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Dorna D, Grabowska A, Paluszczak J. Natural products modulating epigenetic mechanisms by affecting histone methylation/demethylation: Targeting cancer cells. Br J Pharmacol 2025; 182:2137-2158. [PMID: 37700551 DOI: 10.1111/bph.16237] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 08/29/2023] [Accepted: 09/04/2023] [Indexed: 09/14/2023] Open
Abstract
Many natural products can exert anticancer or chemopreventive activity by interfering with the cellular epigenetic machinery. Many studies indicate the relevance of affecting DNA methylation and histone acetylation, however the influence on the mechanisms related to histone methylation are often overlooked. This may be associated with the lagging evidence that changes in the action of histone methylation writers and erasers, and subsequent alterations in the profile of histone methylation are causally related with carcinogenesis. Recent animal studies have shown that targeting histone methylation/demethylation affects the course of experimentally induced carcinogenesis. Existing data suggest that numerous natural compounds from different chemical groups, including green tea polyphenols and other flavonoids, curcuminoids, stilbene derivatives, phenolic acids, isothiocyanates, alkaloids and terpenes, can affect the expression and activity of crucial enzymes involved in the methylation and demethylation of histone lysine and arginine residues. These activities have been associated with the modulation of cancer-related gene expression and functional changes, including reduced cell proliferation and migration, and enhanced apoptosis in various cancer models. Most studies focused on the modulation of the expression and/or activity of two proteins - EZH2 (a H3K27 methyltransferase) and LSD1 (lysine demethylase 1A - a H3K4/9 demethylase), or the effects on the global levels of histone methylation caused by the phytochemicals, but data regarding other histone methyltransferases or demethylases are scarce. While the field remains relatively unexplored, this review aims to explore the impact of natural products on the enzymes related to histone methylation/demethylation, showing their relevance to carcinogenesis and cancer progression. LINKED ARTICLES: This article is part of a themed issue Natural Products and Cancer: From Drug Discovery to Prevention and Therapy. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.10/issuetoc.
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Affiliation(s)
- Dawid Dorna
- Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, Poznań, Poland
| | - Adriana Grabowska
- Department of Molecular Neurooncology, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznań, Poland
| | - Jarosław Paluszczak
- Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, Poznań, Poland
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2
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Zhang X, Xiao L, Zhou X, Xu J, Liao L, Wu P, Liao Z, Duan X. Identification of a chromatin regulator signature and potential candidate drugs for primary open-angle glaucoma. Epigenomics 2025; 17:377-387. [PMID: 40091789 PMCID: PMC11980481 DOI: 10.1080/17501911.2025.2479420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 03/10/2025] [Indexed: 03/19/2025] Open
Abstract
AIMS This research aims to establish a chromatin regulator (CR) signature to provide new epigenetic insights into the pathogenesis of primary open-angle glaucoma (POAG). MATERIALS & METHODS The expression profile of CRs in trabecular meshwork (TM) tissues was analyzed by bioinformatics analysis; The selected hub CRs were further verified by cell experiments. RESULTS We found the immune microenvironment of the TMwas changed in POAG patients and identified 3 differentially expressed CRs that were relevant to immunity. Then, we successfully constructed and proved a predicted signature based on these 3 CRs, which could effectively predict the risk of POAG. The genes co-expressed with these 3 CRs and miRNAs with are gulatory relationship were identified, and a miRNA-hub CR network was successfully constructed. The results of the Gene Set Enrichment analysis indicated that these 3 hub CRs were all associated with neurodegenerative diseases. Moreover, the human trabecular meshwork cell (HTMC) oxidative stress model was constructed, and KDM5B was significantly down-regulated in this cell model. Finally, we found 10 agents that might be helpful for patients with POAG. CONCLUSIONS Dysregulation of CR expression in TM tissues may be involved in the occurrence and progression of POAG through multiple mechanisms.
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Affiliation(s)
- Xinyue Zhang
- Glaucoma Institute, Hunan Engineering Research Center for Glaucoma with Artificial Intelligence in Diagnosis and Application of New Materials, Changsha Aier Eye Hospital, Changsha, Hunan, China
- Aier School of Ophthalmology, Central South University, Changsha, Hunan, China
| | - Lulu Xiao
- Glaucoma Institute, Hunan Engineering Research Center for Glaucoma with Artificial Intelligence in Diagnosis and Application of New Materials, Changsha Aier Eye Hospital, Changsha, Hunan, China
- Aier Eye Hospital, Jinan University, Guangzhou, China
| | - Xiaoyu Zhou
- Glaucoma Institute, Hunan Engineering Research Center for Glaucoma with Artificial Intelligence in Diagnosis and Application of New Materials, Changsha Aier Eye Hospital, Changsha, Hunan, China
| | - Jiahao Xu
- Glaucoma Institute, Hunan Engineering Research Center for Glaucoma with Artificial Intelligence in Diagnosis and Application of New Materials, Changsha Aier Eye Hospital, Changsha, Hunan, China
| | - Li Liao
- Aier School of Ophthalmology, Central South University, Changsha, Hunan, China
| | - Ping Wu
- Aier School of Ophthalmology, Central South University, Changsha, Hunan, China
| | - Zhimin Liao
- Glaucoma Institute, Hunan Engineering Research Center for Glaucoma with Artificial Intelligence in Diagnosis and Application of New Materials, Changsha Aier Eye Hospital, Changsha, Hunan, China
| | - Xuanchu Duan
- Glaucoma Institute, Hunan Engineering Research Center for Glaucoma with Artificial Intelligence in Diagnosis and Application of New Materials, Changsha Aier Eye Hospital, Changsha, Hunan, China
- Aier School of Ophthalmology, Central South University, Changsha, Hunan, China
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Zhu W, Ni Q, Wang Z, Zhang R, Liu F, Chang H. MiR-101-3p targets the PI3K-AKT signaling pathway via Birc5 to inhibit invasion, proliferation, and epithelial-mesenchymal transition in hepatocellular carcinoma. Clin Exp Med 2025; 25:88. [PMID: 40106068 PMCID: PMC11923034 DOI: 10.1007/s10238-025-01622-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Accepted: 02/28/2025] [Indexed: 03/22/2025]
Abstract
MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate numerous genes in cells. Abnormal expression of miRNAs can lead to cancer. However, the roles and underlying mechanisms of miRNAs in hepatocellular carcinoma (HCC) are not fully understood. Using molecular biology techniques, we designed eukaryotic expression vectors with enhanced expression of miR-101-3p to transfect human hepatocellular carcinoma cell lines. Subsequent to this, cell cloning experiments, CCK8 assays, and Transwell migration experiments were executed to assess their impact on liver cancer cell proliferation and invasion. Dual-luciferase assays were employed to validate the molecular interaction between miR-101-3p and Birc5. Through rescue experiments aimed at manipulating the expression levels of Birc5, we scrutinized the influence of miR-101-3p on liver cancer cell proliferation and invasion. Furthermore, Western blot analysis was utilized to monitor alterations in the expression levels of E-cadherin, N-cadherin, and vimentin proteins within each cell group. In vivo investigations were conducted using nude mice implanted with hepatocellular carcinoma cells transfected with Birc5. Additionally, further exploration was carried out by combining this model with the PI3K/AKT pathway inhibitor miltefosine to elucidate its effects on tumor proliferation. In vitro functional analysis of miR-101-3p revealed that treatment of HCC cells with its corresponding mimic significantly inhibited cell proliferation, colony formation, invasion, and epithelial-mesenchymal transition. Additionally, miR-101-3p exerts its anti-tumor effects by targeting the shared gene Birc5. Experiments using nude mouse models demonstrate that Birc5 promotes tumor proliferation by phosphorylating the PI3K/AKT signaling pathway. Inhibiting the PI3K/AKT signaling pathway shows suppressive effects on liver cancer proliferation. MiR-101-3p plays crucial roles in inhibiting the proliferation, invasion and epithelial-mesenchymal transition of HCC cells by targeting Birc5 and downregulating the PI3K-AKT signaling pathway. These findings provide new insights for the molecular treatment of HCC.
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Affiliation(s)
- Wenyuan Zhu
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China
| | - Qingqiang Ni
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China
| | - Zhengjian Wang
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China
| | - Ruxuan Zhang
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China
| | - Fangfeng Liu
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China.
| | - Hong Chang
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China.
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Costa S, La Rocca G, Cavalieri V. Epigenetic Regulation of Chromatin Functions by MicroRNAs and Long Noncoding RNAs and Implications in Human Diseases. Biomedicines 2025; 13:725. [PMID: 40149701 PMCID: PMC11939841 DOI: 10.3390/biomedicines13030725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Revised: 03/12/2025] [Accepted: 03/14/2025] [Indexed: 03/29/2025] Open
Abstract
The bulk of RNA produced from the genome of complex organisms consists of a very large number of transcripts lacking protein translational potential and collectively known as noncoding RNAs (ncRNAs). Initially thought to be mere products of spurious transcriptional noise, ncRNAs are now universally recognized as pivotal players in cell regulatory networks across a broad spectrum of biological processes. Owing to their critical regulatory roles, ncRNA dysfunction is closely associated with the etiopathogenesis of various human malignancies, including cancer. As such, ncRNAs represent valuable diagnostic biomarkers as well as potential targets for innovative therapeutic intervention. In this review, we focus on microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), the two most extensively studied classes in the field of ncRNA biology. After outlining key concepts of miRNA and lncRNA biogenesis pathways, we examine their multiple roles in mediating epigenetic regulation of gene expression and chromatin organization. Finally, by providing numerous examples of specific miRNAs and lncRNAs, we discuss how dysregulation of these mechanisms contributes to the onset and/or progression of various human diseases.
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Affiliation(s)
| | | | - Vincenzo Cavalieri
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STeBiCeF), University of Palermo, Viale delle Scienze Bld. 16, 90128 Palermo, Italy
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Zwamel AH, Ahmad AT, Altalbawy FMA, Malathi H, Singh A, Jabir MS, Aminov Z, Lal M, Kumar A, Jawad SF. Exosomal RNAs and EZH2: unraveling the molecular dialogue driving tumor progression. Med Oncol 2025; 42:103. [PMID: 40075013 DOI: 10.1007/s12032-025-02648-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Accepted: 02/24/2025] [Indexed: 03/14/2025]
Abstract
The EZH2 gene encodes an enzyme that is part of the epigenetic factor Polycomb Repressive Complex 2 (PRC2). In order to control gene expression, PRC2 mainly modifies chromatin structure. In this complex process, EZH2 methylates histone proteins, which in turn suppresses further RNA transcriptions. As a result, EZH2 dysregulations can occasionally induce abnormal gene expression patterns, which can aid in the development and progression of cancer. Non-coding RNAs significantly impact the expression of EZH2 through epigenetic mechanisms. Meanwhile, normal and cancerous cells frequently release vesicles into the extracellular matrix, also known as exosomes, that occasionally carry RNA molecules from their origin cells, including messenger RNAs, microRNAs, and other non-coding RNAs. Thus exosomes are granted the ability to regulate numerous physiological functions and act as crucial messengers between cells by influencing gene expression in the recipient cell. We conducted this review to focus on EZH2's substantial biological role and the mechanisms that regulate it, driven by the desire to understand the possible impact of exosomal RNAs on EZH2 expression.
