiliation(s)
- Siyu Shen
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, P.R. China
| | - Haifeng Zhuang
- Department of Clinical Hematology and Transfusion, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, P.R. China
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El Nachef L, Bouchet A, Bourguignon M, Foray N. When DNA Mutations Interplay with Cellular Proliferation: A Narrative History of Theories of Carcinogenesis. Cancers (Basel) 2024; 16:2104. [PMID: 38893223 PMCID: PMC11171183 DOI: 10.3390/cancers16112104] [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: 04/13/2024] [Revised: 05/14/2024] [Accepted: 05/29/2024] [Indexed: 06/21/2024] Open
Abstract
While cancer is one of the most documented diseases, how normal cells become cancerous is still debated. To address this question, in the first part of this review, we investigated the long succession of theories of carcinogenesis since antiquity. Initiated by Hippocrates, Aristotle, and Galen, the humoral theory interpreted cancer as an excess of acid, the black bile. The discovery of the circulation of blood by Harvey in 1628 destroyed the basis of the humoral theory but revived the spontaneous generation hypothesis which was also promoted by Aristotle. In 1859, the theory of microbes promoted by Pasteur demonstrated the irrelevance of this last theory and contributed to the emergence of the germ cancer theory, opposed to the cellular theory of cancer, in which cancer was supposed to be caused by microbes or transformed cells, respectively. These theories were progressively refined by the notions of initiation, promotion, and progression thanks to advances in mutagenesis and cellular proliferation. In the second part of this review, recent discoveries and paradigms in carcinogenesis, notably the role of the protein ATM, a major actor of the stress response involved in both mutagenesis and cellular proliferation, were discussed to better understand the current state of the art of carcinogenesis.
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Affiliation(s)
- Laura El Nachef
- Inserm U1296 Unit, “Radiation: Defense, Health and Environment”, 28 Rue Laennec, 69008 Lyon, France; (L.E.N.); (A.B.); (M.B.)
| | - Audrey Bouchet
- Inserm U1296 Unit, “Radiation: Defense, Health and Environment”, 28 Rue Laennec, 69008 Lyon, France; (L.E.N.); (A.B.); (M.B.)
| | - Michel Bourguignon
- Inserm U1296 Unit, “Radiation: Defense, Health and Environment”, 28 Rue Laennec, 69008 Lyon, France; (L.E.N.); (A.B.); (M.B.)
- Département de Biophysique et Médecine Nucléaire, Université Paris Saclay, Versailles St. Quentin-en-Yvelines, 78035 Versailles, France
| | - Nicolas Foray
- Inserm U1296 Unit, “Radiation: Defense, Health and Environment”, 28 Rue Laennec, 69008 Lyon, France; (L.E.N.); (A.B.); (M.B.)
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Ishidoya M, Fujita T, Tasaka S, Fujii H. Real-time MBDi-RPA using methyl-CpG binding protein 2: A real-time detection method for simple and rapid estimation of CpG methylation status. Anal Chim Acta 2024; 1302:342486. [PMID: 38580404 DOI: 10.1016/j.aca.2024.342486] [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: 11/17/2023] [Revised: 02/21/2024] [Accepted: 03/14/2024] [Indexed: 04/07/2024]
Abstract
BACKGROUND Analysis of CpG methylation is informative for cancer diagnosis. Previously, we developed a novel method to discriminate CpG methylation status in target DNA by blocking recombinase polymerase amplification (RPA), an isothermal DNA amplification technique, using methyl-CpG binding domain (MBD) protein 2 (MBD2). The method was named MBD protein interference-RPA (MBDi-RPA). In this study, MBDi-RPA was performed using methyl-CpG binding protein 2 (MeCP2), another MBD family protein, as the blocking agent. RESULTS MBDi-RPA using MeCP2 detected low levels of CpG methylation, showing that it had higher sensitivity than MBDi-RPA using MBD2. We also developed real-time RPA, which enabled rapid analysis of DNA amplification without the need for laborious agarose gel electrophoresis and used it in combination with MBDi-RPA. We termed this method real-time MBDi-RPA. The method using MeCP2 could determine the abundance ratio of CpG-methylated target DNA simply and rapidly, although highly sensitive detection was challenging. SIGNIFICANCE AND NOVELTY Real-time MBDi-RPA using MeCP2 could be potentially useful for estimating CpG methylation status in target DNA prior to more detailed analyses.
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Affiliation(s)
- Mina Ishidoya
- Department of Respiratory Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan
| | - Toshitsugu Fujita
- Department of Biochemistry and Genome Biology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan.
| | - Sadatomo Tasaka
- Department of Respiratory Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan
| | - Hodaka Fujii
- Department of Biochemistry and Genome Biology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan
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Lopes SR, Martins C, Santos IC, Teixeira M, Gamito É, Alves AL. Colorectal cancer screening: A review of current knowledge and progress in research. World J Gastrointest Oncol 2024; 16:1119-1133. [PMID: 38660635 PMCID: PMC11037045 DOI: 10.4251/wjgo.v16.i4.1119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 01/16/2024] [Accepted: 02/18/2024] [Indexed: 04/10/2024] Open
Abstract
Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide, being the third most commonly diagnosed malignancy and the second leading cause of cancer-related deaths globally. Despite the progress in screening, early diagnosis, and treatment, approximately 20%-25% of CRC patients still present with metastatic disease at the time of their initial diagnosis. Furthermore, the burden of disease is still expected to increase, especially in individuals younger than 50 years old, among whom early-onset CRC incidence has been increasing. Screening and early detection are pivotal to improve CRC-related outcomes. It is well established that CRC screening not only reduces incidence, but also decreases deaths from CRC. Diverse screening strategies have proven effective in decreasing both CRC incidence and mortality, though variations in efficacy have been reported across the literature. However, uncertainties persist regarding the optimal screening method, age intervals and periodicity. Moreover, adherence to CRC screening remains globally low. In recent years, emerging technologies, notably artificial intelligence, and non-invasive biomarkers, have been developed to overcome these barriers. However, controversy exists over the actual impact of some of the new discoveries on CRC-related outcomes and how to effectively integrate them into daily practice. In this review, we aim to cover the current evidence surrounding CRC screening. We will further critically assess novel approaches under investigation, in an effort to differentiate promising innovations from mere novelties.
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Affiliation(s)
- Sara Ramos Lopes
- Department of Gastroenterology, Centro Hospitalar de Setúbal, Setúbal 2910-446, Portugal
| | - Claudio Martins
- Department of Gastroenterology, Centro Hospitalar de Setúbal, Setúbal 2910-446, Portugal
| | - Inês Costa Santos
- Department of Gastroenterology, Centro Hospitalar de Setúbal, Setúbal 2910-446, Portugal
| | - Madalena Teixeira
- Department of Gastroenterology, Centro Hospitalar de Setúbal, Setúbal 2910-446, Portugal
| | - Élia Gamito
- Department of Gastroenterology, Centro Hospitalar de Setúbal, Setúbal 2910-446, Portugal
| | - Ana Luisa Alves
- Department of Gastroenterology, Centro Hospitalar de Setúbal, Setúbal 2910-446, Portugal
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Qi YC, Bai H, Hu SL, Li SJ, Li QZ. Coregulatory effects of multiple histone modifications in key ferroptosis-related genes for lung adenocarcinoma. Epigenomics 2024; 16:609-633. [PMID: 38511238 PMCID: PMC11160448 DOI: 10.2217/epi-2023-0403] [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: 11/18/2023] [Accepted: 02/22/2024] [Indexed: 03/22/2024] Open
Abstract
Aim: The present study was designed to investigate the coregulatory effects of multiple histone modifications (HMs) on gene expression in lung adenocarcinoma (LUAD). Materials & methods: Ten histones for LUAD were analyzed using ChIP-seq and RNA-seq data. An innovative computational method is proposed to quantify the coregulatory effects of multiple HMs on gene expression to identify strong coregulatory genes and regions. This method was applied to explore the coregulatory mechanisms of key ferroptosis-related genes in LUAD. Results: Nine strong coregulatory regions were identified for six ferroptosis-related genes with diverse coregulatory patterns (CA9, PGD, CDKN2A, PML, OTUB1 and NFE2L2). Conclusion: This quantitative method could be used to identify important HM coregulatory genes and regions that may be epigenetic regulatory targets in cancers.
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Affiliation(s)
- Ye-Chen Qi
- Laboratory of Theoretical Biophysics, School of Physical Science & Technology, Inner Mongolia University, Hohhot, 010021, China
| | - Hui Bai
- Laboratory of Theoretical Biophysics, School of Physical Science & Technology, Inner Mongolia University, Hohhot, 010021, China
| | - Si-Le Hu
- Laboratory of Theoretical Biophysics, School of Physical Science & Technology, Inner Mongolia University, Hohhot, 010021, China
| | - Shu-Juan Li
- Laboratory of Theoretical Biophysics, School of Physical Science & Technology, Inner Mongolia University, Hohhot, 010021, China
| | - Qian-Zhong Li
- Laboratory of Theoretical Biophysics, School of Physical Science & Technology, Inner Mongolia University, Hohhot, 010021, China
- The State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, Inner Mongolia University, Hohhot, 010070, China
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Rivera-Peña B, Folawiyo O, Turaga N, Rodríguez-Benítez RJ, Felici ME, Aponte-Ortiz JA, Pirini F, Rodríguez-Torres S, Vázquez R, López R, Sidransky D, Guerrero-Preston R, Báez A. Promoter DNA methylation patterns in oral, laryngeal and oropharyngeal anatomical regions are associated with tumor differentiation, nodal involvement and survival. Oncol Lett 2024; 27:89. [PMID: 38268779 PMCID: PMC10804364 DOI: 10.3892/ol.2024.14223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Accepted: 11/23/2023] [Indexed: 01/26/2024] Open
Abstract
Differentially methylated regions (DMRs) can be used as head and neck squamous cell carcinoma (HNSCC) diagnostic, prognostic and therapeutic targets in precision medicine workflows. DNA from 21 HNSCC and 10 healthy oral tissue samples was hybridized to a genome-wide tiling array to identify DMRs in a discovery cohort. Downstream analyses identified differences in promoter DNA methylation patterns in oral, laryngeal and oropharyngeal anatomical regions associated with tumor differentiation, nodal involvement and survival. Genome-wide DMR analysis showed 2,565 DMRs common to the three subsites. A total of 738 DMRs were unique to laryngeal cancer (n=7), 889 DMRs were unique to oral cavity cancer (n=10) and 363 DMRs were unique to pharyngeal cancer (n=6). Based on the genome-wide analysis and a Gene Ontology analysis, 10 candidate genes were selected to test for prognostic value and association with clinicopathological features. TIMP3 was associated with tumor differentiation in oral cavity cancer (P=0.039), DAPK1 was associated with nodal involvement in pharyngeal cancer (P=0.017) and PAX1 was associated with tumor differentiation in laryngeal cancer (P=0.040). A total of five candidate genes were selected, DAPK1, CDH1, PAX1, CALCA and TIMP3, for a prevalence study in a larger validation cohort: Oral cavity cancer samples (n=42), pharyngeal cancer tissues (n=25) and laryngeal cancer samples (n=52). PAX1 hypermethylation differed across HNSCC anatomic subsites (P=0.029), and was predominantly detected in laryngeal cancer. Kaplan-Meier survival analysis (P=0.043) and Cox regression analysis of overall survival (P=0.001) showed that DAPK1 methylation is associated with better prognosis in HNSCC. The findings of the present study showed that the HNSCC subsites oral cavity, pharynx and larynx display substantial differences in aberrant DNA methylation patterns, which may serve as prognostic biomarkers and therapeutic targets.
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Affiliation(s)
- Bianca Rivera-Peña
- Department of Biology, University of Puerto Rico, San Juan 00925, Puerto Rico
- Department of Pharmacology, University of Puerto Rico School of Medicine, San Juan 00936, Puerto Rico
- Department of Otolaryngology-Head and Neck Surgery, University of Puerto Rico School of Medicine, San Juan 00936, Puerto Rico
| | - Oluwasina Folawiyo
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Nitesh Turaga
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Rosa J. Rodríguez-Benítez
- Department of General Social Sciences, Faculty of Social Sciences, University of Puerto Rico, San Juan 00925, Puerto Rico
| | - Marcos E. Felici
- Oral Health Division, Puerto Rico Department of Health, San Juan 00927, Puerto Rico
| | - Jaime A. Aponte-Ortiz
- Department of General Surgery, University of Puerto Rico School of Medicine, San Juan 00936, Puerto Rico
| | - Francesca Pirini
- Biosciences Laboratory, IRCCS Instituto Romagnolo per lo Studio dei Tumori ‘Dino Amadori’, Meldola I-47014, Italy
| | | | - Roger Vázquez
- Department of Biology, University of Puerto Rico, San Juan 00925, Puerto Rico
| | - Ricardo López
- Department of Biology, University of Puerto Rico, San Juan 00925, Puerto Rico
| | - David Sidransky
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Rafael Guerrero-Preston
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
- Department of Research and Development, LifeGene-Biomarks, San Juan 00909, Puerto Rico
| | - Adriana Báez
- Department of Pharmacology, University of Puerto Rico School of Medicine, San Juan 00936, Puerto Rico
- Department of Otolaryngology-Head and Neck Surgery, University of Puerto Rico School of Medicine, San Juan 00936, Puerto Rico
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Malavasi E, Adamo M, Zamprogno E, Vella V, Giamas G, Gagliano T. Decoding the Tumour Microenvironment: Molecular Players, Pathways, and Therapeutic Targets in Cancer Treatment. Cancers (Basel) 2024; 16:626. [PMID: 38339377 PMCID: PMC10854614 DOI: 10.3390/cancers16030626] [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: 11/23/2023] [Revised: 12/16/2023] [Accepted: 01/30/2024] [Indexed: 02/12/2024] Open
Abstract
The tumour microenvironment (TME) is a complex and constantly evolving collection of cells and extracellular components. Cancer cells and the surrounding environment influence each other through different types of processes. Characteristics of the TME include abnormal vasculature, altered extracellular matrix, cancer-associated fibroblast and macrophages, immune cells, and secreted factors. Within these components, several molecules and pathways are altered and take part in the support of the tumour. Epigenetic regulation, kinases, phosphatases, metabolic regulators, and hormones are some of the players that influence and contribute to shaping the tumour and the TME. All these characteristics contribute significantly to cancer progression, metastasis, and immune escape, and may be the target for new approaches for cancer treatment.
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Affiliation(s)
- Eleonora Malavasi
- Cancer Cell Signalling Laboratory, Department of Medicine, University of Udine, 33100 Udine, Italy; (E.M.); (M.A.); (E.Z.)
| | - Manuel Adamo
- Cancer Cell Signalling Laboratory, Department of Medicine, University of Udine, 33100 Udine, Italy; (E.M.); (M.A.); (E.Z.)
- School of Life Sciences, University of Sussex, Brighton BN1 9QG, UK;
| | - Elisa Zamprogno
- Cancer Cell Signalling Laboratory, Department of Medicine, University of Udine, 33100 Udine, Italy; (E.M.); (M.A.); (E.Z.)
| | - Viviana Vella
- School of Life Sciences, University of Sussex, Brighton BN1 9QG, UK;
| | - Georgios Giamas
- School of Life Sciences, University of Sussex, Brighton BN1 9QG, UK;
| | - Teresa Gagliano
- Cancer Cell Signalling Laboratory, Department of Medicine, University of Udine, 33100 Udine, Italy; (E.M.); (M.A.); (E.Z.)
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12
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Liu J, Huang B, Ding F, Li Y. Environment factors, DNA methylation, and cancer. ENVIRONMENTAL GEOCHEMISTRY AND HEALTH 2023; 45:7543-7568. [PMID: 37715840 DOI: 10.1007/s10653-023-01749-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 08/30/2023] [Indexed: 09/18/2023]
Abstract
Today, the rapid development of science and technology and the rapid change in economy and society are changing the way of life of human beings and affecting the natural, living, working, and internal environment on which human beings depend. At the same time, the global incidence of cancer has increased significantly yearly, and cancer has become the number one killer that threatens human health. Studies have shown that diet, living habits, residential environment, mental and psychological factors, intestinal flora, genetics, social factors, and viral and non-viral infections are closely related to human cancer. However, the molecular mechanisms of the environment and cancer development remain to be further explored. In recent years, DNA methylation has become a key hub and bridge for environmental and cancer research. Some environmental factors can alter the hyper/hypomethylation of human cancer suppressor gene promoters, proto-oncogene promoters, and the whole genome, causing low/high expression or gene mutation of related genes, thereby exerting oncogenic or anticancer effects. It is expected to develop early warning markers of cancer environment based on DNA methylation, thereby providing new methods for early detection of cancers, diagnosis, and targeted therapy. This review systematically expounds on the internal mechanism of environmental factors affecting cancer by changing DNA methylation, aiming to help establish the concept of cancer prevention and improve people's health.
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Affiliation(s)
- Jie Liu
- Department of General Surgery, Second Hospital of Lanzhou University, Lan Zhou, China
- Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lan Zhou, China
| | - Binjie Huang
- Department of General Surgery, Second Hospital of Lanzhou University, Lan Zhou, China
- Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lan Zhou, China
| | - Feifei Ding
- Department of General Surgery, Second Hospital of Lanzhou University, Lan Zhou, China
- Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lan Zhou, China
| | - Yumin Li
- Department of General Surgery, Second Hospital of Lanzhou University, Lan Zhou, China.
- Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lan Zhou, China.
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Su J, Song S, Dou Y, Jia X, Song S, Ding X. Methylation specific enzyme-linked oligonucleotide assays (MS-ELONA) for ultrasensitive DNA methylation analysis. Biosens Bioelectron 2023; 238:115587. [PMID: 37586263 DOI: 10.1016/j.bios.2023.115587] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 07/28/2023] [Accepted: 08/08/2023] [Indexed: 08/18/2023]
Abstract
Methylation of the promoter region of cancer related genes plays a crucial role in the occurrence and development of cancer, and the degree of methylation has great potential for the early cancer diagnosis. At present, the technology used to quantify DNA methylation is mainly based on the DNA sequencing which are time-consuming and high-cost in the relating application. We have developed an ultrasensitive method of methylation specific enzyme-linked oligonucleotide assays (MS-ELONA) to detect and quantify the level of DNA methylation. We could detect as little as 2 pg of methylated DNA in the 100000-fold excess of unmethylated genes, and discriminate prostate cancer from benign prostatic hyperplasia (BPH) and control with serum samples. We also demonstrate the reversibility of DNA methylation modification by treatment with demethylation drugs. With 16-channel electrochemical work station, our research reveals a simple and inexpensive method to quantify the methylation level of specially appointed genes, and have the potential to be applied in the clinical research.
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Affiliation(s)
- Jing Su
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China; State Key Laboratory of Oncogenes and Related Genes, Institute for Personalized Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800, China
| | - Shasha Song
- Pathology Department, Yantai Fushan People's Hospital, Yantai, China
| | - Yanzhi Dou
- Shanghai Institute of Microsystem and Information Technology, Chinse Academy of Sciences, Shanghai 200050, China
| | - Xiaolong Jia
- Department of Urology, The First Affiliated Hospital of Ningbo University, Liuting Street, Ningbo 315010, China
| | - Shiping Song
- Institute of Materiobiology, Department of Chemistry, College of Science, Shanghai University, Shanghai 200444, China; Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800, China.
| | - Xianting Ding
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China; State Key Laboratory of Oncogenes and Related Genes, Institute for Personalized Medicine, Shanghai Jiao Tong University, Shanghai, China.
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14
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Asari Y, Yamazaki J, Thandar O, Suzuki T, Aoshima K, Takeuchi K, Kinoshita R, Kim S, Hosoya K, Ishizaki T, Kagawa Y, Jelinek J, Yokoyama S, Sasaki N, Ohta H, Nakamura K, Takiguchi M. Diverse genome-wide DNA methylation alterations in canine hepatocellular tumours. Vet Med Sci 2023; 9:2006-2014. [PMID: 37483163 PMCID: PMC10508506 DOI: 10.1002/vms3.1204] [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: 07/24/2022] [Revised: 06/02/2023] [Accepted: 07/06/2023] [Indexed: 07/25/2023] Open
Abstract
BACKGROUND Canine hepatocellular tumours (HCTs) are common primary liver tumours. However, the exact mechanisms of tumourigenesis remain unclear. Although some genetic mutations have been reported, DNA methylation alterations in canine HCT have not been well studied. OBJECTIVES In this study, we aimed to analyse the DNA methylation status of canine HCT. METHODS Tissues from 33 hepatocellular carcinomas, 3 hepatocellular adenomas, 1 nodular hyperplasia, 21 non-tumour livers from the patients and normal livers from 5 healthy dogs were used. We analysed the DNA methylation levels of 72,367 cytosine-guanine dinucleotides (CpG sites) in all 63 samples. RESULTS AND CONCLUSIONS Although a large fraction of CpG sites that were highly methylated in the normal liver became hypomethylated in tumours from most patients, we also found some patients with less remarkable change or no change in DNA methylation. Hierarchical clustering analysis revealed that 32 of 37 tumour samples differed from normal livers, although the remaining 5 tumour livers fell into the same cluster as normal livers. In addition, the number of hypermethylated genes in tumour livers varied among tumour cases, suggesting various DNA methylation patterns in different tumour groups. However, patient and clinical parameters, such as age, were not associated with DNA methylation status. In conclusion, we found that HCTs undergo aberrant and diverse patterns of genome-wide DNA methylation compared with normal liver tissue, suggesting a complex epigenetic mechanism in canine HCT.
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Affiliation(s)
- Yu Asari
- Laboratory of Veterinary Internal Medicine, Graduate School of Veterinary MedicineHokkaido UniversitySapporoJapan
| | - Jumpei Yamazaki
- Veterinary Teaching HospitalGraduate School of Veterinary MedicineHokkaido UniversitySapporoJapan
- Translational Research Unit, Veterinary Teaching Hospital, Graduate School of Veterinary MedicineHokkaido UniversitySapporoJapan
- One Health Research Center, Cancer Research UnitHokkaido UniversitySapporoJapan
| | - Oo Thandar
- Laboratory of Veterinary Internal Medicine, Graduate School of Veterinary MedicineHokkaido UniversitySapporoJapan
| | - Tamami Suzuki
- Laboratory of Comparative Pathology, Graduate School of Veterinary MedicineHokkaido UniversitySapporoJapan
| | - Keisuke Aoshima
- One Health Research Center, Cancer Research UnitHokkaido UniversitySapporoJapan
- Laboratory of Comparative Pathology, Graduate School of Veterinary MedicineHokkaido UniversitySapporoJapan
| | - Kyosuke Takeuchi
- Veterinary Teaching HospitalGraduate School of Veterinary MedicineHokkaido UniversitySapporoJapan
| | - Ryohei Kinoshita
- Veterinary Teaching HospitalGraduate School of Veterinary MedicineHokkaido UniversitySapporoJapan
- One Health Research Center, Cancer Research UnitHokkaido UniversitySapporoJapan
| | - Sangho Kim
- One Health Research Center, Cancer Research UnitHokkaido UniversitySapporoJapan
- Laboratory of Veterinary Surgery, Graduate School of Veterinary MedicineHokkaido UniversitySapporoJapan
| | - Kenji Hosoya
- One Health Research Center, Cancer Research UnitHokkaido UniversitySapporoJapan
- Laboratory of Veterinary Surgery, Graduate School of Veterinary MedicineHokkaido UniversitySapporoJapan
| | - Teita Ishizaki
- Veterinary Teaching HospitalGraduate School of Veterinary MedicineHokkaido UniversitySapporoJapan
- Laboratory of Comparative Pathology, Graduate School of Veterinary MedicineHokkaido UniversitySapporoJapan
- North LabSapporoJapan
| | | | | | - Shoko Yokoyama
- Veterinary Teaching HospitalGraduate School of Veterinary MedicineHokkaido UniversitySapporoJapan
- Translational Research Unit, Veterinary Teaching Hospital, Graduate School of Veterinary MedicineHokkaido UniversitySapporoJapan
- One Health Research Center, Cancer Research UnitHokkaido UniversitySapporoJapan
| | - Noboru Sasaki
- Laboratory of Veterinary Internal Medicine, Graduate School of Veterinary MedicineHokkaido UniversitySapporoJapan
| | - Hiroshi Ohta
- Laboratory of Veterinary Internal Medicine, Graduate School of Veterinary MedicineHokkaido UniversitySapporoJapan
| | - Kensuke Nakamura
- Laboratory of Veterinary Internal Medicine, Graduate School of Veterinary MedicineHokkaido UniversitySapporoJapan
| | - Mitsuyoshi Takiguchi
- Laboratory of Veterinary Internal Medicine, Graduate School of Veterinary MedicineHokkaido UniversitySapporoJapan
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15
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Shahraki K, Shahraki K, Ghasemi Boroumand P, Sheervalilou R. Promotor methylation in ocular surface squamous neoplasia development: epigenetics implications in molecular diagnosis. Expert Rev Mol Diagn 2023; 23:753-769. [PMID: 37493058 DOI: 10.1080/14737159.2023.2240238] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Accepted: 07/20/2023] [Indexed: 07/27/2023]
Abstract
INTRODUCTION Cancer is heavily influenced by epigenetic mechanisms that include DNA methylation, histone modifications, and non-coding RNA. A considerable proportion of human malignancies are believed to be associated with global DNA hypomethylation, with localized hypermethylation at promoters of certain genes. AREA COVERED The present review aims to emphasize on recent investigations on the epigenetic landscape of ocular surface squamous neoplasia, that could be targeted/explored using novel approaches such as personalized medicine. EXPERT OPINION While the former is thought to contribute to genomic instability, promoter-specific hypermethylation might facilitate tumorigenesis by silencing tumor suppressor genes. Ocular surface squamous neoplasia, the most prevalent type of ocular surface malignancy, is suggested to be affected by epigenetic mechanisms, as well. Although the exact role of epigenetics in ocular surface squamous neoplasia has mostly been unexplored, recent findings have greatly contributed to our understanding regarding this pathology of the eye.
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Affiliation(s)
- Kourosh Shahraki
- Ocular Tissue Engineering Research Center, Ophthalmic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Ophthalmology, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Kianoush Shahraki
- Department of Ophthalmology, Zahedan University of Medical Sciences, Zahedan, Iran
- Cornea Department, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Paria Ghasemi Boroumand
- ENT, Head and Neck Research Center and Department, Iran University of Medical Science, Tehran, Iran
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Fujita M, Goto M, Tanaka M, Yoshida W. Detection of CpG methylation level using methyl-CpG-binding domain-fused fluorescent protein. ANALYTICAL METHODS : ADVANCING METHODS AND APPLICATIONS 2023; 15:2294-2299. [PMID: 37010025 DOI: 10.1039/d3ay00227f] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/19/2023]
Abstract
Methylation of cytosine to 5-methylcytosine on CpG dinucleotides is the most frequently studied epigenetic modification involved in the regulation of gene expression. In normal tissues, tissue-specific CpG methylation patterns are established during development. In contrast, alterations in methylation patterns have been observed in abnormal cells, such as cancer cells. Cancer type-specific CpG methylation patterns have been identified and used as biomarkers for cancer diagnosis. In this study, we developed a hybridization-based CpG methylation level sensing system using a methyl-CpG-binding domain (MBD)-fused fluorescent protein. In this system, the target DNA is captured by a complementary methylated probe DNA. When the target DNA is methylated, a symmetrically methylated CpG is formed in the double-stranded DNA. MBD specifically recognizes symmetrical methyl-CpG on double-stranded DNA; therefore, the methylation level is quantified by measuring the fluorescence intensity of the bound MBD-fused fluorescent protein. We prepared MBD-fused AcGFP1 and quantified the CpG methylation levels of the target DNA against SEPT9, BRCA1, and long interspersed nuclear element-1 (LINE-1) using MBD-AcGFP1. This detection principle can be applied to the simultaneous and genome-wide modified base detection systems using microarrays coupled with modified base binding proteins fused to fluorescent proteins.
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Affiliation(s)
- Marika Fujita
- Graduate School of Bionics, Tokyo University of Technology, 1404-1 Katakuramachi, Hachioji, Tokyo, 192-0982, Japan.
| | - Masanori Goto
- Graduate School of Bionics, Tokyo University of Technology, 1404-1 Katakuramachi, Hachioji, Tokyo, 192-0982, Japan.
| | - Masayoshi Tanaka
- Department of Chemical Science and Engineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa, 226-8503, Japan.
| | - Wataru Yoshida
- Graduate School of Bionics, Tokyo University of Technology, 1404-1 Katakuramachi, Hachioji, Tokyo, 192-0982, Japan.