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Affiliation(s)
- Ahmed Hussein Zwamel
- Medical Laboratory Technique College, The Islamic University, Najaf, Iraq
- Medical Laboratory Technique College, The Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- Medical Laboratory Technique College, The Islamic University of Babylon, Babylon, Iraq
| | | | - Farag M A Altalbawy
- Department of Chemistry, University College of Duba, University of Tabuk, Tabuk, Saudi Arabia.
| | - H Malathi
- Department of Biotechnology and Genetics, School of Sciences, JAIN (Deemed to Be University), Bengaluru, Karnataka, India
| | - Amandeep Singh
- Chandigarh Pharmacy College, Chandigarh Group of Colleges, Jhanjeri, Mohali, 140307, Punjab, India
| | - Majid S Jabir
- Department of Applied Sciences, University of Technology, Baghdad, Iraq
| | - Zafar Aminov
- Department of Public Health and Healthcare Management, Samarkand State Medical University, Samarkand, Uzbekistan
| | - Madan Lal
- Department of Medicine, National Institute of Medical Sciences, NIMS University, Rajasthan, Jaipur, India
| | - Abhinav Kumar
- Department of Nuclear and Renewable Energy, Ural Federal University Named after the First President of Russia Boris Yeltsin, Ekaterinburg 620002, Russia
- Department of Technical Sciences, Western Caspian University, Baku, Azerbaijan
- Department of Mechanical Engineering, Karpagam Academy of Higher Education, Coimbatore, 641021, India
| | - Sabrean F Jawad
- Department of Pharmacy, Al-Mustaqbal University College, Babylon, Iraq
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6
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Dey Bhowmik A, Shaw P, Gopinatha Pillai MS, Rao G, Dwivedi SKD. Evolving landscape of detection and targeting miRNA/epigenetics for therapeutic strategies in ovarian cancer. Cancer Lett 2024; 611:217357. [PMID: 39615646 DOI: 10.1016/j.canlet.2024.217357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 11/22/2024] [Accepted: 11/25/2024] [Indexed: 12/14/2024]
Abstract
Ovarian cancer (OC) accounts for the highest mortality rates among all gynecologic malignancies. The high mortality of OC is often associated with delayed detection, prolonged latency, enhanced metastatic potential, acquired drug resistance, and frequent recurrence. This review comprehensively explores key aspects of OC, including cancer diagnosis, mechanisms of disease resistance, and the pivotal role of epigenetic regulation, particularly by microRNAs (miRs) in cancer progression. We highlight the intricate regulatory mechanisms governing miR expression within the context of OC and the current status of epigenetic advancement in the therapeutic development and clinical trial progression. Through network analysis we elucidate the regulatory interactions between dysregulated miRs in OC and their targets which are involved in different signaling pathways. By exploring these interconnected facets and critical analysis, we endeavor to provide a nuanced understanding of the molecular dynamics underlying OC, its detection and shedding light on potential avenues for miRs and epigenetics-based therapeutic intervention and management strategies.
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Affiliation(s)
- Arpan Dey Bhowmik
- Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA; Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
| | - Pallab Shaw
- Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA; Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
| | - Mohan Shankar Gopinatha Pillai
- Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA; Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
| | - Geeta Rao
- Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA; Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
| | - Shailendra Kumar Dhar Dwivedi
- Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA; Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
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Mu X, Wei Y, Fan X, Zhang R, Xi W, Zheng G, Yang AG. Aberrant activation of a miR-101-UBE2D1 axis contributes to the advanced progression and chemotherapy sensitivity in human hepatocellular carcinoma. Cell Death Discov 2024; 10:422. [PMID: 39353886 PMCID: PMC11445525 DOI: 10.1038/s41420-024-02193-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 09/19/2024] [Accepted: 09/23/2024] [Indexed: 10/03/2024] Open
Abstract
Chemotherapeutic drugs, such as cisplatin (cis-dichlorodiamineplatinum [II], cDDP) and 5-fluorouracil (5Fu), are widely used in transarterial chemoembolization (TACE), which is a standard therapy for patients with hepatocellular carcinoma (HCC). Chemoresistance is a major cause of TACE treatment failure in HCC patients. Our previous studies have identified the expression levels of miR-101 responsive genes, such as EED, EZH2, STMN1 and JUNB, exhibit significant correlation with the occurrence and progression of HCC, while the role of miR-101 responsive gene signatures in the chemoresistance of HCC treatment remains unclear. In this study, we identified ubiquitin-coupled enzyme E2D1 (UBE2D1) as a crucial regulatory factor in the chemoresistance of HCC, which is a direct target of miR-101 and exhibits significant correlation with miR-101-responsive gene signatures. The bioinformatics analysis showed the expression of UBE2D1 was significantly increased in HCC tissues and was closely correlated with the poor prognosis. In addition, we analyzed the role of miR-101/UBE2D1 axis in regulating chemo-sensitive of HCC cells. Our results showed that miR-101 increases the DNA damage and apoptosis of HCC cells by inhibiting the expression of UBE2D1, which in turn increases the sensitivity of HCC cells to cDDP and 5Fu both in vitro and in vivo. Therefore, simultaneous assessment of miR-101 and UBE2D1 expression levels might provide an effective approach in preselecting HCC patients with survival benefit from TACE treatment. Moreover, further elucidation of the underlying molecular mechanisms of the miR-101/UBE2D1 axis could provide novel insight for targeted therapy of HCC.
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Affiliation(s)
- Xiuli Mu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Yuchen Wei
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Xin Fan
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China
- Department of Otolaryngology Head and Neck Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Rui Zhang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Wenjin Xi
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Guoxu Zheng
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China.
| | - An-Gang Yang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China.
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8
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Walweel N, Aydin O. Enhancing Therapeutic Efficacy in Cancer Treatment: Integrating Nanomedicine with Autophagy Inhibition Strategies. ACS OMEGA 2024; 9:27832-27852. [PMID: 38973850 PMCID: PMC11223161 DOI: 10.1021/acsomega.4c02234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 05/01/2024] [Accepted: 05/30/2024] [Indexed: 07/09/2024]
Abstract
The complicated stepwise lysosomal degradation process known as autophagy is in charge of destroying and eliminating damaged organelles and defective cytoplasmic components. This mechanism promotes metabolic adaptability and nutrition recycling. Autophagy functions as a quality control mechanism in cells that support homeostasis and redox balance under normal circumstances. However, the role of autophagy in cancer is controversial because, mostly depending on the stage of the tumor, it may either suppress or support the disease. While autophagy delays the onset of tumors and slows the dissemination of cancer in the early stages of tumorigenesis, numerous studies demonstrate that autophagy promotes the development and spread of tumors as well as the evolution and development of resistance to several anticancer drugs in advanced cancer stages. In this Review, we primarily emphasize the therapeutic role of autophagy inhibition in improving the treatment of multiple cancers and give a broad overview of how its inhibition modulates cancer responses. There have been various attempts to inhibit autophagy, including the use of autophagy inhibitor drugs, gene silencing therapy (RNA interference), and nanoparticles. In this Review, all these topics are thoroughly covered and illustrated by recent studies and field investigations.
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Affiliation(s)
- Nada Walweel
- Department
of Biomedical Engineering, Erciyes University, Kayseri 38039, Turkey
- NanoThera
Lab, ERFARMA-Drug Application and Research Center, Erciyes University, Kayseri 38280, Turkey
| | - Omer Aydin
- Department
of Biomedical Engineering, Erciyes University, Kayseri 38039, Turkey
- NanoThera
Lab, ERFARMA-Drug Application and Research Center, Erciyes University, Kayseri 38280, Turkey
- ERNAM-Nanotechnology
Research and Application Center, Erciyes
University, Kayseri 38039, Turkey
- ERKAM-Clinical-Engineering
Research and Implementation Center, Erciyes
University, Kayseri 38030, Turkey
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9
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Mishra J, Chakraborty S, Nandi P, Manna S, Baral T, Niharika, Roy A, Mishra P, Patra SK. Epigenetic regulation of androgen dependent and independent prostate cancer. Adv Cancer Res 2024; 161:223-320. [PMID: 39032951 DOI: 10.1016/bs.acr.2024.05.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/23/2024]
Abstract
Prostate cancer is one of the most common malignancies among men worldwide. Besides genetic alterations, epigenetic modulations including DNA methylation, histone modifications and miRNA mediated alteration of gene expression are the key driving forces for the prostate tumor development and cancer progression. Aberrant expression and/or the activity of the epigenetic modifiers/enzymes, results in aberrant expression of genes involved in DNA repair, cell cycle regulation, cell adhesion, apoptosis, autophagy, tumor suppression and hormone response and thereby disease progression. Altered epigenome is associated with prostate cancer recurrence, progression, aggressiveness and transition from androgen-dependent to androgen-independent phenotype. These epigenetic modifications are reversible and various compounds/drugs targeting the epigenetic enzymes have been developed that are effective in cancer treatment. This chapter focuses on the epigenetic alterations in prostate cancer initiation and progression, listing different epigenetic biomarkers for diagnosis and prognosis of the disease and their potential as therapeutic targets. This chapter also summarizes different epigenetic drugs approved for prostate cancer therapy and the drugs available for clinical trials.
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Affiliation(s)
- Jagdish Mishra
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha, India
| | - Subhajit Chakraborty
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha, India
| | - Piyasa Nandi
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha, India
| | - Soumen Manna
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha, India
| | - Tirthankar Baral
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha, India
| | - Niharika
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha, India
| | - Ankan Roy
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha, India
| | - Prahallad Mishra
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha, India
| | - Samir Kumar Patra
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha, India.
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Li X, Liao C, Wu J, Yi B, Zha R, Deng Q, Xu J, Guo C, Lu J. Distinct serum exosomal miRNA profiles detected in acute and asymptomatic dengue infections: A community-based study in Baiyun District, Guangzhou. Heliyon 2024; 10:e31546. [PMID: 38807894 PMCID: PMC11130723 DOI: 10.1016/j.heliyon.2024.e31546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 05/16/2024] [Accepted: 05/17/2024] [Indexed: 05/30/2024] Open
Abstract
Background In recent years, research on exosomal miRNAs has provided new insights into exploring the mechanism of viral infection and disease prevention. This study aimed to investigate the serum exosomal miRNA expression profile of dengue-infected individuals through a community survey of dengue virus (DENV) infection. Methods A seroprevalence study of 1253 healthy persons was first conducted to ascertain the DENV infection status in Baiyun District, Guangzhou. A total of 18 serum samples, including 6 healthy controls (HC), 6 asymptomatic DENV infections (AsymptDI), and 6 confirmed dengue fever patients (AcuteDI), were collected for exosome isolation and then sRNA sequencing. Through bioinformatics analysis, we discovered distinct serum exosomal miRNA profiles among the different groups and identified differentially expressed miRNAs (DEMs). These findings were further validated by qRT-PCR. Results The community survey of DENV infection indicated that the DENV IgG antibody positivity rate among the population was 11.97 % in the study area, with asymptomatic infected individuals accounting for 93.06 % of the anti-DENV IgG positives. The age and Guangzhou household registration were associated with DENV IgG antibody positivity by logistic regression analysis. Distinct miRNA profiles were observed between healthy individuals and DENV infections. A total of 1854 miRNAs were identified in 18 serum exosome samples from the initial analysis of the sequencing data. Comparative analysis revealed 23 DEMs comprising 5 upregulated and 18 downregulated miRNAs in the DENV-infected group (mergedDI). In comparison to AcuteDI, 18 upregulated miRNAs were identified in AsymptDI. Moreover, functional enrichment of the predicted target genes of DEMs indicated that these miRNAs were involved in biological processes and pathways related to cell adhesion, focal adhesion, endocytosis, and ECM-receptor interaction. Eight DEMs were validated by qRT-PCR. Conclusion The Baiyun District of Guangzhou exhibits a notable proportion of asymptomatic DENV infections as suggested in other research, highlighting the need for enhanced monitoring and screening of asymptomatic persons and the elderly. Differential miRNA expression among healthy, symptomatic and asymptomatic DENV-infected individuals suggests their potential as biomarkers for distinguishing DENV infection and offers new avenues of investigating the mechanisms underlying DENV asymptomatic infections.