- School of Bioscience and Biotechnology, Tokyo University of Technology, 1404-1 Katakuramachi, Hachioji, Tokyo, 192-0982, Japan
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17
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Chen Q, Xu Z, Lin J, Deng Z, Qian J, Qian W. The validation and clinical significance of LPCAT1 down-regulation in acute myeloid leukemia. Mol Biol Rep 2023; 50:4955-4963. [PMID: 37079124 DOI: 10.1007/s11033-023-08449-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 04/12/2023] [Indexed: 04/21/2023]
Abstract
BACKGROUND Overexpression of lysophosphatidylcholine acyltransferase 1 (LPCAT1) has been found in various solid cancers and is associated with disease progression, metastasis, and recurrence. However, the expression pattern of LPCAT1 in acute myeloid leukemia (AML) bone marrow remains unknown. The present study aimed to compare LPCAT1 expression differences in bone marrow samples from AML patients and healthy controls and assess the clinical relevance of LPCAT1 in AML. METHODS AND RESULTS LPCAT1 expression in bone marrow was significantly lower in AML than in healthy controls predicted by public databases. Furthermore, real-time quantitative PCR (RQ-PCR) validated that LPCAT1 expression in bone marrow was significantly down-regulated in AML compared to healthy controls [0.056 (0.000-0.846) vs 0.253 (0.031-1.000)]. The DiseaseMeth version 2.0 and The Cancer Genome Atlas analysis revealed that the LPCAT1 promoter was hypermethylated in AML, and there was a strong negative correlation between LPCAT1 expression and methylation (R = - 0.610, P < 0.001). RQ-PCR revealed that the frequency of LPCAT1 low expression was lower in the FAB-M4/M5 subtype than in the other subtypes (P = 0.018). The ROC curve revealed that LPCAT1 expression could serve as a potential diagnostic marker for differentiating AML from controls with an area under the ROC curve of 0.819 (95% CI 0.743-0.894, P < 0.001). In cytogenetically normal AML, patients with LPCAT1 low expression had significantly longer overall survival than those without LPCAT1 low expression (median 19 versus 5.5 months, P = 0.036). CONCLUSIONS LPCAT1 is down-regulated in AML bone marrow, and LPCAT1 down-regulation could be used as a potential biomarker for AML diagnosis and prognosis.
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Affiliation(s)
- Qin Chen
- Laboratory Center, Affiliated People's Hospital of Jiangsu University, Zhenjiang, People's Republic of China
| | - Zijun Xu
- Laboratory Center, Affiliated People's Hospital of Jiangsu University, Zhenjiang, People's Republic of China
| | - Jiang Lin
- Laboratory Center, Affiliated People's Hospital of Jiangsu University, Zhenjiang, People's Republic of China
| | - Zhaoqun Deng
- Laboratory Center, Affiliated People's Hospital of Jiangsu University, Zhenjiang, People's Republic of China
| | - Jun Qian
- Department of Hematology, Affiliated People's Hospital of Jiangsu University, Zhenjiang, People's Republic of China.
| | - Wei Qian
- Laboratory Center, Affiliated People's Hospital of Jiangsu University, Zhenjiang, People's Republic of China.
- Department of Otolaryngology-Head and Neck Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, People's Republic of China.
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18
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Feng S, Yang C, Wang J, Fan X, Ying X. Aggrephagy-related LncRNAs index: A predictor for HCC prognosis, immunotherapy efficacy, and chemosensitivity. Technol Health Care 2023:THC220738. [PMID: 36872811 DOI: 10.3233/thc-220738] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/06/2023]
Abstract
BACKGROUND Due to the complexity and heterogeneity of hepatocellular carcinoma, the existing clinical staging criterias are insufficient to accurately reflect the tumor microenvironment and predict the prognosis of HCC patients. Aggrephagy, as a type of selective autophagy, is associated with various phenotypes of malignant tumors. OBJECTIVE This study aimed to identify and validate a prognostic model based on aggrephagy-related LncRNAs to assess the prognosis and immunotherapeutic response of HCC patients. METHODS Based on the TCGA-LIHC cohort, aggrephagy-related LncRNAs were identified. Univariate Cox regression analysis and lasso and multivariate Cox regression were used to construct a risk-scoring system based on eight ARLs. CIBERSORT, ssGSEA, and other algorithms were used to evaluate and present the immune landscape of tumor microenvironment. RESULTS The high-risk group had a worse overall survival (OS) than the low-risk group. Patients in the high-risk group are more likely to benefit from immunotherapy because of their high infiltration level and high immune checkpoint expression. CONCLUSION The ARLs signature is a powerful predictor of prognosis for HCC patients, and the nomogram based on this model can help clinicians accurately determine the prognosis of HCC patients and screen for specific subgroups of patients who are more sensitive to immunotherapy and chemotherapy.
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Affiliation(s)
- Shengchun Feng
- Department of Clinical Laboratory, Jinhua Municipal Central Hospital, Jinhua, Zhejiang, China.,Department of Clinical Laboratory, Jinhua Municipal Central Hospital, Jinhua, Zhejiang, China
| | - Chunyan Yang
- Department of Ultrasound Medicine, Chongqing University Cancer Hospital, Chongqing, China.,Department of Clinical Laboratory, Jinhua Municipal Central Hospital, Jinhua, Zhejiang, China
| | - Jun Wang
- Department of Hepatopancreatobiliary Surgery, The People's Hospital of Lishui, Lishui, Zhejiang, China
| | - Xiaopeng Fan
- Department of Hepatopancreatobiliary Surgery, The People's Hospital of Lishui, Lishui, Zhejiang, China
| | - Xiaowei Ying
- Department of Hepatopancreatobiliary Surgery, The People's Hospital of Lishui, Lishui, Zhejiang, China
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Miyata T, Shimamura H, Asano R, Yoshida W. Universal Design of Luciferase Fusion Proteins for Epigenetic Modifications Detection Based on Bioluminescence Resonance Energy Transfer. Anal Chem 2023; 95:3799-3805. [PMID: 36748925 DOI: 10.1021/acs.analchem.2c05066] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Global hypomethylation and promoter hypermethylation of tumor-suppressor genes are the hallmarks of cancer. We previously reported a global DNA methylation level sensing system based on dual-color bioluminescence resonance energy transfer (BRET) using methyl-CpG binding domain (MBD)-fused firefly luciferase (Fluc) and unmethyl-CpG binding domain (CXXC)-fused Oplophorus luciferase (Oluc). Moreover, BRET-based hydroxymethylation and hemi-methylation level sensing systems have been developed using hydroxymethyl-CpG and hemi-methyl-CpG binding domain-fused Fluc. These studies suggest that target epigenetic modifications can be simultaneously quantified using target-modification-binding protein-fused luciferases. In this study, we focused on the SnoopTag (SnT)/SnoopCatcher (SnC) protein ligation system to establish a universal design for fusion protein construction for any combination. SnT spontaneously forms an isopeptide bond with SnC; therefore, any kind of fusion protein would be constructed by the SnT/SnC system. To establish the proof of concept, MBD-SnT, CXXC-SnT, and SnC-Oluc were prepared and ligated MBD-SnT or CXXC-SnT to SnC-Oluc. The ligation products of MBD-SnT-SnC-Oluc and CXXC-SnT-SnC-Oluc showed luciferase activity and specific binding activity to methyl-CpG and unmethyl-CpG, respectively. The BRET signal using MBD-SnT-SnC-Oluc and CXXC-SnT-SnC-Oluc increased the amount of methyl-CpG and unmethyl-CpG in genomic DNA, respectively. There was a significant negative correlation between the BRET signals; therefore, the global DNA methylation level was quantified using the BRET signals (R2 = 0.99, and R.S.D. <3.5%). These results indicate that the SnT/SnC protein ligation system can be utilized to construct target modification-binding protein-fused luciferases in any combination that detects target modifications in genomic DNA based on BRET.
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Affiliation(s)
- Takamichi Miyata
- Graduate School of Bionics, Tokyo University of Technology, 1404-1 Katakura-machi, Hachioji, Tokyo192-0982, Japan
| | - Hazuki Shimamura
- Graduate School of Bionics, Tokyo University of Technology, 1404-1 Katakura-machi, Hachioji, Tokyo192-0982, Japan
| | - Ryutaro Asano
- Department of Biotechnology and Life Science, Graduate School of Engineering, Tokyo University of Agriculture and Technology, 2-24-16 Naka-cho, Koganei, Tokyo184-8588, Japan
| | - Wataru Yoshida
- Graduate School of Bionics, Tokyo University of Technology, 1404-1 Katakura-machi, Hachioji, Tokyo192-0982, Japan.,School of Bioscience and Biotechnology, Tokyo University of Technology, 1404-1 Katakura-machi, Hachioji, Tokyo192-0982, Japan
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Khan FH, Bhat BA, Sheikh BA, Tariq L, Padmanabhan R, Verma JP, Shukla AC, Dowlati A, Abbas A. Microbiome dysbiosis and epigenetic modulations in lung cancer: From pathogenesis to therapy. Semin Cancer Biol 2022; 86:732-742. [PMID: 34273520 DOI: 10.1016/j.semcancer.2021.07.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 06/25/2021] [Accepted: 07/11/2021] [Indexed: 02/07/2023]
Abstract
The lung microbiome plays an essential role in maintaining healthy lung function, including host immune homeostasis. Lung microbial dysbiosis or disruption of the gut-lung axis can contribute to lung carcinogenesis by causing DNA damage, inducing genomic instability, or altering the host's susceptibility to carcinogenic insults. Thus far, most studies have reported the association of microbial composition in lung cancer. Mechanistic studies describing host-microbe interactions in promoting lung carcinogenesis are limited. Considering cancer as a multifaceted disease where epigenetic dysregulation plays a critical role, epigenetic modifying potentials of microbial metabolites and toxins and their roles in lung tumorigenesis are not well studied. The current review explains microbial dysbiosis and epigenetic aberrations in lung cancer and potential therapeutic opportunities.
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Affiliation(s)
- Faizan Haider Khan
- Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway, Galway, Ireland
| | | | | | - Lubna Tariq
- Department of Biotechnology, Baba Ghulam Shah Badshah University, Rajouri, India
| | - Roshan Padmanabhan
- Department of Medicine, Case Western Reserve University, and University Hospital, Cleveland, OH, 44106, USA
| | - Jay Prakash Verma
- Institute of Environment and Sustainable Development, Banaras Hindu University Varanasi, India
| | | | - Afshin Dowlati
- Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA; University Hospitals Seidman Cancer Center, Cleveland, OH, 44106, USA; Developmental Therapeutics Program, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, 44116, USA
| | - Ata Abbas
- Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA; Developmental Therapeutics Program, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, 44116, USA.
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Wang X, Ye F, Xiong M, Xiu B, Chi W, Zhang Q, Xue J, Chen M, Zhang L, Wu J, Chi Y. Cross-talk of four types of RNA modification proteins with adenosine reveals the landscape of multivariate prognostic patterns in breast cancer. Front Genet 2022; 13:943378. [PMID: 36118888 PMCID: PMC9479131 DOI: 10.3389/fgene.2022.943378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 08/10/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Breast cancer (BC) is the most common malignant tumour, and its heterogeneity is one of its major characteristics. N6-methyladenosine (m6A), N1-methyladenosine (m1A), alternative polyadenylation (APA), and adenosine-to-inosine (A-to-I) RNA editing constitute the four most common adenosine-associated RNA modifications and represent the most typical and critical forms of epigenetic regulation contributing to the immunoinflammatory response, tumorigenesis and tumour heterogeneity. However, the cross-talk and potential combined profiles of these RNA-modified proteins (RMPs) in multivariate prognostic patterns of BC remain unknown.Methods: A total of 48 published RMPs were analysed and found to display significant expression alterations and genomic mutation rates between tumour and normal tissues in the TCGA-BRCA cohort. Data from 4188 BC patients with clinical outcomes were downloaded from the Gene Expression Omnibus (GEO), the Cancer Genome Atlas (TCGA), and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), normalized and merged into one cohort. The prognostic value and interconnections of these RMPs were also studied. The four prognosis-related genes (PRGs) with the greatest prognostic value were then selected to construct diverse RMP-associated prognostic models through univariate Cox (uniCox) regression analysis, differential expression analysis, Least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox (multiCox) regression. Alterations in biological functional pathways, genomic mutations, immune infiltrations, RNAss scores and drug sensitivities among different models, as well as their prognostic value, were then explored.Results: Utilizing a large number of samples and a comprehensive set of genes contributing to adenosine-associated RNA modification, our study revealed the joint potential bio-functions and underlying features of these diverse RMPs and provided effective models (PRG clusters, gene clusters and the risk model) for predicting the clinical outcomes of BC. The individuals with higher risk scores showed poor prognoses, cell cycle function enrichment, upregulation of stemness scores, higher tumour mutation burdens (TMBs), immune activation and specific drug resistance. This work highlights the significance of comprehensively examining post-transcriptional RNA modification genes.Conclusion: Here, we designed and verified an advanced forecasting model to reveal the underlying links between BC and RMPs and precisely predict the clinical outcomes of multivariate prognostic patterns for individuals.
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Affiliation(s)
- Xuliren Wang
- Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Fangdie Ye
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Min Xiong
- Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Bingqiu Xiu
- Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Weiru Chi
- Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Qi Zhang
- Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Jingyan Xue
- Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Ming Chen
- Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Liyi Zhang
- Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Jiong Wu
- Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, China
- Collaborative Innovation Center for Cancer Medicine, Shanghai, China
- *Correspondence: Jiong Wu, ; Yayun Chi,
| | - Yayun Chi
- Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, China
- *Correspondence: Jiong Wu, ; Yayun Chi,
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22
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Ahmed YW, Alemu BA, Bekele SA, Gizaw ST, Zerihun MF, Wabalo EK, Teklemariam MD, Mihrete TK, Hanurry EY, Amogne TG, Gebrehiwot AD, Berga TN, Haile EA, Edo DO, Alemu BD. Epigenetic tumor heterogeneity in the era of single-cell profiling with nanopore sequencing. Clin Epigenetics 2022; 14:107. [PMID: 36030244 PMCID: PMC9419648 DOI: 10.1186/s13148-022-01323-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 08/12/2022] [Indexed: 11/29/2022] Open
Abstract
Nanopore sequencing has brought the technology to the next generation in the science of sequencing. This is achieved through research advancing on: pore efficiency, creating mechanisms to control DNA translocation, enhancing signal-to-noise ratio, and expanding to long-read ranges. Heterogeneity regarding epigenetics would be broad as mutations in the epigenome are sensitive to cause new challenges in cancer research. Epigenetic enzymes which catalyze DNA methylation and histone modification are dysregulated in cancer cells and cause numerous heterogeneous clones to evolve. Detection of this heterogeneity in these clones plays an indispensable role in the treatment of various cancer types. With single-cell profiling, the nanopore sequencing technology could provide a simple sequence at long reads and is expected to be used soon at the bedside or doctor's office. Here, we review the advancements of nanopore sequencing and its use in the detection of epigenetic heterogeneity in cancer.