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Affiliation(s)
- Xiaokang Li
- School of Public Health, Sun Yat-Sen University, Guangzhou, 510080, China
- One Health Center of Excellence for Research & Training, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Conghui Liao
- School of Public Health, Sun Yat-Sen University, Guangzhou, 510080, China
- One Health Center of Excellence for Research & Training, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Jiani Wu
- School of Public Health, Sun Yat-Sen University, Guangzhou, 510080, China
- One Health Center of Excellence for Research & Training, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Boyang Yi
- School of Public Health, Sun Yat-Sen University, Guangzhou, 510080, China
- One Health Center of Excellence for Research & Training, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Renyun Zha
- School of Public Health, Sun Yat-Sen University, Guangzhou, 510080, China
- One Health Center of Excellence for Research & Training, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Qiang Deng
- School of Public Health, Sun Yat-Sen University, Guangzhou, 510080, China
- One Health Center of Excellence for Research & Training, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Jianhua Xu
- Guangzhou Baiyun District Center for Disease Control and Prevention, Guangzhou, 510445, China
| | - Cheng Guo
- School of Public Health, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Jiahai Lu
- School of Public Health, Sun Yat-Sen University, Guangzhou, 510080, China
- One Health Center of Excellence for Research & Training, Sun Yat-Sen University, Guangzhou, 510080, China
- National Medical Products Administration Key Laboratory for Quality Monitoring and Evaluation of Vaccines and Biological Products, Guangzhou, 510080, China
- Hainan Key Novel Thinktank “Hainan Medical University ‘One Health’ Research Center”, Haikou, 571199, China
- Research Institute of Sun Yat-Sen University in Shenzhen, Shenzhen, 518057, China
- Key Laboratory of Tropical Diseases Control, Sun Yat-Sen University, Ministry of Education, Guangzhou, 510080, China
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11
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Zheng D, Zhang Y, Yang S, Su N, Bakhoum M, Zhang G, Naderinezhad S, Mao Z, Wang Z, Zhou T, Li W. Androgen deprivation induces neuroendocrine phenotypes in prostate cancer cells through CREB1/EZH2-mediated downregulation of REST. Cell Death Discov 2024; 10:246. [PMID: 38777812 PMCID: PMC11111810 DOI: 10.1038/s41420-024-02031-1] [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: 11/21/2023] [Revised: 05/11/2024] [Accepted: 05/14/2024] [Indexed: 05/25/2024] Open
Abstract
Although effective initially, prolonged androgen deprivation therapy (ADT) promotes neuroendocrine differentiation (NED) and prostate cancer (PCa) progression. It is incompletely understood how ADT transcriptionally induces NE genes in PCa cells. CREB1 and REST are known to positively and negatively regulate neuronal gene expression in the brain, respectively. No direct link between these two master neuronal regulators has been elucidated in the NED of PCa. We show that REST mRNA is downregulated in NEPC cell and mouse models, as well as in patient samples. Phenotypically, REST overexpression increases ADT sensitivity, represses NE genes, inhibits colony formation in culture, and xenograft tumor growth of PCa cells. As expected, ADT downregulates REST in PCa cells in culture and in mouse xenografts. Interestingly, CREB1 signaling represses REST expression. In studying the largely unclear mechanism underlying transcriptional repression of REST by ADT, we found that REST is a direct target of EZH2 epigenetic repression. Finally, genetic rescue experiments demonstrated that ADT induces NED through EZH2's repression of REST, which is enhanced by ADT-activated CREB1 signaling. In summary, our study has revealed a key pathway underlying NE gene upregulation by ADT, as well as established novel relationships between CREB1 and REST, and between EZH2 and REST, which may also have implications in other cancer types and in neurobiology.
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Affiliation(s)
- Dayong Zheng
- Texas Therapeutics Institute; Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA
- Department of Oncology, Shunde Hospital, Southern Medical University, Foshan, China
- The First People's Hospital of Shunde, Foshan, China
| | - Yan Zhang
- Texas Therapeutics Institute; Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA
- Department of Pain, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Sukjin Yang
- Texas Therapeutics Institute; Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Ning Su
- Texas Therapeutics Institute; Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Michael Bakhoum
- Texas Therapeutics Institute; Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Guoliang Zhang
- Texas Therapeutics Institute; Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Samira Naderinezhad
- Texas Therapeutics Institute; Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA
- University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
| | - Zhengmei Mao
- Texas Therapeutics Institute; Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Zheng Wang
- Texas Therapeutics Institute; Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Ting Zhou
- Texas Therapeutics Institute; Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Wenliang Li
- Texas Therapeutics Institute; Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.
- University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA.
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12
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Ma Y, Fang F, Liao K, Zhang J, Wei C, Liao Y, Zhao B, Fang Y, Chen Y, Zhang X, Tang D. Identification and validation of the clinical prediction model and biomarkers based on chromatin regulators in colon cancer by integrated analysis of bulk- and single-cell RNA sequencing data. Transl Cancer Res 2024; 13:1290-1313. [PMID: 38617504 PMCID: PMC11009811 DOI: 10.21037/tcr-23-1886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 02/08/2024] [Indexed: 04/16/2024]
Abstract
BACKGROUND Chromatin regulators (CRs) are implicated in the development of cancer, but a comprehensive investigation of their role in colon adenocarcinoma (COAD) is inadequate. The purpose of this study is to find CRs that can provide recommendations for clinical diagnosis and treatment, and to explore the reasons why they serve as critical CRs. METHODS We obtained data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Weighted Gene Co-Expression Network Analysis (WGCNA) screened tumor-associated CRs. LASSO-Cox regression was used to construct the model and to screen key CRs together with support vector machine (SVM), the univariate Cox regression. We used single-cell data to explore the expression of CRs in cells and their communication. Immune infiltration, immune checkpoints, mutation, methylation, and drug sensitivity analyses were performed. Gene expression was verified by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). Pan-cancer analysis was used to explore the importance of hub CRs. RESULTS We finally obtained 32 tumor-associated CRs. The prognostic model was constructed based on RCOR2, PPARGC1A, PKM, RAC3, PHF19, MYBBP1A, ORC1, and EYA2 by the LASSO-Cox regression. Single-cell data revealed that the model was immune-related. Combined with immune infiltration analysis, immune checkpoint analysis, and tumor immune dysfunction and exclusion (TIDE) analysis, the low-score risk group had more immune cell infiltration and better immune response. Mutation and methylation analysis showed that multiple CRs may be mutated and methylated in colon cancer. Drug sensitivity analysis revealed that the low-risk group may be more sensitive to several drugs and PKM was associated with multiple drugs. Combined with machine learning, PKM is perhaps the most critical gene in CRs. Pan-cancer analysis showed that PKM plays a role in the prognosis of cancers. CONCLUSIONS We developed a prognostic model for COAD based on CRs. Increased expression of the core gene PKM is linked with a poor prognosis in several malignancies.
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Affiliation(s)
- Yichao Ma
- Clinical Medical College, Yangzhou University, Yangzhou, China
- Department of General Surgery, Institute of General Surgery, Northern Jiangsu People’s Hospital, Clinical Medical College, Yangzhou University, Yangzhou, China
| | - Fang Fang
- Department of General Surgery, Institute of General Surgery, Northern Jiangsu People’s Hospital, Clinical Medical College, Yangzhou University, Yangzhou, China
| | - Kai Liao
- College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, China
| | - Jingqiu Zhang
- Department of General Surgery, Institute of General Surgery, Northern Jiangsu People’s Hospital, Clinical Medical College, Yangzhou University, Yangzhou, China
| | - Chen Wei
- Clinical Medical College, Yangzhou University, Yangzhou, China
- Department of General Surgery, Institute of General Surgery, Northern Jiangsu People’s Hospital, Clinical Medical College, Yangzhou University, Yangzhou, China
| | - Yiqun Liao
- Department of Clinical Medical college, Dalian Medical University, Dalian, China
| | - Bin Zhao
- Department of Clinical Medical college, Dalian Medical University, Dalian, China
| | - Yongkun Fang
- Department of Clinical Medical college, Dalian Medical University, Dalian, China
| | - Yuji Chen
- Clinical Medical College, Yangzhou University, Yangzhou, China
- Department of General Surgery, Institute of General Surgery, Northern Jiangsu People’s Hospital, Clinical Medical College, Yangzhou University, Yangzhou, China
| | - Xinyue Zhang
- College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, China
| | - Dong Tang
- Clinical Medical College, Yangzhou University, Yangzhou, China
- Department of General Surgery, Institute of General Surgery, Northern Jiangsu People’s Hospital, Clinical Medical College, Yangzhou University, Yangzhou, China
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13
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Kumar S, Malviya R, Sundram S. Nutritional neurology: Unraveling cellular mechanisms of natural supplements in brain health. HUMAN NUTRITION & METABOLISM 2024; 35:200232. [DOI: 10.1016/j.hnm.2023.200232] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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14
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Ma Q, Yang F, Xiao B, Guo X. Emerging roles of circular RNAs in tumorigenesis, progression, and treatment of gastric cancer. J Transl Med 2024; 22:207. [PMID: 38414006 PMCID: PMC10897999 DOI: 10.1186/s12967-024-05001-4] [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: 01/01/2024] [Accepted: 02/15/2024] [Indexed: 02/29/2024] Open
Abstract
With an estimated one million new cases reported annually, gastric cancer (GC) ranks as the fifth most diagnosed malignancy worldwide. The early detection of GC remains a major challenge, and the prognosis worsens either when patients develop resistance to chemotherapy or radiotherapy or when the cancer metastasizes. The precise pathogenesis underlying GC is not well understood, which further complicates its treatment. Circular RNAs (circRNAs), a recently discovered class of noncoding RNAs that originate from parental genes through "back-splicing", have been shown to play a key role in various biological processes in both eukaryotes and prokaryotes. CircRNAs have been linked to cardiovascular diseases, diabetes, hypertension, Alzheimer's disease, and the occurrence and progression of tumors. Prior studies have established that circRNAs play a crucial role in GC, impacting tumorigenesis, diagnosis, progression, and therapy resistance. This review aims to summarize how circRNAs contribute to GC tumorigenesis and progression, examine their roles in the development of drug resistance, discuss their potential as biotechnological drugs, and summarize their response to therapeutic drugs and microorganism in GC.
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Affiliation(s)
- Qiang Ma
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, People's Republic of China
- Translational Medicine Research Center & School of Laboratory Medicine, North Sichuan Medical College, Nanchong, 637000, People's Republic of China
| | - Feifei Yang
- College of Pharmacy, Chongqing Medical University, Chongqing, 400016, People's Republic of China
| | - Bin Xiao
- College of Pharmacy, Chongqing Medical University, Chongqing, 400016, People's Republic of China.
| | - Xiaolan Guo
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, People's Republic of China.
- Translational Medicine Research Center & School of Laboratory Medicine, North Sichuan Medical College, Nanchong, 637000, People's Republic of China.
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15
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Quah S, Sundaram GM, Subramanian G, Vaz C, Tan JSL, Kabir RF, Ong JMR, Oon HH, Theng C, Sampath P. IL-17-Mediated Downregulation of miR-101 Facilitates the Expression of EZH2 to Promote Epidermal Hyperplasia in Psoriasis. J Invest Dermatol 2024; 144:403-407.e7. [PMID: 37574185 DOI: 10.1016/j.jid.2023.07.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 07/20/2023] [Accepted: 07/21/2023] [Indexed: 08/15/2023]
Affiliation(s)
- Shan Quah
- A∗STAR Skin Research Labs (A∗SRL), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
| | | | - Gowtham Subramanian
- A∗STAR Skin Research Labs (A∗SRL), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
| | - Candida Vaz
- Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
| | - Jonathan S L Tan
- A∗STAR Skin Research Labs (A∗SRL), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
| | - Ramisa Fariha Kabir
- A∗STAR Skin Research Labs (A∗SRL), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
| | - Jesslyn M R Ong
- A∗STAR Skin Research Labs (A∗SRL), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
| | - Hazel H Oon
- Skin Research Institute of Singapore (SRIS), Singapore, Singapore; Division of Dermatology, National Skin Centre, Singapore, Singapore
| | - Colin Theng
- The Skin Specialist & Laser Clinic, Mount Alvernia Medical Centre, Singapore, Singapore
| | - Prabha Sampath
- A∗STAR Skin Research Labs (A∗SRL), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore; Skin Research Institute of Singapore (SRIS), Singapore, Singapore; Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore; Program in Cancer & Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.
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16
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Qin H, Liu C, Li C, Feng C, Bo Huang. Advances in bi-directional relationships for EZH2 and oxidative stress. Exp Cell Res 2024; 434:113876. [PMID: 38070859 DOI: 10.1016/j.yexcr.2023.113876] [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: 08/07/2023] [Revised: 11/14/2023] [Accepted: 12/03/2023] [Indexed: 12/23/2023]
Abstract
Over the past two decades, polycomb repressive complex 2(PRC2) has emerged as a vital repressive complex in overall cell fate determination. In mammals, enhancer of zeste homolog 2 (EHZ2), which is the core component of PRC2, has also been recognized as an important regulator of inflammatory, redox, tumorigenesis and damage repair signalling networks. To exert these effects, EZH2 must regulate target genes epigenetically or interact directly with other gene expression-regulating factors, such as LncRNAs and microRNAs. Our review provides a comprehensive summary of research advances, discoveries and trends regarding the regulatory mechanisms between EZH2 and reactive oxygen species (ROS). First, we outline novel findings about how EZH2 regulates the generation of ROS at the molecular level. Then, we summarize how oxidative stress controls EHZ2 alteration (upregulation, downregulation, or phosphorylation) via various molecules and signalling pathways. Finally, we address why EZH2 and oxidative stress have an undefined relationship and provide potential future research ideas.
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Affiliation(s)
- Heng Qin
- Department of Pulmonary and Critical Care Medicine, Xinqiao Hospital, Army Medical University, Chongqing, 400037, PR China.
| | - Chang Liu
- Department of Orthopedics, Xinqiao Hospital, Army Medical University, Chongqing, 400037, PR China.
| | - Changqing Li
- Department of Orthopedics, Xinqiao Hospital, Army Medical University, Chongqing, 400037, PR China.
| | - Chencheng Feng
- Department of Orthopedics, Xinqiao Hospital, Army Medical University, Chongqing, 400037, PR China.
| | - Bo Huang
- Department of Orthopedics, Xinqiao Hospital, Army Medical University, Chongqing, 400037, PR China.
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17
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Lin T, Guo X, Du Q, Liu W, Zhong X, Wang S, Cao L. MicroRNA let-7c-5p Alleviates in Hepatocellular Carcinoma by Targeting Enhancer of Zeste Homolog 2: A Study Intersecting Bioinformatic Analysis and Validated Experiments. Crit Rev Immunol 2024; 44:23-39. [PMID: 38505919 DOI: 10.1615/critrevimmunol.2024051519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/21/2024]
Abstract
Enhancer of zeste homolog 2 (EZH2)gene has a prognostic role in hepatocellular carcinoma (HCC). This study aimed to identify the role of microRNAs (miRNAs) let-7c-5p by targeting EZH2 in HCC. We downloaded gene and miRNA RNA-seq data from The Cancer Genome Atlas (TCGA) database. Differences in EZH2 expression between different groups were analyzed and the association of EZH2 expression with HCC prognosis was detected using Cox regression analysis. The miRNA-EZH2-pathway network was constructed. Dual-luciferase reporter assay was performed to detect the hsa-let-7c-5p-EZH2. Cell proliferation, migration, invasion, and apoptosis were detected by CCK-8, Wound healing, Transwell, and Flow cytometry, respectively. RT-qPCR and Western blot were used to detect the expression of let-7c-5p and EZH2. EZH2 was upregulated in HCC tumors (P < 0.0001). Cox regression analysis showed that TCGA HCC patients with high EZH2 expression levels showed a short survival time [hazard ratio (HR) = 1.677, 95% confidence interval (CI) 1.316-2.137; P < 0.0001]. Seven miRNAs were negatively correlated with EZH2 expression and were significantly downregulated in HCC tumor samples (P < 0.0001), in which hsa-let-7c-5p was associated with prognosis in HCC (HR = 0.849 95% CI 0.739-0.975; P = 0.021). We identified 14 immune cells that showed significant differences in EZH2 high- and low-expression groups. Additionally, let-7c-5p inhibited HCC cell proliferation, migration, and invasion and reversed the promoted effects of EZH2 on HCC cell malignant characteristics. hsa-let-7c-5p-EZH2 significantly suppressed HCC malignant characteristics, which can be used for HCC prognosis.
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Affiliation(s)
- Tianyu Lin
- Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University
| | - Xinli Guo
- Department of Operating Room, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, China
| | - Qian Du
- Department of General Surgery, The 903rd Hospital of PLA, Hangzhou 310000, China
| | - Wei Liu
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, China
| | - Xin Zhong
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, China
| | - Suihan Wang
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, China
| | - Liping Cao
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, China
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18
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Liu J, Fan H, Liang X, Chen Y. Polycomb repressor complex: Its function in human cancer and therapeutic target strategy. Biomed Pharmacother 2023; 169:115897. [PMID: 37981459 DOI: 10.1016/j.biopha.2023.115897] [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: 09/13/2023] [Revised: 11/07/2023] [Accepted: 11/13/2023] [Indexed: 11/21/2023] Open
Abstract
The Polycomb Repressor Complex (PRC) plays a pivotal role in gene regulation during development and disease, with dysregulation contributing significantly to various human cancers. The intricate interplay between PRC and cellular signaling pathways sheds light on cancer complexity. PRC presents promising therapeutic opportunities, with inhibitors undergoing rigorous evaluation in preclinical and clinical studies. In this review, we emphasize the critical role of PRC complex in gene regulation, particularly PcG proteins mediated chromatin compaction through phase separation. We also highlight the pathological implications of PRC complex dysregulation in various tumors, elucidating underlying mechanisms driving cancer progression. The burgeoning field of therapeutic strategies targeting PRC complexes, notably EZH2 inhibitors, has advanced significantly. However, we explore the need for combination therapies to enhance PRC targeted treatments efficacy, providing a glimpse into the future of cancer therapeutics.
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Affiliation(s)
- Jingrong Liu
- Ganjiang Chinese Medicine Innovation Center, Nanchang 330000, China
| | - Hongjie Fan
- Ganjiang Chinese Medicine Innovation Center, Nanchang 330000, China
| | - Xinmiao Liang
- Ganjiang Chinese Medicine Innovation Center, Nanchang 330000, China; CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
| | - Yang Chen
- Ganjiang Chinese Medicine Innovation Center, Nanchang 330000, China; CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
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19
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Szczepanek J, Tretyn A. MicroRNA-Mediated Regulation of Histone-Modifying Enzymes in Cancer: Mechanisms and Therapeutic Implications. Biomolecules 2023; 13:1590. [PMID: 38002272 PMCID: PMC10669115 DOI: 10.3390/biom13111590] [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: 09/21/2023] [Revised: 10/22/2023] [Accepted: 10/26/2023] [Indexed: 11/26/2023] Open
Abstract
In the past decade, significant advances in molecular research have provided a deeper understanding of the intricate regulatory mechanisms involved in carcinogenesis. MicroRNAs, short non-coding RNA sequences, exert substantial influence on gene expression by repressing translation or inducing mRNA degradation. In the context of cancer, miRNA dysregulation is prevalent and closely associated with various stages of carcinogenesis, including initiation, progression, and metastasis. One crucial aspect of the cancer phenotype is the activity of histone-modifying enzymes that govern chromatin accessibility for transcription factors, thus impacting gene expression. Recent studies have revealed that miRNAs play a significant role in modulating these histone-modifying enzymes, leading to significant implications for genes related to proliferation, differentiation, and apoptosis in cancer cells. This article provides an overview of current research on the mechanisms by which miRNAs regulate the activity of histone-modifying enzymes in the context of cancer. Both direct and indirect mechanisms through which miRNAs influence enzyme expression are discussed. Additionally, potential therapeutic implications arising from miRNA manipulation to selectively impact histone-modifying enzyme activity are presented. The insights from this analysis hold significant therapeutic promise, suggesting the utility of miRNAs as tools for the precise regulation of chromatin-related processes and gene expression. A contemporary focus on molecular regulatory mechanisms opens therapeutic pathways that can effectively influence the control of tumor cell growth and dissemination.
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Affiliation(s)
- Joanna Szczepanek
- Centre for Modern Interdisciplinary Technologies, Nicolaus Copernicus University, ul. Wilenska 4, 87-100 Torun, Poland
| | - Andrzej Tretyn
- Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, ul. Lwowska 1, 87-100 Torun, Poland;
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20
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Li W, Zheng D, Zhang Y, Yang S, Su N, Bakhoum M, Zhang G, Naderinezhad S, Mao Z, Wang Z, Zhou T. Androgen deprivation induces neuroendocrine phenotypes in prostate cancer cells through CREB1/EZH2-mediated downregulation of REST. RESEARCH SQUARE 2023:rs.3.rs-3270539. [PMID: 37886478 PMCID: PMC10602109 DOI: 10.21203/rs.3.rs-3270539/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/28/2023]
Abstract
Although effective initially, prolonged androgen deprivation therapy (ADT) promotes neuroendocrine differentiation (NED) and prostate cancer (PCa) progression. It is incompletely understood how ADT transcriptionally induces NE genes in PCa cells. CREB1 and REST are known to positively and negatively regulate neuronal gene expression in the brain, respectively. No direct link between these two master neuronal regulators has been elucidated in the NED of PCa. We show that REST mRNA is downregulated in NEPC cell and mouse models, as well as in patient samples. Phenotypically, REST overexpression increases ADT sensitivity, represses NE genes, inhibits colony formation in culture, and xenograft tumor growth of PCa cells. As expected, ADT downregulates REST in PCa cells in culture and in mouse xenografts. Interestingly, CREB1 signaling represses REST expression. In studying the largely unclear mechanism underlying transcriptional repression of REST by ADT, we found that REST is a direct target of EZH2 epigenetic repression. Finally, genetic rescue experiments demonstrated that ADT induces NED through EZH2's repression of REST, which is enhanced by ADT-activated CREB signaling. In summary, our study has revealed a key pathway underlying NE gene upregulation by ADT, as well as established novel relationships between CREB1 and REST, and between EZH2 and REST, which may also have implications in other cancer types and in neurobiology.
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Affiliation(s)
- Wenliang Li
- The University of Texas Health Science Center at Houston
| | - Dayong Zheng
- Integrated Hospital of Traditional Chinese Medicine, Southern Medical University
| | - Yan Zhang
- The University of Texas Health Science Center at Houston
| | - Sukjin Yang
- The University of Texas Health Science Center at Houston
| | - Ning Su
- The University of Texas Health Science Center at Houston
| | | | - Guoliang Zhang
- Shanghai Sixth People's Hospital, Shanghai Jiaotong University
| | | | - Zhengmei Mao
- The University of Texas Health Science Center at Houston
| | - Zheng Wang
- The University of Texas Health Science Center at Houston
| | - Ting Zhou
- The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston
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21
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Zhang M, Li Z, Liu Y, Ding X, Wang Y, Fan S. The ceramide synthase (CERS/LASS) family: Functions involved in cancer progression. Cell Oncol (Dordr) 2023; 46:825-845. [PMID: 36947340 DOI: 10.1007/s13402-023-00798-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/07/2023] [Indexed: 03/23/2023] Open
Abstract
INTRODUCTION Ceramide synthases (CERSes) are also known longevity assurance (LASS) genes. CERSes play important roles in the regulation of cancer progression. The CERS family is expressed in a variety of human tumours and is involved in tumorigenesis. They are closely associated with the progression of liver, breast, cervical, ovarian, colorectal, head and neck squamous cell, gastric, lung, prostate, oesophageal, pancreatic and blood cancers. CERSes play diverse and important roles in the regulation of cell survival, proliferation, apoptosis, migration, invasion, and drug resistance. The differential expression of CERSes in tumour and nontumour cells and survival analysis of cancer patients suggest that some CERSes could be used as potential prognostic markers. They are also important potential targets for cancer therapy. METHODS In this review, we summarize the available evidence on the inhibitory or promotive roles of CERSes in the progression of many cancers. Furthermore, we summarize the identified upstream and downstream molecular mechanisms that may regulate the function of CERSes in cancer settings.