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Affiliation(s)
- Yohannis Wondwosen Ahmed
- Department of Medical Biochemistry, School of Medicine, College of Health Sciences, Addis Ababa University, P.O. Box: 9086, Addis Ababa, Ethiopia.
| | - Berhan Ababaw Alemu
- Department of Medical Biochemistry, School of Medicine, St. Paul's Hospital, Millennium Medical College, Addis Ababa, Ethiopia
| | - Sisay Addisu Bekele
- Department of Medical Biochemistry, School of Medicine, College of Health Sciences, Addis Ababa University, P.O. Box: 9086, Addis Ababa, Ethiopia
| | - Solomon Tebeje Gizaw
- Department of Medical Biochemistry, School of Medicine, College of Health Sciences, Addis Ababa University, P.O. Box: 9086, Addis Ababa, Ethiopia
| | - Muluken Fekadie Zerihun
- Department of Medical Biochemistry, School of Medicine, College of Health Sciences, Addis Ababa University, P.O. Box: 9086, Addis Ababa, Ethiopia
| | - Endriyas Kelta Wabalo
- Department of Medical Biochemistry, School of Medicine, College of Health Sciences, Addis Ababa University, P.O. Box: 9086, Addis Ababa, Ethiopia
| | - Maria Degef Teklemariam
- Department of Medical Biochemistry, School of Medicine, College of Health Sciences, Addis Ababa University, P.O. Box: 9086, Addis Ababa, Ethiopia
| | - Tsehayneh Kelemu Mihrete
- Department of Medical Biochemistry, School of Medicine, College of Health Sciences, Addis Ababa University, P.O. Box: 9086, Addis Ababa, Ethiopia
| | - Endris Yibru Hanurry
- Department of Medical Biochemistry, School of Medicine, College of Health Sciences, Addis Ababa University, P.O. Box: 9086, Addis Ababa, Ethiopia
| | - Tensae Gebru Amogne
- Department of Medical Biochemistry, School of Medicine, College of Health Sciences, Addis Ababa University, P.O. Box: 9086, Addis Ababa, Ethiopia
| | - Assaye Desalegne Gebrehiwot
- Department of Medical Anatomy, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
| | - Tamirat Nida Berga
- Department of Medical Biochemistry, School of Medicine, College of Health Sciences, Addis Ababa University, P.O. Box: 9086, Addis Ababa, Ethiopia
| | - Ebsitu Abate Haile
- Department of Medical Biochemistry, School of Medicine, College of Health Sciences, Addis Ababa University, P.O. Box: 9086, Addis Ababa, Ethiopia
| | - Dessiet Oma Edo
- Department of Medical Biochemistry, School of Medicine, College of Health Sciences, Addis Ababa University, P.O. Box: 9086, Addis Ababa, Ethiopia
| | - Bizuwork Derebew Alemu
- Department of Statistics, College of Natural and Computational Sciences, Mizan Tepi University, Tepi, Ethiopia
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23
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Selective CDK9 Inhibition by Natural Compound Toyocamycin in Cancer Cells. Cancers (Basel) 2022; 14:cancers14143340. [PMID: 35884401 PMCID: PMC9324262 DOI: 10.3390/cancers14143340] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 06/24/2022] [Accepted: 07/04/2022] [Indexed: 11/30/2022] Open
Abstract
Simple Summary By combining drug screens, transcriptomic studies, and in vitro assays, our study identified the natural product toyocamycin as a potent and selective CDK9 inhibitor. Thus, toyocamycin can be used as a new small molecule to modulate CDK9 activity in preclinical research. Through docking simulations, we identified its specific binding sites, which could spark some interest to design novel small molecule CDK9 inhibitors. Abstract Aberrant transcription in cancer cells involves the silencing of tumor suppressor genes (TSGs) and activation of oncogenes. Transcriptomic changes are associated with epigenomic alterations such as DNA-hypermethylation, histone deacetylation, and chromatin condensation in promoter regions of silenced TSGs. To discover novel drugs that trigger TSG reactivation in cancer cells, we used a GFP-reporter system whose expression is silenced by promoter DNA hypermethylation and histone deacetylation. After screening a natural product drug library, we identified that toyocamycin, an adenosine-analog, induces potent GFP reactivation and loss of clonogenicity in human colon cancer cells. Connectivity-mapping analysis revealed that toyocamycin produces a pharmacological signature mimicking cyclin-dependent kinase (CDK) inhibitors. RNA-sequencing revealed that the toyocamycin transcriptomic signature resembles that of a specific CDK9 inhibitor (HH1). Specific inhibition of RNA Pol II phosphorylation level and kinase assays confirmed that toyocamycin specifically inhibits CDK9 (IC50 = 79 nM) with a greater efficacy than other CDKs (IC50 values between 0.67 and 15 µM). Molecular docking showed that toyocamycin efficiently binds the CDK9 catalytic site in a conformation that differs from other CDKs, explained by the binding contribution of specific amino acids within the catalytic pocket and protein backbone. Altogether, we demonstrated that toyocamycin exhibits specific CDK9 inhibition in cancer cells, highlighting its potential for cancer chemotherapy.
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24
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Wang P, Xu G, Gao E, Xu Y, Liang L, Jiang G, Duan L. Identification of Prognostic DNA Methylation Signatures in Lung Adenocarcinoma. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:8802303. [PMID: 35814273 PMCID: PMC9259289 DOI: 10.1155/2022/8802303] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 06/04/2022] [Indexed: 12/03/2022]
Abstract
BACKGROUND Increasing evidence exists of a link between DNA methylation and tumor immunotherapy. However, the impact of DNA methylation on the characteristics of the lung adenocarcinoma microenvironment and its effect on immunotherapy remain unclear. METHOD This study collected TCGA-LUAD related data sets (LUAD) to explore the characteristics and regulation of 20 DNA methylation-related genes. We further identified two DNA methylation subtypes by analysing the expression profiles of these 20 DNA methylation-related genes. Subsequently, the differences in immune cell infiltration (ICI) and the expression of immune-related signaling factors among different DNA methylation subtypes were explored, and the differentially expressed genes (DEGs) among different LUAD DNA methylation subtypes were identified. Using univariate Cox to screen differentially expressed genes meaningful for survival, a DNA methylation score (DMS) was constructed based on the weight of the first and second dimensions after dimensionality reduction by principal component analysis (PCA). Our study found that DMS can better evaluate the prognosis of lung adenocarcinoma. RESULTS Based on DMS, LUAD samples were divided into two groups with high and low scores. The differences in clinical characteristics, tumor mutation load, and tumor immune cell infiltration between different DMS groups of LUAD were deeply explored, and the prediction ability of DMS for the benefit of immunotherapy was evaluated. CONCLUSIONS DMS is a valuable tool for predicting survival, clinicopathological features, and immunotherapeutic efficacy, which may help to promote personalized LUAD immunotherapy in the future.
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Affiliation(s)
- Pengli Wang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China
| | - Gaoran Xu
- Department of Thyroid and Breast Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Erji Gao
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China
| | - Yong Xu
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China
| | - Leilei Liang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China
| | - Gening Jiang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China
| | - Liang Duan
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China
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25
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Yang G, Shan D, Zhao R, Li G. Metabolism-Associated DNA Methylation Signature Stratifies Lower-Grade Glioma Patients and Predicts Response to Immunotherapy. Front Cell Dev Biol 2022; 10:902298. [PMID: 35784470 PMCID: PMC9240391 DOI: 10.3389/fcell.2022.902298] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 05/23/2022] [Indexed: 11/24/2022] Open
Abstract
Metabolism and DNA methylation (DNAm) are closely linked. The value of the metabolism-DNAm interplay in stratifying glioma patients has not been explored. In the present study, we aimed to stratify lower-grade glioma (LGG) patients based on the DNAm associated with metabolic reprogramming. Four data sets of LGGs from three databases (TCGA/CGGA/GEO) were used in this study. By screening the Kendall’s correlation of DNAm with 87 metabolic processes from KEGG, we identified 391 CpGs with a strong correlation with metabolism. Based on these metabolism-associated CpGs, we performed consensus clustering and identified three distinct subgroups of LGGs. These three subgroups were characterized by distinct molecular features and clinical outcomes. We also constructed a subgroup-related, quantifiable CpG signature with strong prognostic power to stratify LGGs. It also serves as a potential biomarker to predict the response to immunotherapy. Overall, our findings provide new perspectives for the stratification of LGGs and for understanding the mechanisms driving malignancy.
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Affiliation(s)
- Guozheng Yang
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China
| | - Dezhi Shan
- Department of Neurosurgery, Beijing Hospital, Chinese Academy of Medical Sciences, Graduate School of Peking Union Medical College, Beijing, China
| | - Rongrong Zhao
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China
- Shandong Key Laboratory of Brain Function Remodeling, Jinan, China
| | - Gang Li
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China
- Shandong Key Laboratory of Brain Function Remodeling, Jinan, China
- *Correspondence: Gang Li,
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26
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Sanchez A, Penault-Llorca F, Bignon YJ, Guy L, Bernard-Gallon D. Effects of GSK-J4 on JMJD3 Histone Demethylase in Mouse Prostate Cancer Xenografts. Cancer Genomics Proteomics 2022; 19:339-349. [PMID: 35430567 DOI: 10.21873/cgp.20324] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 02/04/2022] [Accepted: 02/10/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND/AIM Histone methylation status is required to control gene expression. H3K27me3 is an epigenetic tri-methylation modification to histone H3 controlled by the demethylase JMJD3. JMJD3 is dysregulated in a wide range of cancers and has been shown to control the expression of a specific growth-modulatory gene signature, making it an interesting candidate to better understand prostate tumor progression in vivo. This study aimed to identify the impact of JMJD3 inhibition by its inhibitor, GSK4, on prostate tumor growth in vivo. MATERIALS AND METHODS Prostate cancer cell lines were implanted into Balb/c nude male mice. The effects of the selective JMJD3 inhibitor GSK-J4 on tumor growth were analyzed by bioluminescence assays and H3K27me3-regulated changes in gene expression were analyzed by ChIP-qPCR and RT-qPCR. RESULTS JMJD3 inhibition contributed to an increase in tumor growth in androgen-independent (AR-) xenografts and a decrease in androgen-dependent (AR+). GSK-J4 treatment modulated H3K27me3 enrichment on the gene panel in DU-145-luc xenografts while it had little effect on PC3-luc and no effect on LNCaP-luc. Effects of JMJD3 inhibition affected the panel gene expression. CONCLUSION JMJD3 has a differential effect in prostate tumor progression according to AR status. Our results suggest that JMJD3 is able to play a role independently of its demethylase function in androgen-independent prostate cancer. The effects of GSK-J4 on AR+ prostate xenografts led to a decrease in tumor growth.
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Affiliation(s)
- Anna Sanchez
- Department of Oncogenetics, Centre Jean Perrin, Clermont-Ferrand, France.,INSERM U 1240 Molecular Imagery and Theranostic Strategies (IMoST), Clermont-Ferrand, France
| | - Frédérique Penault-Llorca
- INSERM U 1240 Molecular Imagery and Theranostic Strategies (IMoST), Clermont-Ferrand, France.,Department of Biopathology, Centre Jean Perrin, Clermont-Ferrand, France
| | - Yves-Jean Bignon
- Department of Oncogenetics, Centre Jean Perrin, Clermont-Ferrand, France.,INSERM U 1240 Molecular Imagery and Theranostic Strategies (IMoST), Clermont-Ferrand, France
| | - Laurent Guy
- INSERM U 1240 Molecular Imagery and Theranostic Strategies (IMoST), Clermont-Ferrand, France.,Department of Urology, Gabriel Montpied Hospital, Clermont-Ferrand, France
| | - Dominique Bernard-Gallon
- Department of Oncogenetics, Centre Jean Perrin, Clermont-Ferrand, France; .,INSERM U 1240 Molecular Imagery and Theranostic Strategies (IMoST), Clermont-Ferrand, France
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27
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Ravi S, Alencar AM, Arakelyan J, Xu W, Stauber R, Wang CCI, Papyan R, Ghazaryan N, Pereira RM. An Update to Hallmarks of Cancer. Cureus 2022; 14:e24803. [PMID: 35686268 PMCID: PMC9169686 DOI: 10.7759/cureus.24803] [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] [Accepted: 05/06/2022] [Indexed: 12/03/2022] Open
Abstract
In the last decade, there has been remarkable progress in research toward understanding and refining the hallmarks of cancer. In this review, we propose a new hallmark - "pro-survival autophagy." The importance of pro-survival autophagy is well established in tumorigenesis, as it is related to multiple steps in cancer progression and vital for some cancers. Autophagy is a potential anti-cancer therapeutic target. For this reason, autophagy is a good candidate as a new hallmark of cancer. We describe two enabling characteristics that play a major role in enabling cells to acquire the hallmarks of cancer - "tumor-promoting microenvironment and macroenvironment" and "cancer epigenetics, genome instability and mutation." We also discuss the recent updates, therapeutic and prognostic implications of the eight hallmarks of cancer described by Hanahan et al. in 2011. Understanding these hallmarks and enabling characteristics is key not only to developing new ways to treat cancer efficiently but also to exploring options to overcome cancer resistance to treatment.