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Affiliation(s)
- Mengmeng Zhang
- School of Life Science, Jiangsu Normal University, Xuzhou, Jiangsu, 221116, China
| | - Zhangyun Li
- School of Life Science, Jiangsu Normal University, Xuzhou, Jiangsu, 221116, China
| | - Yuwei Liu
- School of Life Science, Jiangsu Normal University, Xuzhou, Jiangsu, 221116, China
| | - Xiao Ding
- School of Life Science, Jiangsu Normal University, Xuzhou, Jiangsu, 221116, China
| | - Yanyan Wang
- Department of Ultrasonic Medicine, The First People's Hospital of Xuzhou, Xuzhou Municipal Hospital Affiliated to Xuzhou Medical University, Xuzhou, Jiangsu, 221000, China.
| | - Shaohua Fan
- School of Life Science, Jiangsu Normal University, Xuzhou, Jiangsu, 221116, China.
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22
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Gautam N, Kaur M, Kashyap S. Meta-analysis of Genetic polymorphism of Enhancer of Zeste Homolog2 gene in cancer susceptibility. J Cancer Res Ther 2023; 19:1079-1092. [PMID: 37787267 DOI: 10.4103/jcrt.jcrt_1112_21] [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] [Indexed: 10/04/2023]
Abstract
The alteration in the expression of enhancer of zeste homolog-2 (EZH2) gene is very well known in the progression, severity, and aggressiveness of cancer. Hence, it is important to study the genomic variation of the EZH2 gene. Previously, many association-based studies investigated the association between rs2302427C>G and cancer susceptibility. However, the result had been inconsistent. Therefore, our meta-analysis aimed to identify the association between EZH2 rs2302427 and cancer risk. A systematic literature search was done for databases PubMed, Google Scholar, Science Direct, and Cochrane library up to September 2020 and statistical analysis was performed by RevMan v 5.3. A total of six studies comprised 1876 cases and 2555 controls were included in the current meta-analysis. The pooled analysis showed that overall, there is significant association of rs2302427 C>G change with reduced cancer risk (odds ratio = 0.60, 95% confidence interval [0.35-1.03], P = 0.07) but non-significantly. Further, the subgroup analysis also revealed that there is no significant difference between the Asian and European population, and both exhibit the protective nature of rs2302427 with cancer. The present meta-analysis indicated that EZH2 rs2302427 has an association with cancer in reducing the risk but for the Indian population studies are required as the Indian population comprises various sub-population genetically isolated for long.
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Affiliation(s)
- Nisha Gautam
- Department of Human Genetics, Punjabi University, Patiala, Punjab, India
| | - Mandeep Kaur
- Department of Human Genetics, Punjabi University, Patiala, Punjab, India
| | - Surender Kashyap
- Atal Medical and Research University, Mandi, Himachal Pradesh, India
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Cai Y, Liu Z, Zhang G, Yang Y, Zhang Y, Wang F, Deng M. miR-101-5p overexpression suppresses the proliferation of goat spermatogonial stem cells by targeting EZH2. Anim Reprod Sci 2023; 255:107281. [PMID: 37352705 DOI: 10.1016/j.anireprosci.2023.107281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 06/09/2023] [Accepted: 06/15/2023] [Indexed: 06/25/2023]
Abstract
MicroRNAs (miRNAs), as post-transcriptional gene mediators, regulate the biological characteristics of spermatogonial stem cells (SSCs), including proliferation, differentiation and apoptosis. However, the potential roles and mechanisms by which miR-101-5p affected the biological characters of goat SSCs have not been fully elucidated. Herein, we reported that miR-101-5p overexpression decreased cell viability (P < 0.01), arrested cell cycle in the G1 phase (P < 0.05), and aggravated apoptosis of goat SSCs (P < 0.01) compared with negative control (NC), as determined by CCK-8 assay and flow cytometry analysis. Additionally, PCNA protein expression was attenuated by miR-101-5p overexpression (P < 0.05). Notably, the expression of SSCs specific genes Oct4 (P < 0.05), PLZF (P < 0.01) and DAZL (P < 0.01) were decreased in miR-101-5p overexpressed SSCs. Furthermore, the dual luciferase reporter assay showed that, when co-transfected with miR-101-5p mimics, the relative luciferase activity of EZH2 wide-type (WT) was inhibited (P < 0.05) compared with the transfection of EZH2 mutant (MUT). EZH2 expression was negatively correlated with miR-101-5p expression in goat SSCs. Collectively, our data implicates that miR-101-5p overexpression aggravates cell apoptosis, and suppresses cell proliferation of goat SSCs via targeting EZH2, which may impair spermatogenesis.
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Affiliation(s)
- Yu Cai
- Jiangsu Livestock Embryo Engineering Laboratory, Nanjing Agricultural University, Nanjing 210095, China
| | - Zifei Liu
- Jiangsu Livestock Embryo Engineering Laboratory, Nanjing Agricultural University, Nanjing 210095, China
| | - Guomin Zhang
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Yingnan Yang
- Jiangsu Livestock Embryo Engineering Laboratory, Nanjing Agricultural University, Nanjing 210095, China
| | - Yanli Zhang
- Jiangsu Livestock Embryo Engineering Laboratory, Nanjing Agricultural University, Nanjing 210095, China
| | - Feng Wang
- Jiangsu Livestock Embryo Engineering Laboratory, Nanjing Agricultural University, Nanjing 210095, China.
| | - Mingtian Deng
- Jiangsu Livestock Embryo Engineering Laboratory, Nanjing Agricultural University, Nanjing 210095, China.
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Lin Z, Tang L, Chen S, Zhang W, Lin J, Gao H, Zhang P. EZH2 Expression in Retinoblastoma: A Potential Therapeutic Target. Ophthalmic Res 2023; 66:1014-1019. [PMID: 37311441 PMCID: PMC10357381 DOI: 10.1159/000531530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 05/30/2023] [Indexed: 06/15/2023]
Abstract
INTRODUCTION The enhancer of zeste homolog 2 (EZH2) is a member of the polycomb repressive complex 2 (PRC2) and is important in cell-cycle regulation. Increased expression of EZH2 has been reported in retinoblastoma (RB). The aim of the study was to determine EZH2 expression, compare this with clinicopathological parameters in RB, and assess its relationship with tumor cell proliferation. METHODS Ninety-nine retrospective cases of enucleated RB were included in the present study. Expression of EZH2 and the marker of cell proliferation, Ki67, were investigated by immunohistochemistry. RESULTS Among the 99 cases of RB in this study, EZH2 was found highly expressed (positive expression rate ≥70%) in 92 cases. EZH2 was expressed in tumor cells but absent in normal retinal tissues. The expression of EZH2 was positively linked to Ki67 expression (r = 0.65, p < 0.001). CONCLUSION Elevated EZH2 expression was found in most RB cases, indicating that EZH2 could be a potential therapeutic target for RB.
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Affiliation(s)
- Zhuangling Lin
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China,
| | - Lijuan Tang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Shuxia Chen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Wenxin Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Jianxian Lin
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Huanhuan Gao
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Ping Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
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Lismer A, Kimmins S. Emerging evidence that the mammalian sperm epigenome serves as a template for embryo development. Nat Commun 2023; 14:2142. [PMID: 37059740 PMCID: PMC10104880 DOI: 10.1038/s41467-023-37820-2] [Citation(s) in RCA: 59] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 03/31/2023] [Indexed: 04/16/2023] Open
Abstract
Although more studies are demonstrating that a father's environment can influence child health and disease, the molecular mechanisms underlying non-genetic inheritance remain unclear. It was previously thought that sperm exclusively contributed its genome to the egg. More recently, association studies have shown that various environmental exposures including poor diet, toxicants, and stress, perturbed epigenetic marks in sperm at important reproductive and developmental loci that were associated with offspring phenotypes. The molecular and cellular routes that underlie how epigenetic marks are transmitted at fertilization, to resist epigenetic reprogramming in the embryo, and drive phenotypic changes are only now beginning to be unraveled. Here, we provide an overview of the state of the field of intergenerational paternal epigenetic inheritance in mammals and present new insights into the relationship between embryo development and the three pillars of epigenetic inheritance: chromatin, DNA methylation, and non-coding RNAs. We evaluate compelling evidence of sperm-mediated transmission and retention of paternal epigenetic marks in the embryo. Using landmark examples, we discuss how sperm-inherited regions may escape reprogramming to impact development via mechanisms that implicate transcription factors, chromatin organization, and transposable elements. Finally, we link paternally transmitted epigenetic marks to functional changes in the pre- and post-implantation embryo. Understanding how sperm-inherited epigenetic factors influence embryo development will permit a greater understanding related to the developmental origins of health and disease.
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Affiliation(s)
- Ariane Lismer
- Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, QC, H3G 1Y6, Canada
| | - Sarah Kimmins
- Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, QC, H3G 1Y6, Canada.
- Department of Pathology and Cell Biology, Faculty of Medicine, University of Montreal Hospital Research Centre, Montreal, QC, H2X 0A9, Canada.
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Papadimitriou MA, Panoutsopoulou K, Pilala KM, Scorilas A, Avgeris M. Epi-miRNAs: Modern mediators of methylation status in human cancers. WILEY INTERDISCIPLINARY REVIEWS. RNA 2023; 14:e1735. [PMID: 35580998 DOI: 10.1002/wrna.1735] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 04/07/2022] [Accepted: 04/11/2022] [Indexed: 02/01/2023]
Abstract
Methylation of the fundamental macromolecules, DNA/RNA, and proteins, is remarkably abundant, evolutionarily conserved, and functionally significant in cellular homeostasis and normal tissue/organism development. Disrupted methylation imprinting is strongly linked to loss of the physiological equilibrium and numerous human pathologies, and most importantly to carcinogenesis, tumor heterogeneity, and cancer progression. Mounting recent evidence has documented the active implication of miRNAs in the orchestration of the multicomponent cellular methylation machineries and the deregulation of methylation profile in the epigenetic, epitranscriptomic, and epiproteomic levels during cancer onset and progression. The elucidation of such regulatory networks between the miRNome and the cellular methylation machineries has led to the emergence of a novel subclass of miRNAs, namely "epi-miRNAs" or "epi-miRs." Herein, we have summarized the existing knowledge on the functional role of epi-miRs in the methylation dynamic landscape of human cancers and their clinical utility in modern cancer diagnostics and tailored therapeutics. This article is categorized under: RNA in Disease and Development > RNA in Disease.
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Affiliation(s)
- Maria-Alexandra Papadimitriou
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Konstantina Panoutsopoulou
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Katerina-Marina Pilala
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Andreas Scorilas
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Margaritis Avgeris
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece.,Laboratory of Clinical Biochemistry - Molecular Diagnostics, Second Department of Pediatrics, School of Medicine, National and Kapodistrian University of Athens, "P. & A. Kyriakou" Children's Hospital, Athens, Greece
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27
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Solorzano J, Carrillo-de Santa Pau E, Laguna T, Busturia A. A genome-wide computational approach to define microRNA-Polycomb/trithorax gene regulatory circuits in Drosophila. Dev Biol 2023; 495:63-75. [PMID: 36596335 DOI: 10.1016/j.ydbio.2022.12.008] [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: 09/13/2022] [Revised: 12/07/2022] [Accepted: 12/26/2022] [Indexed: 01/02/2023]
Abstract
Characterization of gene regulatory networks is fundamental to understanding homeostatic development. This process can be simplified by analyzing relatively simple genomes such as the genome of Drosophila melanogaster. In this work we have developed a computational framework in Drosophila to explore for the presence of gene regulatory circuits between two large groups of transcriptional regulators: the epigenetic group of the Polycomb/trithorax (PcG/trxG) proteins and the microRNAs (miRNAs). We have searched genome-wide for miRNA targets in PcG/trxG transcripts as well as for Polycomb Response Elements (PREs) in miRNA genes. Our results show that 10% of the analyzed miRNAs could be controlling PcG/trxG gene expression, while 40% of those miRNAs are putatively controlled by the selected set of PcG/trxG proteins. The integration of these analyses has resulted in the predicted existence of 3 classes of miRNA-PcG/trxG crosstalk interactions that define potential regulatory circuits. In the first class, miRNA-PcG circuits are defined by miRNAs that reciprocally crosstalk with PcG. In the second, miRNA-trxG circuits are defined by miRNAs that reciprocally crosstalk with trxG. In the third class, miRNA-PcG/trxG shared circuits are defined by miRNAs that crosstalk with both PcG and trxG regulators. These putative regulatory circuits may uncover a novel mechanism in Drosophila for the control of PcG/trxG and miRNAs levels of expression. The computational framework developed here for Drosophila melanogaster can serve as a model case for similar analyses in other species. Moreover, our work provides, for the first time, a new and useful resource for the Drosophila community to consult prior to experimental studies investigating the epigenetic regulatory networks of miRNA-PcG/trxG mediated gene expression.