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Affiliation(s)
- Swapna Ravi
- Department of Medicine, St. Luke's Hospital, Duluth, USA
| | - Antonio M Alencar
- Department of Medical Oncology, Hospital Universitário da Universidade Federal do Maranhão, Hospital São Domingos, São Luís, BRA
| | - Jemma Arakelyan
- Department of Oncology/Solid Tumors, Yerevan State Medical University, Hematology Center After Prof. R. Yeolyan, Yerevan, ARM
| | - Weihao Xu
- Department of Business Development, Harbour BioMed, Boston, USA
| | - Roberta Stauber
- Department of Oncology, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, BRA
| | - Cheng-Chi I Wang
- Department of Research and Development, Beltie Bio, Inc, San Diego, USA
| | - Ruzanna Papyan
- Department of Pediatric Oncology and Hematology, Yerevan State Medical University, Pediatric Center and Blood Disorders Center of Armenia, Yerevan, ARM
| | - Narine Ghazaryan
- Department of Molecular Biology, L.A. Orbeli Institute of Physiology National Academy of Sciences, Republic of Armenia (NAS RA) Hematology Center After Prof. R. Yeolyan, Yerevan, ARM
| | - Rosalina M Pereira
- Department of Neurology, University of Texas Southwestern Medical Center, Dallas, USA
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28
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Hindle A, Bose C, Lee J, Palade PT, Peterson CJ, Reddy PH, Awasthi S, Singh SP. Rlip Depletion Alters Oncogene Transcription at Multiple Distinct Regulatory Levels. Cancers (Basel) 2022; 14:cancers14030527. [PMID: 35158795 PMCID: PMC8833773 DOI: 10.3390/cancers14030527] [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: 11/30/2021] [Revised: 01/07/2022] [Accepted: 01/15/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Rlip76 is a multifunctional membrane protein that facilitates cancer growth, and its depletion kills cancer cells. We recently found that Rlip depletion also results in broad changes to oncogene and tumor suppressor transcription. The present studies were designed to decipher the unknown downstream signaling pathways and transcriptional regulatory mechanisms driving the effect. Building on prior findings that Rlip depletion induces broad methylomic changes, we found using bioluminescence reporter assays that depletion of Rlip also exerts transcriptional control over several cancer genes through methylation-independent changes in transcription factor-mediated activation of their promoter regions and through additional as yet unidentified mechanisms. These findings have important implications for Rlip-targeted cancer therapy. Abstract Rlip76 (Rlip) is a multifunctional membrane protein that facilitates the high metabolic rates of cancer cells through the efflux of toxic metabolites and other functions. Rlip inhibition or depletion results in broad-spectrum anti-cancer effects in vitro and in vivo. Rlip depletion effectively suppresses malignancy and causes global reversion of characteristic CpG island methylomic and transcriptomic aberrations in the p53-null mouse model of spontaneous carcinogenesis through incompletely defined signaling and transcriptomic mechanisms. The methylome and transcriptome are normally regulated by the concerted actions of several mechanisms that include chromatin remodeling, promoter methylation, transcription factor interactions, and miRNAs. The present studies investigated the interaction of Rlip depletion or inhibition with the promoter methylation and transcription of selected cancer-related genes identified as being affected by Rlip depletion in our previous studies. We constructed novel promoter CpG island/luciferase reporter plasmids that respond only to CpG methylation and transcription factors. We found that Rlip depletion regulated expression by a transcription factor-based mechanism that functioned independently of promoter CpG methylation, lipid peroxidation, and p53 status.
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Affiliation(s)
- Ashly Hindle
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; (A.H.); (C.B.); (J.L.); (C.J.P.); (P.H.R.)
| | - Chhanda Bose
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; (A.H.); (C.B.); (J.L.); (C.J.P.); (P.H.R.)
| | - Jihyun Lee
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; (A.H.); (C.B.); (J.L.); (C.J.P.); (P.H.R.)
- Division of Hematology & Oncology, Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Philip T. Palade
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA;
| | - Christopher J. Peterson
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; (A.H.); (C.B.); (J.L.); (C.J.P.); (P.H.R.)
| | - P. Hemachandra Reddy
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; (A.H.); (C.B.); (J.L.); (C.J.P.); (P.H.R.)
- Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
- Department of Public Health, Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
- Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
- Department of Speech, Language and Hearing Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Sanjay Awasthi
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; (A.H.); (C.B.); (J.L.); (C.J.P.); (P.H.R.)
- Division of Hematology & Oncology, Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
- UMC Cancer Center, UMC Health System, Lubbock, TX 79415, USA
- Correspondence: (S.A.); (S.P.S.); Tel.: +1-806-743-3543 (S.A.); +1-806-743-1540 (S.P.S.)
| | - Sharda P. Singh
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; (A.H.); (C.B.); (J.L.); (C.J.P.); (P.H.R.)
- Division of Hematology & Oncology, Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
- Correspondence: (S.A.); (S.P.S.); Tel.: +1-806-743-3543 (S.A.); +1-806-743-1540 (S.P.S.)
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29
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Zhang J, Fan J, Wang P, Ge G, Li J, Qi J, Kong W, Gong Y, He S, Ci W, Li X, Zhou L. Construction of diagnostic and subtyping models for renal cell carcinoma by genome-wide DNA methylation profiles. Transl Androl Urol 2022; 10:4161-4172. [PMID: 34984182 PMCID: PMC8661251 DOI: 10.21037/tau-21-674] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 10/21/2021] [Indexed: 12/03/2022] Open
Abstract
Background Renal cell carcinoma (RCC) is one of the most common urological cancers and has a poor prognosis. RCC is classified into several subtypes, among which kidney renal clear cell carcinoma (KIRC) and kidney renal papillary cell carcinoma (KIRP) are the two most common subtypes. Due to the lack of adequate screening and comparative analysis of RCC subtypes, effective diagnosis and treatment strategies have not yet been achieved. Methods In this study, 450K methylation array data were collected from The Cancer Genome Atlas (TCGA). The ‘limma moderated t-test’ and LASSO were used to construct diagnostic and subtyping models, and survival analysis was conducted online by GEPIA. Results We built a model with 15 methylation sites, which showed high diagnostic and subtyping performance in specificity and sensitivity. At the same time, for potential clinical usability, we calculated the diagnostic and subtyping scores to classify RCC from normal tissue and distinguish the different RCC subtypes. Additionally, the CpG sites were mapped to their corresponding genes, which could also be used to predict the prognosis of RCC. Conclusions Different methylation sites can be used as diagnostic and subtyping markers that are specific to RCC and RCC subtypes (KIRC and KIRP) with high sensitivity and accuracy.
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Affiliation(s)
- Jianye Zhang
- Department of Urology, Peking University First Hospital, Beijing, China.,Key Laboratory of Genomics & Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.,Institute of Urology, Peking University, Beijing, China.,National Urological Cancer Center, Beijing, China.,Urogenital Diseases (Male) Molecular Diagnosis & Treatment Centre, Peking University, Beijing, China
| | - Jian Fan
- Department of Urology, Peking University First Hospital, Beijing, China.,Key Laboratory of Genomics & Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.,Institute of Urology, Peking University, Beijing, China.,National Urological Cancer Center, Beijing, China.,Urogenital Diseases (Male) Molecular Diagnosis & Treatment Centre, Peking University, Beijing, China
| | - Ping Wang
- Key Laboratory of Genomics & Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
| | - Guangzhe Ge
- Key Laboratory of Genomics & Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
| | - Juan Li
- Key Laboratory of Genomics & Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
| | - Jie Qi
- Key Laboratory of Genomics & Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
| | - Wenwen Kong
- Key Laboratory of Genomics & Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
| | - Yanqing Gong
- Department of Urology, Peking University First Hospital, Beijing, China.,Institute of Urology, Peking University, Beijing, China.,National Urological Cancer Center, Beijing, China.,Urogenital Diseases (Male) Molecular Diagnosis & Treatment Centre, Peking University, Beijing, China
| | - Shiming He
- Department of Urology, Peking University First Hospital, Beijing, China.,Institute of Urology, Peking University, Beijing, China.,National Urological Cancer Center, Beijing, China.,Urogenital Diseases (Male) Molecular Diagnosis & Treatment Centre, Peking University, Beijing, China
| | - Weimin Ci
- Key Laboratory of Genomics & Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
| | - Xuesong Li
- Department of Urology, Peking University First Hospital, Beijing, China.,Institute of Urology, Peking University, Beijing, China.,National Urological Cancer Center, Beijing, China.,Urogenital Diseases (Male) Molecular Diagnosis & Treatment Centre, Peking University, Beijing, China
| | - Liqun Zhou
- Department of Urology, Peking University First Hospital, Beijing, China.,Institute of Urology, Peking University, Beijing, China.,National Urological Cancer Center, Beijing, China.,Urogenital Diseases (Male) Molecular Diagnosis & Treatment Centre, Peking University, Beijing, China
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Du H, Zhang L. DOT1L Epigenetically Induces the Expression Level of FoxM1 through H3K79me2 and Affects the Malignant Behaviors of Head and Neck Squamous Cell Carcinoma Cells. J HARD TISSUE BIOL 2022. [DOI: 10.2485/jhtb.31.101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Huanle Du
- Otolaryngology Head and Neck Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine
| | - Lin Zhang
- Otolaryngology Head and Neck Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine
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Park MT, Kim SD, Han YK, Hyun JW, Lee HJ, Yi JM. Enhancement of Radiosensitivity by DNA Hypomethylating Drugs through Apoptosis and Autophagy in Human Sarcoma Cells. Biomol Ther (Seoul) 2022; 30:80-89. [PMID: 34887366 PMCID: PMC8724837 DOI: 10.4062/biomolther.2021.174] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 11/17/2021] [Accepted: 11/18/2021] [Indexed: 12/16/2022] Open
Abstract
The targeting of DNA methylation in cancer using DNA hypomethylating drugs has been well known to sensitize cancer cells to chemotherapy and immunotherapy by affecting multiple pathways. Herein, we investigated the combinational effects of DNA hypomethylating drugs and ionizing radiation (IR) in human sarcoma cell lines both in vitro and in vivo. Clonogenic assays were performed to determine the radiosensitizing properties of two DNA hypomethylating drugs on sarcoma cell lines we tested in this study with multiple doses of IR. We analyzed the effects of 5-aza-dC or SGI-110, as DNA hypomethylating drugs, in combination with IR in vitro on the proliferation, apoptosis, caspase-3/7 activity, migration/invasion, and Western blotting using apoptosis- or autophagy-related factors. To confirm the combined effect of DNA hypomethylating drugs and IR in our in vitro experiment, we generated the sarcoma cells in nude mouse xenograft models. Here, we found that the combination of DNA hypomethylating drugs and IR improved anticancer effects by inhibiting cell proliferation and by promoting synergistic cell death that is associated with both apoptosis and autophagy in vitro and in vivo. Our data demonstrated that the combination effects of DNA hypomethylating drugs with radiation exhibited greater cellular effects than the use of a single agent treatment, thus suggesting that the combination of DNA hypomethylating drugs and radiation may become a new radiotherapy to improve therapeutic efficacy for cancer treatment.
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Affiliation(s)
- Moon-Taek Park
- Research Center, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Busan 46033, Republic of Korea
| | - Sung-Dae Kim
- Research Center, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Busan 46033, Republic of Korea
| | - Yu Kyeong Han
- Department of Microbiology and Immunology, College of Medicine, Inje University, Busan 47392, Republic of Korea
| | - Jin Won Hyun
- Jeju National University School of Medicine and Jeju Research Center for Natural Medicine, Jeju 63243, Republic of Korea
| | - Hae-June Lee
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Republic of Korea
| | - Joo Mi Yi
- Department of Microbiology and Immunology, College of Medicine, Inje University, Busan 47392, Republic of Korea
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32
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Cammarata G, de Miguel-Perez D, Russo A, Peleg A, Dolo V, Rolfo C, Taverna S. Emerging noncoding RNAs contained in extracellular vesicles: rising stars as biomarkers in lung cancer liquid biopsy. Ther Adv Med Oncol 2022; 14:17588359221131229. [PMID: 36353504 PMCID: PMC9638531 DOI: 10.1177/17588359221131229] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 09/12/2022] [Indexed: 11/06/2022] Open
Abstract
Lung cancer has a high morbidity and mortality rate, and affected patients have a
poor prognosis and low survival. The therapeutic approaches for lung cancer
treatment, including surgery, radiotherapy, and chemotherapy, are not completely
effective, due to late diagnosis. Although the identification of genetic drivers
has contributed to the improvement of lung cancer clinical management, the
discovery of new diagnostic and prognostic tools remains a critical issue.
Liquid biopsy (LB) represents a minimally invasive approach and practical
alternative source to investigate tumor-derived alterations and to facilitate
the selection of targeted therapies. LB allows for the testing of different
analytes such as circulating tumor cells, extracellular vesicles (EVs),
tumor-educated platelets, and cell-free nucleic acids including DNAs, RNAs, and
noncoding RNAs (ncRNAs). Several regulatory factors control the key cellular
oncogenic pathways involved in cancers. ncRNAs have a wide range of regulatory
effects in lung cancers. This review focuses on emerging regulatory ncRNAs,
freely circulating in body fluids or shuttled by EVs, such as circular-RNAs,
small nucleolar-RNAs, small nuclear-RNAs, and piwi-RNAs, as new biomarkers for
early detection, prognosis, and monitoring of therapeutic strategy of lung
cancer treatment.
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Affiliation(s)
- Giuseppe Cammarata
- Institute of Translational Pharmacology (IFT), National Research Council (CNR) of Italy, Palermo, Italy
| | - Diego de Miguel-Perez
- Center for Thoracic Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Alessandro Russo
- Medical Oncology Unit, A.O. Papardo & Department of Human Pathology, University of Messina, Messina, Italy
| | - Ariel Peleg
- Center for Thoracic Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Vincenza Dolo
- Department of Life, Health and Environmental Sciences, University of L’Aquila, L’Aquila, Italy
| | - Christian Rolfo
- Center for Thoracic Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, Box 1079, New York, NY 10029-6574, USA
| | - Simona Taverna
- Institute of Translational Pharmacology (IFT), National Research Council (CNR) of Italy, Via Ugo La Malfa, 153, Palermo 90146, Italy
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Bao Y, Gabrielpillai J, Dietrich J, Zarbl R, Strieth S, Schröck F, Dietrich D. Fibroblast growth factor (FGF), FGF receptor (FGFR), and cyclin D1 (CCND1) DNA methylation in head and neck squamous cell carcinomas is associated with transcriptional activity, gene amplification, human papillomavirus (HPV) status, and sensitivity to tyrosine kinase inhibitors. Clin Epigenetics 2021; 13:228. [PMID: 34933671 PMCID: PMC8693503 DOI: 10.1186/s13148-021-01212-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 12/08/2021] [Indexed: 12/11/2022] Open
Abstract
Background Dysregulation of fibroblast growth factor receptor (FGFR) signaling pathway has been observed in head and neck squamous cell carcinoma (HNSCC) and is a promising therapeutic target for selective tyrosine kinase inhibitors (TKIs). Potential predictive biomarkers for response to FGFR-targeted therapies are urgently needed. Understanding the epigenetic regulation of FGF pathway related genes, i.e. FGFRs, FGFs, and CCND1, could enlighten the way towards biomarker-selected FGFR-targeted therapies. Methods We performed DNA methylation analysis of the encoding genes FGFR1, FGFR2, FGFR3, FGFR4, FGF1-14, FGF16-23, and CCND1 at single CpG site resolution (840 CpG sites) employing The Cancer Genome Research Atlas (TCGA) HNSCC cohort comprising N = 530 tumor tissue and N = 50 normal adjacent tissue samples. We correlated DNA methylation to mRNA expression with regard to human papilloma virus (HPV) and gene amplification status. Moreover, we investigated the correlation of methylation with sensitivity to the selective FGFR inhibitors PD 173074 and AZD4547 in N = 40 HPV(−) HNSCC cell lines. Results We found sequence-contextually nuanced CpG methylation patterns in concordance with epigenetically regulated genes. High methylation levels were predominantly found in the promoter flank and gene body region, while low methylation levels were present in the central promoter region for most of the analyzed CpG sites. FGFRs, FGFs, and CCND1 methylation differed significantly between tumor and normal adjacent tissue and was associated with HPV and gene amplification status. CCND1 promoter methylation correlated with CCND1 amplification. For most of the analyzed CpG sites, methylation levels correlated to mRNA expression in tumor tissue. Furthermore, we found significant correlations of DNA methylation of specific CpG sites with response to the FGFR1/3–selective inhibitors PD 173074 and AZD4547, predominantly within the transcription start site of CCND1. Conclusions Our results suggest an epigenetic regulation of CCND1, FGFRs, and FGFs via DNA methylation in HNSCC and warrants further investigation of DNA methylation as a potential predictive biomarker for response to selective FGFR inhibitors in clinical trials. Supplementary Information The online version contains supplementary material available at 10.1186/s13148-021-01212-4.
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Affiliation(s)
- Yilin Bao
- Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center Bonn (UKB), Sigmund-Freud-Str. 25, 53105, Bonn, Germany.,Department of Otolaryngology, Head and Neck Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Jennis Gabrielpillai
- Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center Bonn (UKB), Sigmund-Freud-Str. 25, 53105, Bonn, Germany
| | - Jörn Dietrich
- Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center Bonn (UKB), Sigmund-Freud-Str. 25, 53105, Bonn, Germany
| | - Romina Zarbl
- Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center Bonn (UKB), Sigmund-Freud-Str. 25, 53105, Bonn, Germany
| | - Sebastian Strieth
- Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center Bonn (UKB), Sigmund-Freud-Str. 25, 53105, Bonn, Germany
| | - Friederike Schröck
- Department of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany
| | - Dimo Dietrich
- Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center Bonn (UKB), Sigmund-Freud-Str. 25, 53105, Bonn, Germany.
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Fatima N, Baqri SSR, Bhattacharya A, Koney NKK, Husain K, Abbas A, Ansari RA. Role of Flavonoids as Epigenetic Modulators in Cancer Prevention and Therapy. Front Genet 2021; 12:758733. [PMID: 34858475 PMCID: PMC8630677 DOI: 10.3389/fgene.2021.758733] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Accepted: 10/26/2021] [Indexed: 12/16/2022] Open
Abstract
Epigenetic regulation involves reversible changes in histones and DNA modifications that can be inherited without any changes in the DNA sequence. Dysregulation of normal epigenetic processes can lead to aberrant gene expression as observed in many diseases, notably cancer. Recent insights into the mechanisms of DNA methylation, histone modifications, and non-coding RNAs involved in altered gene expression profiles of tumor cells have caused a paradigm shift in the diagnostic and therapeutic approaches towards cancer. There has been a surge in search for compounds that could modulate the altered epigenetic landscape of tumor cells, and to exploit their therapeutic potential against cancers. Flavonoids are naturally occurring phenol compounds which are abundantly found among phytochemicals and have potentials to modulate epigenetic processes. Knowledge of the precise flavonoid-mediated epigenetic alterations is needed for the development of epigenetics drugs and combinatorial therapeutic approaches against cancers. This review is aimed to comprehensively explore the epigenetic modulations of flavonoids and their anti-tumor activities.
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Affiliation(s)
- Nishat Fatima
- Department of Chemistry, Shia Postgraduate College, Lucknow, India
| | | | - Atrayee Bhattacharya
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States
| | - Nii Koney-Kwaku Koney
- Department of Anatomy, University of Ghana Medical School, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Kazim Husain
- Department of Molecular Medicine, University of South Florida, Tampa, FL, United States
| | - Ata Abbas
- Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, OH, United States.,Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, United States
| | - Rais A Ansari
- Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL, United States
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Chai P, Jia R, Li Y, Zhou C, Gu X, Yang L, Shi H, Tian H, Lin H, Yu J, Zhuang A, Ge S, Jia R, Fan X. Regulation of epigenetic homeostasis in uveal melanoma and retinoblastoma. Prog Retin Eye Res 2021; 89:101030. [PMID: 34861419 DOI: 10.1016/j.preteyeres.2021.101030] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 11/16/2021] [Accepted: 11/19/2021] [Indexed: 12/13/2022]
Abstract
Uveal melanoma (UM) and retinoblastoma (RB), which cause blindness and even death, are the most frequently observed primary intraocular malignancies in adults and children, respectively. Epigenetic studies have shown that changes in the epigenome contribute to the rapid progression of both UM and RB following classic genetic changes. The loss of epigenetic homeostasis plays an important role in oncogenesis by disrupting the normal patterns of gene expression. The targetable nature of epigenetic modifications provides a unique opportunity to optimize treatment paradigms and establish new therapeutic options for both UM and RB with these aberrant epigenetic modifications. We aimed to review the research findings regarding relevant epigenetic changes in UM and RB. Herein, we 1) summarize the literature, with an emphasis on epigenetic alterations, including DNA methylation, histone modifications, RNA modifications, noncoding RNAs and an abnormal chromosomal architecture; 2) elaborate on the regulatory role of epigenetic modifications in biological processes during tumorigenesis; and 3) propose promising therapeutic candidates for epigenetic targets and update the list of epigenetic drugs for the treatment of UM and RB. In summary, we endeavour to depict the epigenetic landscape of primary intraocular malignancy tumorigenesis and provide potential epigenetic targets in the treatment of these tumours.
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Affiliation(s)
- Peiwei Chai
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, PR China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200025, PR China
| | - Ruobing Jia
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, PR China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200025, PR China
| | - Yongyun Li
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, PR China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200025, PR China
| | - Chuandi Zhou
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, PR China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200025, PR China
| | - Xiang Gu
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, PR China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200025, PR China
| | - Ludi Yang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, PR China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200025, PR China
| | - Hanhan Shi
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, PR China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200025, PR China
| | - Hao Tian
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, PR China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200025, PR China
| | - Huimin Lin
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, PR China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200025, PR China
| | - Jie Yu
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, PR China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200025, PR China
| | - Ai Zhuang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, PR China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200025, PR China
| | - Shengfang Ge
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, PR China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200025, PR China
| | - Renbing Jia
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, PR China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200025, PR China
| | - Xianqun Fan
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, PR China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200025, PR China.
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Shafabakhsh R, Arianfar F, Vosough M, Mirzaei HR, Mahjoubin-Tehran M, Khanbabaei H, Kowsari H, Shojaie L, Azar MEF, Hamblin MR, Mirzaei H. Autophagy and gastrointestinal cancers: the behind the scenes role of long non-coding RNAs in initiation, progression, and treatment resistance. Cancer Gene Ther 2021; 28:1229-1255. [PMID: 33432087 DOI: 10.1038/s41417-020-00272-7] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 10/06/2020] [Accepted: 11/23/2020] [Indexed: 02/07/2023]
Abstract
Gastrointestinal (GI) cancers comprise a heterogeneous group of complex disorders that affect different organs, including esophagus, stomach, gallbladder, liver, biliary tract, pancreas, small intestine, colon, rectum, and anus. Recently, an explosion in nucleic acid-based technologies has led to the discovery of long non-coding RNAs (lncRNAs) that have been found to possess unique regulatory functions. This class of RNAs is >200 nucleotides in length, and is characterized by their lack of protein coding. LncRNAs exert regulatory effects in GI cancer development by affecting different functions such as the proliferation and metastasis of cancer cells, apoptosis, glycolysis and angiogenesis. Over the past few decades, considerable evidence has revealed the important role of autophagy in both GI cancer progression and suppression. In addition, recent studies have confirmed a significant correlation between lncRNAs and the regulation of autophagy. In this review, we summarize how lncRNAs play a behind the scenes role in the pathogenesis of GI cancers through regulation of autophagy.
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Affiliation(s)
- Rana Shafabakhsh
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Farzaneh Arianfar
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Massoud Vosough
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, 1665659911, Iran
| | - Hamid Reza Mirzaei
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Mahjoubin-Tehran
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Biotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hashem Khanbabaei
- Medical Physics Department, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Hamed Kowsari
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Layla Shojaie
- Research Center for Liver Diseases, Keck School of Medicine, Department of Medicine, University of Southern California, Los Angeles, CA, USA
| | | | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, 2028, South Africa.
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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Zhang L, Song ZS, Wang ZS, Guo YL, Xu CG, Shen H. High Expression of SLC16A1 as a Biomarker to Predict Poor Prognosis of Urological Cancers. Front Oncol 2021; 11:706883. [PMID: 34631536 PMCID: PMC8493816 DOI: 10.3389/fonc.2021.706883] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Accepted: 07/12/2021] [Indexed: 11/15/2022] Open
Abstract
Objective Tumor metabolism has always been the focus of cancer research. SLC16A1, as a key factor in catalysis of monocarboxylate transport across the plasma membrane, has been found to be associated with the occurrence and metastasis of a variety of cancers, but its prognostic significance and mechanism in different tumors are still unclear. Methods Based on the gene expression matrix and clinical information of human cancer tissues acquired from TCGA and GTEX databases, the differential expression of SLC16A1 in different tumors and normal tissues was analyzed. To confirm the association between its expression, the mutation of MMRS gene, and the expression level of DNMTs. Univariate Cox regression was applied to analyze the association between SLC16A1 expression and patient prognosis. The effect of SLC16A1 expression on patient survival was examined by Kaplan Meier analysis. GSEA was used to identify related signaling pathways. Results The expression of SLC16A1 was differentially expressed in most tumors, especially in the urinary tract where it is commonly highly expressed, and differential expression of SLC16A1 in different clinical stages. SLC16A1 expression was significantly positively correlated with MMRS gene mutation and DNMTS expression. Moreover, high SLC16A1 expression was associated with poorer overall survival (OS) and progression-free survival (PFS) in urological cancers. In particular, the results of the enrichment analysis showed that SLC16A1 was associated with processes such as cell adhesion and many signaling pathways affecting cell cycle were significantly enriched in the group with high-expressed SLC16A1. Conclusion SLC16A1 expression was upregulated in urological cancer. SLC16A1 may promote tumor development by regulating the epigenetic process of urological cancer and demonstrated a great potential as a prognostic biomarker of urological cancer patients.
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Affiliation(s)
- Ling Zhang
- Department of Pathology, Wuhan No.1 Hospital, Wuhan, China
| | - Zheng-Shuai Song
- Department of Urology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhi-Shun Wang
- Department of Urology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yong-Lian Guo
- Department of Urology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chang-Geng Xu
- Department of Urology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hao Shen
- Department of Urology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Luo J, Xu J, Ou L, Zhou Y, Yun H, Yang Y, Wu X, Wang Y. Role of hypermethylated-lncRNAs in the prognosis of bladder cancer patients. J Int Med Res 2021; 49:3000605211049946. [PMID: 34617815 PMCID: PMC8504649 DOI: 10.1177/03000605211049946] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE To explore the hypermethylated long non-coding (lnc)RNAs involved in bladder carcinogenesis and prognosis. METHODS Reduced representation bisulfite sequencing and RNA sequencing were performed on five paired tumor and adjacent normal tissue samples from bladder cancer patients. The differentially methylated regions around transcription start sites and differentially expressed genes, including lncRNAs, were analyzed. Correlations between DNA methylation modifications and the expression of lncRNAs were examined. Survival analysis was surveyed on the GEPIA web server. RESULTS We identified 19,560 hypomethylated and 68,781 hypermethylated differentially methylated regions around transcription start sites in bladder cancer tissues. In total, 2321 differentially expressed genes were found in bladder tumors, among which, 367 were upregulated and 1954 were downregulated. There were 141 downregulated genes involving eight lncRNAs that were consistently hypermethylated, while 24 upregulated genes were consistently hypomethylated. Survival analysis demonstrated that hypermethylation of lncRNAs LINC00683 and MSC-AS1 were associated with poor overall survival in bladder cancer patients. CONCLUSION Some lncRNAs are controlled by DNA methylation in bladder cancer and they might be important factors in bladder carcinogenesis. Hypermethylated lncRNAs including LINC00683 and MSC-AS1 have the potential to be prognostic biomarkers for bladder cancer.