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Affiliation(s)
- Jacobo Solorzano
- Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Nicolas Cabrera 1, 28049, Madrid, Spain; Centre de Recherches en Cancerologie de Toulouse, 2 Av. Hubert Curien, 31100, Toulouse, France
| | - Enrique Carrillo-de Santa Pau
- Computational Biology Group, Precision Nutrition and Cancer Research Program, IMDEA Food Institute, CEI UAM+CSIC, 28049, Madrid, Spain
| | - Teresa Laguna
- Computational Biology Group, Precision Nutrition and Cancer Research Program, IMDEA Food Institute, CEI UAM+CSIC, 28049, Madrid, Spain.
| | - Ana Busturia
- Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Nicolas Cabrera 1, 28049, Madrid, Spain.
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Zhao Y, Li D, Zhou P, Zhao Y, Kuang J. microRNA-29b-3p attenuates diabetic nephropathy in mice by modifying EZH2. Hormones (Athens) 2023; 22:223-233. [PMID: 36692688 DOI: 10.1007/s42000-022-00426-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 11/30/2022] [Indexed: 01/25/2023]
Abstract
OBJECTIVE Diabetic nephropathy (DN) is the leading cause of end-stage renal disease around the world. This study investigated the role of microRNA (miR)-29b-3p in DN and the mechanism of the miR-29b-3p/EZH2 axis in DN. METHODS Peripheral blood samples of DN patients were collected and miR-29b-3p and EZH2 expression levels were evaluated using RT-qPCR. DN mouse models were successfully established, and then treated with miR-29b-3p overexpression or EZH2 silence. IL-1β, IL-6, and TNF-α levels were assessed by ELISA. Blood glucose, serum creatinine (Scr), 24-h urine volume, 24-h urine protein, and blood urea nitrogen (BUN) levels were examined by automatic biochemical analyzer detection. HE staining was performed to observe the renal histopathology, and TUNEL staining was implemented to test apoptosis in renal tissues. The binding relationship between miR-29b-3p and EZH2 was validated by using a bioinformatics website and dual luciferase reporter gene assay. RESULTS miR-29b-3p was lowly expressed, and EZH2 was highly expressed in patients with DN. Overexpressing miR-29b-3p or silencing EZH2 attenuated renal dysfunction, suppressed inflammation and apoptosis, and relieved renal injuries in mice with DN. miR-29b-3p inhibited EZH2, and miR-29b-3p overexpression mitigated renal injuries in DN mice by repressing EZH2. CONCLUSION miR-29b-3p suppresses EZH2 expression thereby inhibiting the progression of DN in mice.
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Affiliation(s)
- Yurong Zhao
- Department of Endocrinology, the Fourth People's Hospital of Shenyang, Shenyang, 110000, Liaoning, China
| | - Dandan Li
- Department of Endocrinology, the Fourth People's Hospital of Shenyang, Shenyang, 110000, Liaoning, China
| | - Ping Zhou
- Department of Anesthesiology, Suizhou Maternal and Child Health Hospital, Suizhou, 441300, Hubei, China
| | - Yujie Zhao
- Shenzhen Yuce Biological Technology Company, Shenzhen, 518172, Guangdong, China
| | - Jinsong Kuang
- Department of Endocrinology, the Fourth People's Hospital of Shenyang, Shenyang, 110000, Liaoning, China.
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Zhai J, Kongsberg WH, Pan Y, Hao C, Wang X, Sun J. Caloric restriction induced epigenetic effects on aging. Front Cell Dev Biol 2023; 10:1079920. [PMID: 36712965 PMCID: PMC9880295 DOI: 10.3389/fcell.2022.1079920] [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: 10/25/2022] [Accepted: 12/31/2022] [Indexed: 01/15/2023] Open
Abstract
Aging is the subject of many studies, facilitating the discovery of many interventions. Epigenetic influences numerous life processes by regulating gene expression and also plays a crucial role in aging regulation. Increasing data suggests that dietary changes can alter epigenetic marks associated with aging. Caloric restriction (CR)is considered an intervention to regulate aging and prolong life span. At present, CR has made some progress by regulating signaling pathways associated with aging as well as the mechanism of action of intercellular signaling molecules against aging. In this review, we will focus on autophagy and epigenetic modifications to elaborate the molecular mechanisms by which CR delays aging by triggering autophagy, epigenetic modifications, and the interaction between the two in caloric restriction. In order to provide new ideas for the study of the mechanism of aging and delaying aging.
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Affiliation(s)
| | | | | | | | | | - Jie Sun
- *Correspondence: Xiaojing Wang, ; Jie Sun,
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30
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Abstract
Dynamic regulation of the chromatin state by Polycomb Repressive Complex 2 (PRC2) provides an important mean for epigenetic gene control that can profoundly influence normal development and cell lineage specification. PRC2 and PRC2-induced methylation of histone H3 lysine 27 (H3K27) are critically involved in a wide range of DNA-templated processes, which at least include transcriptional repression and gene imprinting, organization of three-dimensional chromatin structure, DNA replication and DNA damage response and repair. PRC2-based genome regulation often goes wrong in diseases, notably cancer. This chapter discusses about different modes-of-action through which PRC2 and EZH2, a catalytic subunit of PRC2, mediate (epi)genomic and transcriptomic regulation. We will also discuss about how alteration or mutation of the PRC2 core or axillary component promotes oncogenesis, how post-translational modification regulates functionality of EZH2 and PRC2, and how PRC2 and other epigenetic pathways crosstalk. Lastly, we will briefly touch on advances in targeting EZH2 and PRC2 dependence as cancer therapeutics.
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Affiliation(s)
- Yiran Guo
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, 27710, USA.
- Duke Cancer Institute, Duke University School of Medicine, Durham, NC, 27710, USA.
| | - Yao Yu
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, 27710, USA
- Duke Cancer Institute, Duke University School of Medicine, Durham, NC, 27710, USA
| | - Gang Greg Wang
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, 27710, USA.
- Duke Cancer Institute, Duke University School of Medicine, Durham, NC, 27710, USA.
- Department of Pathology, Duke University School of Medicine, Durham, NC, 27710, USA.
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31
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Xu C, Zhao S, Cai L. Epigenetic (De)regulation in Prostate Cancer. Cancer Treat Res 2023; 190:321-360. [PMID: 38113006 PMCID: PMC11421856 DOI: 10.1007/978-3-031-45654-1_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2023]
Abstract
Prostate cancer (PCa) is a heterogeneous disease exhibiting both genetic and epigenetic deregulations. Epigenetic alterations are defined as changes not based on DNA sequence, which include those of DNA methylation, histone modification, and chromatin remodeling. Androgen receptor (AR) is the main driver for PCa and androgen deprivation therapy (ADT) remains a backbone treatment for patients with PCa; however, ADT resistance almost inevitably occurs and advanced diseases develop termed castration-resistant PCa (CRPC), due to both genetic and epigenetic changes. Due to the reversible nature of epigenetic modifications, inhibitors targeting epigenetic factors have become promising anti-cancer agents. In this chapter, we focus on recent studies about the dysregulation of epigenetic regulators crucially involved in the initiation, development, and progression of PCa and discuss the potential use of inhibitors targeting epigenetic modifiers for treatment of advanced PCa.
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Affiliation(s)
- Chenxi Xu
- Department of Pathology, Duke University School of Medicine, Durham, NC, 27710, USA
- Duke Cancer Institute, Duke University School of Medicine, Durham, NC, 27710, USA
| | - Shuai Zhao
- Department of Pathology, Duke University School of Medicine, Durham, NC, 27710, USA
- Duke Cancer Institute, Duke University School of Medicine, Durham, NC, 27710, USA
| | - Ling Cai
- Department of Pathology, Duke University School of Medicine, Durham, NC, 27710, USA.
- Duke Cancer Institute, Duke University School of Medicine, Durham, NC, 27710, USA.
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Remarkable Synergy When Combining EZH2 Inhibitors with YM155 Is H3K27me3-Independent. Cancers (Basel) 2022; 15:cancers15010208. [PMID: 36612203 PMCID: PMC9818370 DOI: 10.3390/cancers15010208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 12/20/2022] [Accepted: 12/28/2022] [Indexed: 01/01/2023] Open
Abstract
Targeting multiple molecules in the same biological network may maximize therapeutic efficacy. In this study, we identified a 27-gene module that is highly expressed in solid tumors, encoding actionable targets including EZH2 and BIRC5. The combination of EZH2 inhibitors and a BIRC5 inhibitor, YM155, results in a remarkable synergistic effect. The action of EZH2 inhibitors in this process is independent of the histone methyltransferase activity of polycomb repressive complex 2. Our study reveals a potential therapeutic approach for treating solid tumors by simultaneously targeting EZH2 and BIRC5.
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33
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Liu N, Yang C, Gao A, Sun M, Lv D. MiR-101: An Important Regulator of Gene Expression and Tumor Ecosystem. Cancers (Basel) 2022; 14:cancers14235861. [PMID: 36497343 PMCID: PMC9739992 DOI: 10.3390/cancers14235861] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 11/23/2022] [Accepted: 11/23/2022] [Indexed: 11/29/2022] Open
Abstract
MiRNAs are small single-stranded non-coding RNAs. MiRNA contributes to the transcriptional and post-transcriptional regulation of mRNA in different cell types, including mRNA transcription inhibition and mRNA decay and phenotypes via the effect of several essential oncogenic processes and tumor microenvironment. MiR-101 is a highly conserved miRNA that was found to alter the expression in various human cancers. MiR-101 has been reported to have tumor oncogenic and suppressive effects to regulate tumorigenesis and tumor progression. In this review, we summarize the new findings about the roles of miR-101 in cancers and the underlying mechanisms of targeting genes degradation and microenvironment regulation, which will improve biological understanding and design of novel therapeutics.
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Affiliation(s)
- Ning Liu
- Department of Oncology, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, China
| | - Chunsheng Yang
- Department of Oncology, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, China
| | - Ang Gao
- Department of Oncology, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, China
| | - Meili Sun
- Department of Oncology, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, China
- Correspondence: (M.S.); (D.L.)
| | - Deguan Lv
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15232, USA
- Correspondence: (M.S.); (D.L.)
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34
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Dudakovic A, Jerez S, Deosthale PJ, Denbeigh JM, Paradise CR, Gluscevic M, Zan P, Begun DL, Camilleri ET, Pichurin O, Khani F, Thaler R, Lian JB, Stein GS, Westendorf JJ, Plotkin LI, van Wijnen AJ. MicroRNA-101a enhances trabecular bone accrual in male mice. Sci Rep 2022; 12:13361. [PMID: 35922466 PMCID: PMC9349183 DOI: 10.1038/s41598-022-17579-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 07/27/2022] [Indexed: 11/09/2022] Open
Abstract
High-throughput microRNA sequencing was performed during differentiation of MC3T3-E1 osteoblasts to develop working hypotheses for specific microRNAs that control osteogenesis. The expression data show that miR-101a, which targets the mRNAs for the epigenetic enzyme Ezh2 and many other proteins, is highly upregulated during osteoblast differentiation and robustly expressed in mouse calvaria. Transient elevation of miR-101a suppresses Ezh2 levels, reduces tri-methylation of lysine 27 in histone 3 (H3K27me3; a heterochromatic mark catalyzed by Ezh2), and accelerates mineralization of MC3T3-E1 osteoblasts. We also examined skeletal phenotypes of an inducible miR-101a transgene under direct control of doxycycline administration. Experimental controls and mir-101a over-expressing mice were exposed to doxycycline in utero and postnatally (up to 8 weeks of age) to maximize penetrance of skeletal phenotypes. Male mice that over-express miR-101a have increased total body weight and longer femora. MicroCT analysis indicate that these mice have increased trabecular bone volume fraction, trabecular number and trabecular thickness with reduced trabecular spacing as compared to controls. Histomorphometric analysis demonstrates a significant reduction in osteoid volume to bone volume and osteoid surface to bone surface. Remarkably, while female mice also exhibit a significant increase in bone length, no significant changes were noted by microCT (trabecular bone parameters) and histomorphometry (osteoid parameters). Hence, miR-101a upregulation during osteoblast maturation and the concomitant reduction in Ezh2 mediated H3K27me3 levels may contribute to the enhanced trabecular bone parameters in male mice. However, the sex-specific effect of miR-101a indicates that more intricate epigenetic mechanisms mediate physiological control of bone formation and homeostasis.
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Affiliation(s)
- Amel Dudakovic
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA.
- Department of Biochemistry & Molecular Biology, Mayo Clinic, Rochester, MN, USA.
| | - Sofia Jerez
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
| | - Padmini J Deosthale
- Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Janet M Denbeigh
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
| | - Christopher R Paradise
- Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN, USA
- Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, USA
| | - Martina Gluscevic
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
- Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, USA
| | - Pengfei Zan
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
- Department of Orthopedic Surgery, School of Medicine, Second Affiliated Hospital of Zhejiang University, Hangzhou, China
- Department of Orthopedic Surgery, School of Medicine, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai, China
| | - Dana L Begun
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
| | | | - Oksana Pichurin
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
| | - Farzaneh Khani
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
| | - Roman Thaler
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
| | - Jane B Lian
- Department of Biochemistry, University of Vermont, Burlington, VT, USA
| | - Gary S Stein
- Department of Biochemistry, University of Vermont, Burlington, VT, USA
| | - Jennifer J Westendorf
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
- Department of Biochemistry & Molecular Biology, Mayo Clinic, Rochester, MN, USA
| | - Lilian I Plotkin
- Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, USA.
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA.
- Richard L Roudebush VA Medical Center, Indianapolis, IN, USA.
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Yedigaryan L, Gatti M, Marini V, Maraldi T, Sampaolesi M. Shared and Divergent Epigenetic Mechanisms in Cachexia and Sarcopenia. Cells 2022; 11:2293. [PMID: 35892590 PMCID: PMC9332174 DOI: 10.3390/cells11152293] [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: 06/24/2022] [Revised: 07/19/2022] [Accepted: 07/20/2022] [Indexed: 01/27/2023] Open
Abstract
Significant loss of muscle mass may occur in cachexia and sarcopenia, which are major causes of mortality and disability. Cachexia represents a complex multi-organ syndrome associated with cancer and chronic diseases. It is often characterized by body weight loss, inflammation, and muscle and adipose wasting. Progressive muscle loss is also a hallmark of healthy aging, which is emerging worldwide as a main demographic trend. A great challenge for the health care systems is the age-related decline in functionality which threatens the independence and quality of life of elderly people. This biological decline can also be associated with functional muscle loss, known as sarcopenia. Previous studies have shown that microRNAs (miRNAs) play pivotal roles in the development and progression of muscle wasting in both cachexia and sarcopenia. These small non-coding RNAs, often carried in extracellular vesicles, inhibit translation by targeting messenger RNAs, therefore representing potent epigenetic modulators. The molecular mechanisms behind cachexia and sarcopenia, including the expression of specific miRNAs, share common and distinctive trends. The aim of the present review is to compile recent evidence about shared and divergent epigenetic mechanisms, particularly focusing on miRNAs, between cachexia and sarcopenia to understand a facet in the underlying muscle wasting associated with these morbidities and disclose potential therapeutic interventions.
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Affiliation(s)
- Laura Yedigaryan
- Translational Cardiomyology Laboratory, Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium; (L.Y.); (V.M.)
| | - Martina Gatti
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy; (M.G.); (T.M.)
| | - Vittoria Marini
- Translational Cardiomyology Laboratory, Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium; (L.Y.); (V.M.)
| | - Tullia Maraldi
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy; (M.G.); (T.M.)
| | - Maurilio Sampaolesi
- Translational Cardiomyology Laboratory, Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium; (L.Y.); (V.M.)
- Histology and Medical Embryology Unit, Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Sapienza University of Rome, 00185 Rome, Italy
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Durmus S, Atahan E, Avci Kilickiran B, Onal B, Cakatay U, Gelisgen R, Uzun H. Significance of Cyclooxgenase-2 gene polymorphism and related miRNAs in pulmonary arterial hypertension. Clin Biochem 2022; 107:33-39. [PMID: 35724768 DOI: 10.1016/j.clinbiochem.2022.06.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 05/23/2022] [Accepted: 06/06/2022] [Indexed: 11/03/2022]
Abstract
BACKGROUND Pulmonary arterial hypertension (PAH) is a rare disease with a poor prognosis. The suppression of cyclooxygenase-2 (COX-2) expression has been known to impair vascular function in endothelial cells; however, the epigenetic factors that cause this are largely obscure. Our aim in this study was to examine the polymorphisms in the gene for COX-2 (PTGS2) and related miRNAs regulating its level in a single-center cohort of patients with PAH. METHOD In this study, three SNPs and miRNAs (rs5275, rs689470, rs20417, miR-26b-5p, miR-146a-5p, and miR-101-5p) in the PTGS2 were screened in PAH and controls by qPCR. In addition, the COX-2 level was determined by immunoassay to examine the effects of epigenetic factors on its expression levels. RESULTS The non-dominant genotypes of rs20417 and rs5275 were found to be related to PAH (OR = 8.56, 95% CI = 3.39-21.63, p < 0.0001 and OR = 7.82, 95% CI = 3.30-18.53, p < 0.0001, respectively). We also observed a significant increase in the miR-26b-5p and miR-146a-5p levels in PAH patients (2.18 and 2.35-fold, respectively; for both, p < 0.05). In addition, it was found that SNPs influenced the COX-2, miR-26b-5p, and miR-146a-5p levels in PAH. A negative correlation was also found between COX-2 levels and miR-26b-5p and miR-146a-5p. CONCLUSIONS As conventional drug therapies may cause lower COX-2 levels, the development of new genetic or epigenetic biomarkers is crucially important for early diagnosis and prognosis. The presence of minor alleles for rs5275 and rs689470 might also be considered as a significant risk factor for developing PAH. Furthermore, locus-specific miRNAs, such as miR-26b-5p and miR-146a-5p, seem to play a critical role in the regulation of PTGS2 expression.
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Affiliation(s)
- Sinem Durmus
- Department of Medical Biochemistry, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Ersan Atahan
- Department of Chest Diseases, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Burcak Avci Kilickiran
- Department of Cardiology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Burak Onal
- Department of Medical Pharmacology, Medical Faculty, Biruni University, Istanbul, Turkey
| | - Ufuk Cakatay
- Department of Medical Biochemistry, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Remise Gelisgen
- Department of Medical Biochemistry, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Hafize Uzun
- Department of Medical Biochemistry, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey; Department of Medical Biochemistry, Faculty of Medicine, İstanbul Atlas University, Istanbul, Turkey.
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Methylation Status of Gene Bodies of Selected microRNA Genes Associated with Neoplastic Transformation in Equine Sarcoids. Cells 2022; 11:cells11121917. [PMID: 35741046 PMCID: PMC9221590 DOI: 10.3390/cells11121917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 06/06/2022] [Accepted: 06/09/2022] [Indexed: 02/04/2023] Open
Abstract
Horses are of great importance in recreation, livestock production, as working animals in poorly developed countries, and for equine-assisted therapy. Equine sarcoids belong to the most commonly diagnosed tumors in this species. They may cause discomfort, pain, and can lead to the permanent impairment of motor function. The molecular bases of their formation are still under investigation. Our previous studies revealed altered microRNA (miRNA) expression and DNA methylation levels in sarcoid tumors. Abnormal patterns of methylation may be responsible for changes in gene expression levels, including microRNAs. Recently, the DNA methylation of gene bodies has also been shown to have an impact on gene expression. Thus, the aim of the study was to investigate the methylation pattern of gene bodies of chosen miRNAs identified in sarcoid tissue (miR-101, miR-10b, miR-200a, and miR-338-3p), which have also been established to play roles in neoplastic transformation. To this end, we applied qRT-PCR, Bisulfite Sequencing PCR (BSP), and Mquant methods. As a result, we identified the statistically significant downregulation of pri-mir-101-1, pri-mir-10b, and pri-mir-200a in the sarcoid samples in comparison to the control. The DNA methylation analysis revealed their hypermethylation. This suggests that DNA methylation may be one mechanism responsible for the downregulation of theses miRNAs. However, the identified differences in the methylation levels are not very high, which implies that other mechanisms may also underlie the downregulation of the expression of these miRNAs in equine sarcoids. For the first time, the results obtained shed light on microRNA expression regulation by gene body methylation in equine sarcoids and provide bases for further deeper studies on other mechanisms influencing the miRNA repertoire.
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Mallick AM, Tripathi A, Mishra S, Mukherjee A, Dutta C, Chatterjee A, Sinha Roy R. Emerging Approaches for Enabling RNAi Therapeutics. Chem Asian J 2022; 17:e202200451. [PMID: 35689534 DOI: 10.1002/asia.202200451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 06/04/2022] [Indexed: 11/07/2022]
Abstract
RNA interference (RNAi) is a primitive evolutionary mechanism developed to escape incorporation of foreign genetic material. siRNA has been instrumental in achieving the therapeutic potential of RNAi by theoretically silencing any gene of interest in a reversible and sequence-specific manner. Extrinsically administered siRNA generally needs a delivery vehicle to span across different physiological barriers and load into the RISC complex in the cytoplasm in its functional form to show its efficacy. This review discusses the designing principles and examples of different classes of delivery vehicles that have proved to be efficient in RNAi therapeutics. We also briefly discuss the role of RNAi therapeutics in genetic and rare diseases, epigenetic modifications, immunomodulation and combination modality to inch closer in creating a personalized therapy for metastatic cancer. At the end, we present, strategies and look into the opportunities to develop efficient delivery vehicles for RNAi which can be translated into clinics.
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Affiliation(s)
- Argha M Mallick
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, 741246, India
| | - Archana Tripathi
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, 741246, India
| | - Sukumar Mishra
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, 741246, India
| | - Asmita Mukherjee
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, 741246, India
| | - Chiranjit Dutta
- Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, 741246, India.,Present address:Department of Biological Sciences, NUS Environmental Research Institute (NERI), National University of Singapore (NUS), Block S2 #05-01, 16 Science Drive 4, Singapore, 117558, Singapore
| | - Ananya Chatterjee
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, 741246, India
| | - Rituparna Sinha Roy
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, 741246, India.,Centre for Advanced Functional Materials, Indian Institute of Science Education and Research Kolkata, 741246, Mohanpur, India.,Centre for Climate and Environmental Studies, Indian Institute of Science Education and Research Kolkata, 741246, Mohanpur, India
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Rojas-Pirela M, Andrade-Alviárez D, Medina L, Castillo C, Liempi A, Guerrero-Muñoz J, Ortega Y, Maya JD, Rojas V, Quiñones W, Michels PA, Kemmerling U. MicroRNAs: master regulators in host-parasitic protist interactions. Open Biol 2022; 12:210395. [PMID: 35702995 PMCID: PMC9198802 DOI: 10.1098/rsob.210395] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
MicroRNAs (miRNAs) are a group of small non-coding RNAs present in a wide diversity of organisms. MiRNAs regulate gene expression at a post-transcriptional level through their interaction with the 3' untranslated regions of target mRNAs, inducing translational inhibition or mRNA destabilization and degradation. Thus, miRNAs regulate key biological processes, such as cell death, signal transduction, development, cellular proliferation and differentiation. The dysregulation of miRNAs biogenesis and function is related to the pathogenesis of diseases, including parasite infection. Moreover, during host-parasite interactions, parasites and host miRNAs determine the probability of infection and progression of the disease. The present review is focused on the possible role of miRNAs in the pathogenesis of diseases of clinical interest caused by parasitic protists. In addition, the potential role of miRNAs as targets for the design of drugs and diagnostic and prognostic markers of parasitic diseases is also discussed.