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Affiliation(s)
- Junhua Luo
- Department of Urology, 74573Peking University Shenzhen Hospital, Peking University Shenzhen Hospital, Shenzhen, P.R. China
| | - Jinming Xu
- Department of Urology, 74573Peking University Shenzhen Hospital, Peking University Shenzhen Hospital, Shenzhen, P.R. China
| | - Longhua Ou
- Department of Urology, 74573Peking University Shenzhen Hospital, Peking University Shenzhen Hospital, Shenzhen, P.R. China
| | - Yingchen Zhou
- Department of Urology, 74573Peking University Shenzhen Hospital, Peking University Shenzhen Hospital, Shenzhen, P.R. China
| | - Haichao Yun
- Department of Urology, 74573Peking University Shenzhen Hospital, Peking University Shenzhen Hospital, Shenzhen, P.R. China
| | - Yu Yang
- Department of Urology, 74573Peking University Shenzhen Hospital, Peking University Shenzhen Hospital, Shenzhen, P.R. China
| | - Xionghui Wu
- Department of Urology, 74573Peking University Shenzhen Hospital, Peking University Shenzhen Hospital, Shenzhen, P.R. China
| | - Yan Wang
- Department of Urology, 74573Peking University Shenzhen Hospital, Peking University Shenzhen Hospital, Shenzhen, P.R. China
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Yamazaki J, Jelinek J, Yokoyama S, Takiguchi M. Genome-wide DNA methylation profile in feline haematological tumours: A preliminary study. Res Vet Sci 2021; 140:221-228. [PMID: 34534903 DOI: 10.1016/j.rvsc.2021.09.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 08/18/2021] [Accepted: 09/06/2021] [Indexed: 01/17/2023]
Abstract
Although DNA methylation has been analysed in few studies for a limited number of loci in cats with diseases, genome-wide profile of DNA methylation has never been addressed. The hypothesis for this study is that next-generation sequencing with sequential digestion of genomic DNA with SmaI and XmaI enzymes could provide highly quantitative information on methylation levels in cats. Using blood from four healthy control cats and two disease cats as well as three feline lymphoma/leukemia cell lines, approximately 74-94 thousand CpG sites across the cat genome could be analysed. CpG sites in CpG island (CGI) were broadly either methylated or unmethylated in normal blood, while CpG sites in non-CpG islands (NCGI) are largely methylated. Lymphoma cell lines showed thousands of CpG sites with gain of methylation at normally unmethylated CGI sites and loss of methylation at normally methylated NCGI sites. Hypermethylated CpG sites located at promoter regions included genes annotated with 'developmental process' and 'anatomical structure morphogenesis' such as HOXD10. This highly quantitative method would be suitable for studies of DNA methylation changes not only in cancer but also in other common diseases in cats.
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Affiliation(s)
- Jumpei Yamazaki
- Translational Research Unit, Veterinary Teaching Hospital, Graduate School of Veterinary Medicine, Hokkaido University, Japan; One Health Research Center, Hokkaido University, Japan; Veterinary Teaching Hospital, Graduate School of Veterinary Medicine, Hokkaido University, Japan.
| | | | - Shoko Yokoyama
- Translational Research Unit, Veterinary Teaching Hospital, Graduate School of Veterinary Medicine, Hokkaido University, Japan; One Health Research Center, Hokkaido University, Japan; Veterinary Teaching Hospital, Graduate School of Veterinary Medicine, Hokkaido University, Japan
| | - Mitsuyoshi Takiguchi
- Veterinary Teaching Hospital, Graduate School of Veterinary Medicine, Hokkaido University, Japan
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Sun L, Wan A, Zhou Z, Chen D, Liang H, Liu C, Yan S, Niu Y, Lin Z, Zhan S, Wang S, Bu X, He W, Lu X, Xu A, Wan G. RNA-binding protein RALY reprogrammes mitochondrial metabolism via mediating miRNA processing in colorectal cancer. Gut 2021; 70:1698-1712. [PMID: 33219048 PMCID: PMC8355885 DOI: 10.1136/gutjnl-2020-320652] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 10/08/2020] [Accepted: 10/27/2020] [Indexed: 01/17/2023]
Abstract
OBJECTIVE Dysregulated cellular metabolism is a distinct hallmark of human colorectal cancer (CRC). However, metabolic programme rewiring during tumour progression has yet to be fully understood. DESIGN We analysed altered gene signatures during colorectal tumour progression, and used a complex of molecular and metabolic assays to study the regulation of metabolism in CRC cell lines, human patient-derived xenograft mouse models and tumour organoid models. RESULTS We identified a novel RNA-binding protein, RALY (also known as hnRNPCL2), that is highly associated with colorectal tumour aggressiveness. RALY acts as a key regulatory component in the Drosha complex, and promotes the post-transcriptional processing of a specific subset of miRNAs (miR-483, miR-676 and miR-877). These miRNAs systematically downregulate the expression of the metabolism-associated genes (ATP5I, ATP5G1, ATP5G3 and CYC1) and thereby reprogramme mitochondrial metabolism in the cancer cell. Analysis of The Cancer Genome Atlas (TCGA) reveals that increased levels of RALY are associated with poor prognosis in the patients with CRC expressing low levels of mitochondrion-associated genes. Mechanistically, induced processing of these miRNAs is facilitated by their N6-methyladenosine switch under reactive oxygen species (ROS) stress. Inhibition of the m6A methylation abolishes the RALY recognition of the terminal loop of the pri-miRNAs. Knockdown of RALY inhibits colorectal tumour growth and progression in vivo and in organoid models. CONCLUSIONS Collectively, our results reveal a critical metabolism-centric role of RALY in tumour progression, which may lead to cancer therapeutics targeting RALY for treating CRC.
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Affiliation(s)
- Lei Sun
- National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, National Engineering Research Center for New Drug and Druggability (cultivation), Guangdong Province Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Arabella Wan
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Zhuolong Zhou
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Dongshi Chen
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Heng Liang
- National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, National Engineering Research Center for New Drug and Druggability (cultivation), Guangdong Province Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Chuwei Liu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Shijia Yan
- National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, National Engineering Research Center for New Drug and Druggability (cultivation), Guangdong Province Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Yi Niu
- National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, National Engineering Research Center for New Drug and Druggability (cultivation), Guangdong Province Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Ziyou Lin
- National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, National Engineering Research Center for New Drug and Druggability (cultivation), Guangdong Province Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Siyue Zhan
- National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, National Engineering Research Center for New Drug and Druggability (cultivation), Guangdong Province Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Shanfeng Wang
- School of Materials Science and Engineering, Sun Yat-Sen University, Guangzhou, China
| | - Xianzhang Bu
- National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, National Engineering Research Center for New Drug and Druggability (cultivation), Guangdong Province Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Weiling He
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China,Center for Precision Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Xiongbin Lu
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA .,Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, IN, USA
| | - Anlong Xu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China .,State Key Laboratory of Biocontrol, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Guohui Wan
- National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, National Engineering Research Center for New Drug and Druggability (cultivation), Guangdong Province Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
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Ghasemi T, Khalaj-Kondori M, Hosseinpour Feizi MA, Asadi P. Aberrant expression of lncRNAs SNHG6, TRPM2-AS1, MIR4435-2HG, and hypomethylation of TRPM2-AS1 promoter in colorectal cancer. Cell Biol Int 2021; 45:2464-2478. [PMID: 34431156 DOI: 10.1002/cbin.11692] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 08/08/2021] [Accepted: 08/22/2021] [Indexed: 01/30/2023]
Abstract
Accumulating evidence has indicated that deregulation of lncRNAs plays essential roles in colorectal cancer (CRC) carcinogenesis. The goal of this study was to analyze the expression of lncRNAs in colorectal cancer and their association with clinicopathological variables. Bioinformatics analysis of published CRC microarray data was performed to identify the important lncRNAs. The expression levels of candidate genes were assessed in the human colon cancer/normal cell lines, CRC, adenomatous colorectal polyps, and their marginal tissues by qRT-PCR. Moreover, the methylation status of the TRPM2-AS1 promoter was studied using qMSP assay. Furthermore, we investigated the molecular mechanisms of these lncRNAs in CRC progression using in silico analysis. Microarray analysis revealed that lncRNAs SNHG6, MIR4435-2HG, and TRPM2-AS1 were upregulated in CRC. These results were validated in colon cell lines. Moreover, qRT-PCR showed that the expression levels of SNHG6 and TRPM2-AS1 were upregulated in the colorectal tumor tissues compared with their paired tissues. Nonetheless, there was no significant increase in MIR4435-2HG expression in CRC samples. Furthermore, we observed a significant hypomethylation of TRPM2-AS1 promoter and its activation in CRC tissues. By in silico analysis, we found that the lncRNAs upregulation could promote proliferation and drug resistance of colorectal cancer cells via miRNAs sponging and modulation of their targets expression. In conclusion, based on our results upregulation of SNHG6 and TRPM2-AS1, and hypomethylation of TRPM2-AS1 promoter might be considered as potential diagnostic biomarkers for CRC initiation and development.
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Affiliation(s)
- Tayyebeh Ghasemi
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Mohammad Khalaj-Kondori
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | | | - Parviz Asadi
- Medical Science Division, Imam Sajjad Hospital, Islamic Azad University, Tabriz, Iran
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Exploring novel capping framework: high substituent pyridine-hydroxamic acid derivatives as potential antiproliferative agents. ACTA ACUST UNITED AC 2021; 29:291-310. [PMID: 34297326 DOI: 10.1007/s40199-021-00406-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 06/26/2021] [Indexed: 10/20/2022]
Abstract
PURPOSE Histone deacetylases (HDACs) play a vital role in the epigenetic regulation of gene expression due to their overexpression in several cancer forms. Therefore, these enzymes are considered as a potential anticancer drug target. Different synthetic and natural structures have been studied as HDACs inhibitors; based on available structural design information, the capping group is important for the biological activity due to the different interactions in the active site entrance. The present study aimed to analyze high substituted pyridine as a capping group, which included carrying out the synthesis, antiproliferative activity analysis, and docking studies of these novel compounds. METHODS To achieve the synthesis of these derivatives, four reaction steps were performed, generating desired products 15a-k. Their effects on cell proliferation and gene expression of p21, cyclin D1, and p53 were determined using the sulphorhodamine B (SRB) method and quantitative real-time polymerase chain reaction. The HDAC1, HDAC6, and HDAC8 isoforms were used for performing docking experiments with our 15a-k products. RESULT The products 15a-k were obtained in overall yields of 40-71%. Compounds 15j and 15k showed the highest antiproliferative activity in the breast (BT-474 and MDA-MB-231) and prostate (PC3) cancer cell lines at a concentration of 10 µM. These compounds increased p21 mRNA levels and decreased cyclin D1 and p53 gene expression. The docking study showed an increment in the strength, and in the number of interactions performed by the capping moiety of the tested molecules compared with SAHA; interactions displayed are mainly van der Waals, π-stacking, and hydrogen bond. CONCLUSION The synthesized compounds 2-thiophene (15j) and 2-furan (15k) pyridine displayed cell growth inhibition, regulation of genes related to cell cycle progression in highly metastatic cancer cell lines. The molecular coupling analysis performed with HDAC1, HDAC6 and HDAC8 showed an increment in the number of interactions performed by the capping moiety and consequently in the strength of the capping group interaction.
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Pan T, Wu F, Li L, Wu S, Zhou F, Zhang P, Sun C, Xia L. The role m 6A RNA methylation is CNS development and glioma pathogenesis. Mol Brain 2021; 14:119. [PMID: 34281602 PMCID: PMC8290532 DOI: 10.1186/s13041-021-00831-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Accepted: 05/31/2021] [Indexed: 12/22/2022] Open
Abstract
Epigenetic abnormalities play a crucial role in many tumors, including glioma. RNA methylation occurs as an epigenetic modification similar to DNA methylation and histone modification. m6A methylation is the most common and most intensively studied RNA methylation, which can be found throughout the RNA life cycle and exert biological functions by affecting RNA metabolism. The m6A modification is primarily associated with three types of protease, which are encoded by the writer, eraser and reader genes, respectively. It has been shown that the m6A methylation has close connections with the occurrence and development of many tumors, including glioma. In this study, the concept and the research progress of m6A methylation are reviewed, especially the role of m6A methylation in glioma. Moreover, we will discuss how glioma is paving the way to the development of new therapeutic options based on the inhibition of m6A deposition.
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Affiliation(s)
- Ting Pan
- School of the Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310053, China.,Department of Gynecological Oncology, Cancer Hospital of University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, People's Republic of China
| | - Fan Wu
- School of the Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Liwen Li
- Department of Neurosurgery, Cancer Hospital of University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, People's Republic of China.,Key Laboratory of Head & Neck Cancer, Translational Research of Zhejiang Province, Hangzhou, 310022, People's Republic of China
| | - Shiyan Wu
- School of the Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310053, China.,Department of Gynecological Oncology, Cancer Hospital of University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, People's Republic of China
| | - Fang Zhou
- School of the Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310053, China.,Department of Gynecological Oncology, Cancer Hospital of University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, People's Republic of China
| | - Ping Zhang
- Department of Gynecological Oncology, Cancer Hospital of University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, People's Republic of China.
| | - Caixing Sun
- Department of Neurosurgery, Cancer Hospital of University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, People's Republic of China. .,Key Laboratory of Head & Neck Cancer, Translational Research of Zhejiang Province, Hangzhou, 310022, People's Republic of China.
| | - Liang Xia
- Department of Neurosurgery, Cancer Hospital of University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, People's Republic of China. .,Key Laboratory of Head & Neck Cancer, Translational Research of Zhejiang Province, Hangzhou, 310022, People's Republic of China.
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Huang J, Li Z, Fu L, Lin D, Wang C, Wang X, Zhang L. RETRACTED ARTICLE: Comprehensive characterization of tumor mutation burden in clear cell renal cell carcinoma based on the three independent cohorts. J Cancer Res Clin Oncol 2021; 147:1745. [PMID: 32617702 DOI: 10.1007/s00432-020-03299-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Accepted: 01/10/2020] [Indexed: 12/15/2022]
Affiliation(s)
- Jing Huang
- Fujian Provincial Key Laboratory of Ecology-Toxicological Effects and Control for Emerging Contaminants, Key Laboratory of Ecological Environment and Information Atlas (Putian University) Fujian Provincial University, Key Laboratory of Loquat Germplasm Innovation and Utilization (Putian University), Fujian Province University, College of Environmental and Biological Engineering, Putian University, Putian, 351100, Fujian, China.
| | - Zhou Li
- School of Public Health, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Lijun Fu
- Fujian Provincial Key Laboratory of Ecology-Toxicological Effects and Control for Emerging Contaminants, Key Laboratory of Ecological Environment and Information Atlas (Putian University) Fujian Provincial University, Key Laboratory of Loquat Germplasm Innovation and Utilization (Putian University), Fujian Province University, College of Environmental and Biological Engineering, Putian University, Putian, 351100, Fujian, China
| | - Dahe Lin
- Fujian Provincial Key Laboratory of Ecology-Toxicological Effects and Control for Emerging Contaminants, Key Laboratory of Ecological Environment and Information Atlas (Putian University) Fujian Provincial University, Key Laboratory of Loquat Germplasm Innovation and Utilization (Putian University), Fujian Province University, College of Environmental and Biological Engineering, Putian University, Putian, 351100, Fujian, China
| | - Chunhua Wang
- Fujian Provincial Key Laboratory of Ecology-Toxicological Effects and Control for Emerging Contaminants, Key Laboratory of Ecological Environment and Information Atlas (Putian University) Fujian Provincial University, Key Laboratory of Loquat Germplasm Innovation and Utilization (Putian University), Fujian Province University, College of Environmental and Biological Engineering, Putian University, Putian, 351100, Fujian, China
| | - Xiumei Wang
- Fujian Provincial Key Laboratory of Ecology-Toxicological Effects and Control for Emerging Contaminants, Key Laboratory of Ecological Environment and Information Atlas (Putian University) Fujian Provincial University, Key Laboratory of Loquat Germplasm Innovation and Utilization (Putian University), Fujian Province University, College of Environmental and Biological Engineering, Putian University, Putian, 351100, Fujian, China
| | - Lifen Zhang
- Fujian Provincial Key Laboratory of Ecology-Toxicological Effects and Control for Emerging Contaminants, Key Laboratory of Ecological Environment and Information Atlas (Putian University) Fujian Provincial University, Key Laboratory of Loquat Germplasm Innovation and Utilization (Putian University), Fujian Province University, College of Environmental and Biological Engineering, Putian University, Putian, 351100, Fujian, China
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Moreno-Acosta P, Molano MÓ, Morales N, Acosta J, GonzÁlez-Prieto C, Mayorga D, Buitrago L, Gamboa O, MejÍa JC, Castro J, Romero-Rojas A, Espenel S, Murray GL, Garland SM, Vallard A, MagnÉ N. hTERT Protein Expression in Cytoplasm and Nucleus and its Association With HPV Infection in Patients With Cervical Cancer. Cancer Genomics Proteomics 2021; 17:615-625. [PMID: 32859640 DOI: 10.21873/cgp.20218] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 05/15/2020] [Accepted: 05/18/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Few studies have analyzed the association between human telomerase reverse transcriptase (hTERT) protein expression (nuclear and cytoplasmic localization), hTERT methylation status, and human papillomavirus (HPV) genotype infection in cervical cancer. PATIENTS AND METHODS One hundred seventy-three patients with cervical cancer were analyzed. hTERT protein expression was detected by immunohistochemistry. hTERT DNA methylation analysis was performed using a PCR-RLB-hTERT assay, targeting two regions of the hTERT promoter. Type specific HPV infection was detected by using GP5+/GP6+PCR-RLB. RESULTS hTERT protein expression was found in both cytoplasm and nucleus (78.0% of the samples showed a cytoplasmic localization and 79.8% had a nuclear localization). A statistically significant association was found between alpha 9 and 7 HPV species with a non-methylation pattern of the hTERT promoter and between these species and high expression of hTERT protein with nuclear localization. CONCLUSION hTERT protein is found in both the nucleus and cytoplasm of patients with cervical cancer and confirm the relationship between the non-methylated status of hTERT promoter and some HPV species as well as the relationship between these species and hTERT protein expression.
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Affiliation(s)
- Pablo Moreno-Acosta
- Research Group in Radiobiology Clinical, Molecular and Cellular, National Cancer Institute, Bogotá, Colombia .,Research Group in Cancer Biology, National Cancer Institute, Bogotá, Colombia
| | - MÓnica Molano
- Centre Women's Infectious Diseases Research, The Royal Women's Hospital, Melbourne, Australia
| | - Nicolas Morales
- Research Group in Cancer Biology, National Cancer Institute, Bogotá, Colombia
| | - Jinneth Acosta
- Pathology Group, National University of Colombia, Bogotá, Colombia
| | | | - Diana Mayorga
- Research Group in Radiobiology Clinical, Molecular and Cellular, National Cancer Institute, Bogotá, Colombia
| | - Lina Buitrago
- Unit of Analysis, National Cancer Institute, Bogotá, Colombia
| | - Oscar Gamboa
- Unit of Analysis, National Cancer Institute, Bogotá, Colombia
| | - Juan Carlos MejÍa
- Group of Pathology Oncology, National Cancer Institute, Bogotá, Colombia
| | - July Castro
- Group of Pathology Oncology, National Cancer Institute, Bogotá, Colombia
| | | | - Sophie Espenel
- Department of Radiation Oncology, Institut de Cancérologie de la Loire-Lucien Neuwirth, Saint-Priest en Jarez, France
| | - Gerald L Murray
- Centre Women's Infectious Diseases Research, The Royal Women's Hospital, Melbourne, Australia.,Department of Obstetrics and Gynecology, University of Melbourne, Parkville, VIC, Australia.,Murdoch Children's Research Institute, Parkville, VIC, Australia
| | - Suzanne M Garland
- Centre Women's Infectious Diseases Research, The Royal Women's Hospital, Melbourne, Australia.,Department of Obstetrics and Gynecology, University of Melbourne, Parkville, VIC, Australia.,Murdoch Children's Research Institute, Parkville, VIC, Australia
| | - Alexis Vallard
- Department of Radiation Oncology, Institut de Cancérologie de la Loire-Lucien Neuwirth, Saint-Priest en Jarez, France
| | - Nicolas MagnÉ
- Department of Radiation Oncology, Institut de Cancérologie de la Loire-Lucien Neuwirth, Saint-Priest en Jarez, France
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The Role of Epigenetics in the Progression of Clear Cell Renal Cell Carcinoma and the Basis for Future Epigenetic Treatments. Cancers (Basel) 2021; 13:cancers13092071. [PMID: 33922974 PMCID: PMC8123355 DOI: 10.3390/cancers13092071] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 04/22/2021] [Accepted: 04/23/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary The accumulated evidence on the role of epigenetic markers of prognosis in clear cell renal cell carcinoma (ccRCC) is reviewed, as well as state of the art on epigenetic treatments for this malignancy. Several epigenetic markers are likely candidates for clinical use, but still have not passed the test of prospective validation. Development of epigenetic therapies, either alone or in combination with tyrosine-kinase inhibitors of immune-checkpoint inhibitors, are still in their infancy. Abstract Clear cell renal cell carcinoma (ccRCC) is curable when diagnosed at an early stage, but when disease is non-confined it is the urologic cancer with worst prognosis. Antiangiogenic treatment and immune checkpoint inhibition therapy constitute a very promising combined therapy for advanced and metastatic disease. Many exploratory studies have identified epigenetic markers based on DNA methylation, histone modification, and ncRNA expression that epigenetically regulate gene expression in ccRCC. Additionally, epigenetic modifiers genes have been proposed as promising biomarkers for ccRCC. We review and discuss the current understanding of how epigenetic changes determine the main molecular pathways of ccRCC initiation and progression, and also its clinical implications. Despite the extensive research performed, candidate epigenetic biomarkers are not used in clinical practice for several reasons. However, the accumulated body of evidence of developing epigenetically-based biomarkers will likely allow the identification of ccRCC at a higher risk of progression. That will facilitate the establishment of firmer therapeutic decisions in a changing landscape and also monitor active surveillance in the aging population. What is more, a better knowledge of the activities of chromatin modifiers may serve to develop new therapeutic opportunities. Interesting clinical trials on epigenetic treatments for ccRCC associated with well established antiangiogenic treatments and immune checkpoint inhibitors are revisited.
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Association between Oral Cancer and Diet: An Update. Nutrients 2021; 13:nu13041299. [PMID: 33920788 PMCID: PMC8071138 DOI: 10.3390/nu13041299] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 04/04/2021] [Accepted: 04/13/2021] [Indexed: 02/08/2023] Open
Abstract
Oral cancer, included within head and neck cancer, is the sixth most common malignant neoplasm in the world. The main etiological factors are tobacco and alcohol, although currently, diet is considered an important determinant for its development. Several dietary nutrients have specific mechanisms of action, contributing to both protection against cancer and increasing the risk for development, growth, and spread. Foods such as fruits, vegetables, curcumin, and green tea can reduce the risk of oral cancer, while the so-called pro-inflammatory diet, rich in red meat and fried foods, can enhance the risk of occurrence. Dietary factors with a protective effect show different mechanisms that complement and overlap with antioxidant, anti-inflammatory, anti-angiogenic, and anti-proliferative effects. The main limitation of in vivo studies is the complexity of isolating the effects related to each one of the nutrients and the relationship with other possible etiological mechanisms. On the contrary, in vitro studies allow determining the specific mechanisms of action of some of the dietary compounds. In conclusion, and despite research limitations, the beneficial effects of a diet rich in vegetables and fruits are attributed to different micronutrients that are also found in fish and animal products. These compounds show antioxidant, anti-inflammatory, anti-angiogenic, and anti-proliferative properties that have a preventive role in the development of oral and other types of cancer.
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Zou X, Zhao Y, Liang X, Wang H, Zhu Y, Shao Q. Double Insurance for OC: miRNA-Mediated Platinum Resistance and Immune Escape. Front Immunol 2021; 12:641937. [PMID: 33868274 PMCID: PMC8047328 DOI: 10.3389/fimmu.2021.641937] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 03/09/2021] [Indexed: 12/14/2022] Open
Abstract
Ovarian cancer (OC) is still the leading cause of death among all gynecological malignancies, despite the recent progress in cancer therapy. Immune escape and drug resistance, especially platinum-based chemotherapy, are significant factors causing disease progression, recurrence and poor prognosis in OC patients. MicroRNAs(miRNAs) are small noncoding RNAs, regulating gene expression at the transcriptional level. Accumulating evidence have indicated their crucial roles in platinum resistance. Importantly, they also act as mediators of tumor immune escape/evasion. In this review, we summarize the recent study of miRNAs involved in platinum resistance of OC and systematically analyses miRNAs involved in the regulation of OC immune escape. Further understanding of miRNAs roles and their possible mechanisms in platinum resistance and tumor escape may open new avenues for improving OC therapy.
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Affiliation(s)
- Xueqin Zou
- Reproductive Sciences Institute, Jiangsu University, Zhenjiang, China.,Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Yangjing Zhao
- Reproductive Sciences Institute, Jiangsu University, Zhenjiang, China.,Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Xiuting Liang
- Department of Obstetrics and Gynecology, Xuzhou Hospital Affiliated to Jiangsu University, Xuzhou, China
| | - Hui Wang
- Reproductive Sciences Institute, Jiangsu University, Zhenjiang, China.,Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Yanling Zhu
- Department of Obstetrics and Gynecology, Xuzhou Hospital Affiliated to Jiangsu University, Xuzhou, China
| | - Qixiang Shao
- Reproductive Sciences Institute, Jiangsu University, Zhenjiang, China.,Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, China.,Jiangsu College of Nursing, School of Medical Science and Laboratory Medicine, Huai'an, China
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Lai P, Wang Y. Epigenetics of cutaneous T-cell lymphoma: biomarkers and therapeutic potentials. Cancer Biol Med 2021; 18:34-51. [PMID: 33628583 PMCID: PMC7877166 DOI: 10.20892/j.issn.2095-3941.2020.0216] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 07/30/2020] [Indexed: 12/31/2022] Open
Abstract
Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of skin-homing non-Hodgkin lymphomas. There are limited options for effective treatment of patients with advanced-stage CTCL, leading to a poor survival rate. Epigenetics plays a pivotal role in regulating gene expression without altering the DNA sequence. Epigenetic alterations are involved in virtually all key cancer-associated pathways and are fundamental to the genesis of cancer. In recent years, the epigenetic hallmarks of CTCL have been gradually elucidated and their potential values in the diagnosis, prognosis, and therapeutic intervention have been clarified. In this review, we summarize the current knowledge of the best-studied epigenetic modifications in CTCL, including DNA methylation, histone modifications, microRNAs, and chromatin remodelers. These epigenetic regulators are essential in the development of CTCL and provide new insights into the clinical treatments of this refractory disease.
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Affiliation(s)
- Pan Lai
- Department of Dermatology and Venereology, Peking University First Hospital, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, National Clinical Research Center for Skin and Immune Diseases, Beijing 100034, China
| | - Yang Wang
- Department of Dermatology and Venereology, Peking University First Hospital, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, National Clinical Research Center for Skin and Immune Diseases, Beijing 100034, China
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SLFN11 promotes CDT1 degradation by CUL4 in response to replicative DNA damage, while its absence leads to synthetic lethality with ATR/CHK1 inhibitors. Proc Natl Acad Sci U S A 2021; 118:2015654118. [PMID: 33536335 PMCID: PMC8017720 DOI: 10.1073/pnas.2015654118] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Schlafen-11 (SLFN11) inactivation in ∼50% of cancer cells confers broad chemoresistance. To identify therapeutic targets and underlying molecular mechanisms for overcoming chemoresistance, we performed an unbiased genome-wide RNAi screen in SLFN11-WT and -knockout (KO) cells. We found that inactivation of Ataxia Telangiectasia- and Rad3-related (ATR), CHK1, BRCA2, and RPA1 overcome chemoresistance to camptothecin (CPT) in SLFN11-KO cells. Accordingly, we validate that clinical inhibitors of ATR (M4344 and M6620) and CHK1 (SRA737) resensitize SLFN11-KO cells to topotecan, indotecan, etoposide, cisplatin, and talazoparib. We uncover that ATR inhibition significantly increases mitotic defects along with increased CDT1 phosphorylation, which destabilizes kinetochore-microtubule attachments in SLFN11-KO cells. We also reveal a chemoresistance mechanism by which CDT1 degradation is retarded, eventually inducing replication reactivation under DNA damage in SLFN11-KO cells. In contrast, in SLFN11-expressing cells, SLFN11 promotes the degradation of CDT1 in response to CPT by binding to DDB1 of CUL4CDT2 E3 ubiquitin ligase associated with replication forks. We show that the C terminus and ATPase domain of SLFN11 are required for DDB1 binding and CDT1 degradation. Furthermore, we identify a therapy-relevant ATPase mutant (E669K) of the SLFN11 gene in human TCGA and show that the mutant contributes to chemoresistance and retarded CDT1 degradation. Taken together, our study reveals new chemotherapeutic insights on how targeting the ATR pathway overcomes chemoresistance of SLFN11-deficient cancers. It also demonstrates that SLFN11 irreversibly arrests replication by degrading CDT1 through the DDB1-CUL4CDT2 ubiquitin ligase.
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