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Affiliation(s)
- Maura Rojas-Pirela
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago de Chile 8380453, Chile,Instituto de Biología, Pontificia Universidad Católica de Valparaíso, Valparaíso 2373223, Chile,Facultad de Farmacia y Bioanálisis, Universidad de Los Andes, Mérida, Venezuela
| | - Diego Andrade-Alviárez
- Laboratorio de Enzimología de Parásitos, Facultad de Ciencias, Universidad de Los Andes, Mérida, Venezuela
| | - Lisvaneth Medina
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago de Chile 8380453, Chile
| | - Christian Castillo
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago de Chile 8380453, Chile,Núcleo de Investigación Aplicada en Ciencias Veterinarias y Agronómicas, Facultad de Medicina Veterinaria y Agronomía, Universidad de Las Américas, Chile
| | - Ana Liempi
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago de Chile 8380453, Chile
| | - Jesús Guerrero-Muñoz
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago de Chile 8380453, Chile
| | - Yessica Ortega
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago de Chile 8380453, Chile,Facultad de Farmacia y Bioanálisis, Universidad de Los Andes, Mérida, Venezuela
| | - Juan Diego Maya
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago de Chile 8380453, Chile
| | - Verónica Rojas
- Instituto de Biología, Pontificia Universidad Católica de Valparaíso, Valparaíso 2373223, Chile
| | - Wilfredo Quiñones
- Laboratorio de Enzimología de Parásitos, Facultad de Ciencias, Universidad de Los Andes, Mérida, Venezuela
| | - Paul A. Michels
- Centre for Immunity, Infection and Evolution and Centre for Translational and Chemical Biology, School of Biological Sciences, The University of Edinburgh, Edinburgh EH9 3FL, UK
| | - Ulrike Kemmerling
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago de Chile 8380453, Chile
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Chen R, Gan Q, Zhao S, Zhang D, Wang S, Yao L, Yuan M, Cheng J. DNA methylation of miR-138 regulates cell proliferation and EMT in cervical cancer by targeting EZH2. BMC Cancer 2022; 22:488. [PMID: 35505294 PMCID: PMC9063191 DOI: 10.1186/s12885-022-09477-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Accepted: 03/22/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Emerging evidence has identified miR-138 as a tumor suppressor that can suppress the proliferation of various cancers. Meanwhile, the cause of abnormal miR-138 expression in cervical cancer remains uncertain. This study clarified the mechanism by which miR-138 regulates proliferation, invasion, metastasis, and EMT in cervical cancer cells. RESULTS miR-138 expression in human cervical cancer and adjacent normal tissue was measured using qPCR. SiHa and C33A cells were used to determine the function of miR-138 via miR-138 mimic or inhibitor transfection, followed by wound healing, Cell Counting Kit-8, flow cytometry, and Transwell assays. Epithelial and mesenchymal marker expression was analyzed using Western blotting. DNA methylation in the miR-138 promoter was examined using bisulfite sequencing PCR. The downstream target genes of miR-138 were identified via bioinformatics analysis and luciferase reporter assays. A tumor xenograft model was employed to validate DNA methylation-induced miR-138 downregulation and tumor growth inhibition in cervical cancer in vivo. miR-138 levels were significantly lower in cervical cancer tissues than in adjacent control tissues. Furthermore, lower miR-138 expression and higher CpG methylation in the miR-138 promoter were identified in lymph node-positive metastatic cervical cancer tumors versus that in non-metastatic tumor tissues. Upon miR-138 overexpression, cell proliferation, metastasis, invasion, and EMT were suppressed. miR-138 agomir transfection and demethylating drug treatment significantly inhibited cervical tumor growth and EMT in tumor xenograft models. DNA methylation inhibited miR-138 transcription, and enhancer of zeste homolog 2 (EZH2) downregulation mediated the tumor suppressor function of miR-138 in cervical cancer. CONCLUSION We demonstrated that miR-138 suppresses tumor progression by targeting EZH2 in cervical cancer and uncovered the role of DNA methylation in the miR-138 promoter in its downregulation. These findings demonstrated the potential of miR-138 to predict disease metastasis and/or function as a therapeutic target in cervical cancer.
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Affiliation(s)
- Rui Chen
- Department of Obstetrics and Gynecology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, People's Republic of China
| | - Qiyu Gan
- Department of Obstetrics and Gynecology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, People's Republic of China
| | - Shuting Zhao
- Department of Obstetrics and Gynecology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, People's Republic of China
| | - Dongrui Zhang
- Department of Obstetrics and Gynecology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, People's Republic of China
| | - Shunli Wang
- Department of Pathology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, People's Republic of China
| | - Lili Yao
- Department of Gynecology, Tumor Hospital Affiliated to Xinjiang Medical University, Urumqi, 830011, People's Republic of China
| | - Min Yuan
- Department of Gynecology, Tumor Hospital Affiliated to Xinjiang Medical University, Urumqi, 830011, People's Republic of China.
| | - Jingxin Cheng
- Department of Obstetrics and Gynecology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, People's Republic of China.
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Natural Bioactive Compounds Targeting Histone Deacetylases in Human Cancers: Recent Updates. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27082568. [PMID: 35458763 PMCID: PMC9027183 DOI: 10.3390/molecules27082568] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 04/07/2022] [Accepted: 04/11/2022] [Indexed: 12/13/2022]
Abstract
Cancer is a complex pathology that causes a large number of deaths worldwide. Several risk factors are involved in tumor transformation, including epigenetic factors. These factors are a set of changes that do not affect the DNA sequence, while modifying the gene’s expression. Histone modification is an essential mark in maintaining cellular memory and, therefore, loss of this mark can lead to tumor transformation. As these epigenetic changes are reversible, the use of molecules that can restore the functions of the enzymes responsible for the changes is therapeutically necessary. Natural molecules, mainly those isolated from medicinal plants, have demonstrated significant inhibitory properties against enzymes related to histone modifications, particularly histone deacetylases (HDACs). Flavonoids, terpenoids, phenolic acids, and alkaloids exert significant inhibitory effects against HDAC and exhibit promising epi-drug properties. This suggests that epi-drugs against HDAC could prevent and treat various human cancers. Accordingly, the present study aimed to evaluate the pharmacodynamic action of different natural compounds extracted from medicinal plants against the enzymatic activity of HDAC.
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Wilson MR, Reske JJ, Koeman J, Adams M, Joshi NR, Fazleabas AT, Chandler RL. SWI/SNF Antagonism of PRC2 Mediates Estrogen-Induced Progesterone Receptor Expression. Cells 2022; 11:1000. [PMID: 35326450 PMCID: PMC8946988 DOI: 10.3390/cells11061000] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 03/08/2022] [Accepted: 03/12/2022] [Indexed: 12/11/2022] Open
Abstract
Endometrial cancer (EC) is characterized by high estrogen levels unopposed by progesterone. Treatment with progestins is standard for early EC, but the response to progestins is dependent on progesterone receptor (PGR) expression. Here, we show that the expression of PGR in endometrial epithelial cells is dependent on ARID1A, a DNA-binding subunit of the SWI/SNF chromatin-remodeling complex that is commonly mutated in EC. In endometrial epithelial cells with estrogen receptor overexpression, we find that ARID1A promotes estrogen signaling and regulates common gene expression programs. Normally, endometrial epithelial cells expressing estrogen receptors respond to estrogen by upregulating the PGR. However, when ARID1A expression is lost, upregulation of PGR expression is significantly reduced. This phenomenon can also occur following the loss of the SWI/SNF subunit BRG1, suggesting a role for ARID1A- and BRG1-containing complexes in PGR regulation. We find that PGR is regulated by a bivalent promoter, which harbors both H3K4me3 and H3K27me3 histone tail modifications. H3K27me3 is deposited by EZH2, and inhibition of EZH2 in the context of ARID1A loss results in restoration of estrogen-induced PGR expression. Our results suggest a role for ARID1A deficiency in the loss of PGR in late-stage EC and a therapeutic utility for EZH2 inhibitors in this disease.
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Affiliation(s)
- Mike R. Wilson
- Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA; (M.R.W.); (J.J.R.); (N.R.J.); (A.T.F.)
| | - Jake J. Reske
- Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA; (M.R.W.); (J.J.R.); (N.R.J.); (A.T.F.)
| | - Julie Koeman
- Genomics Core Facility, Van Andel Research Institute, Grand Rapids, MI 49503, USA; (J.K.); (M.A.)
| | - Marie Adams
- Genomics Core Facility, Van Andel Research Institute, Grand Rapids, MI 49503, USA; (J.K.); (M.A.)
| | - Niraj R. Joshi
- Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA; (M.R.W.); (J.J.R.); (N.R.J.); (A.T.F.)
| | - Asgerally T. Fazleabas
- Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA; (M.R.W.); (J.J.R.); (N.R.J.); (A.T.F.)
- Department of Women’s Health, Spectrum Health System, Grand Rapids, MI 49341, USA
| | - Ronald L. Chandler
- Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA; (M.R.W.); (J.J.R.); (N.R.J.); (A.T.F.)
- Department of Women’s Health, Spectrum Health System, Grand Rapids, MI 49341, USA
- Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA
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Yi Y, Li Y, Li C, Wu L, Zhao D, Li F, Fazli L, Wang R, Wang L, Dong X, Zhao W, Chen K, Cao Q. Methylation-dependent and -independent roles of EZH2 synergize in CDCA8 activation in prostate cancer. Oncogene 2022; 41:1610-1621. [PMID: 35094010 PMCID: PMC9097394 DOI: 10.1038/s41388-022-02208-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 01/06/2022] [Accepted: 01/20/2022] [Indexed: 12/13/2022]
Abstract
Cell division cycle-associated 8 (CDCA8) is a component of chromosomal passenger complex (CPC) that participates in mitotic regulation. Although cancer-related CDCA8 hyperactivation has been widely observed, its molecular mechanism remains elusive. Here, we report that CDCA8 overexpression maintains tumorigenicity and is associated with poor clinical outcome in patients with prostate cancer (PCa). Notably, enhancer of zeste homolog 2 (EZH2) is identified to be responsible for CDCA8 activation in PCa. Genome-wide assays revealed that EZH2-induced H3K27 trimethylation represses let-7b expression and thus protects the let-7b-targeting CDCA8 transcripts. More importantly, EZH2 facilitates the self-activation of E2F1 by recruiting E2F1 to its own promoter region in a methylation-independent manner. The high level of E2F1 further promotes transcription of CDCA8 along with the other CPC subunits. Taken together, our study suggests that EZH2-mediated cell cycle regulation in PCa relies on both its methyltransferase and non-methyltransferase activities.
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Affiliation(s)
- Yang Yi
- Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
- Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX, 77030, USA
| | - Yanqiang Li
- Basic and Translational Research Division, Department of Cardiology, Boston Children's Hospital, Boston, MA, 02115, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA
| | - Chao Li
- Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
- Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX, 77030, USA
- Department of Urology, the Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Longxiang Wu
- Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
- Department of Urology, Xiangya Hospital of Central South University, Changsha, 410008, China
| | - Dongyu Zhao
- Basic and Translational Research Division, Department of Cardiology, Boston Children's Hospital, Boston, MA, 02115, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA
| | - Fuxi Li
- Key Laboratory of Stem Cells and Tissue Engineering (Sun Yat-Sen University), Ministry of Education, Guangzhou, 510080, China
| | - Ladan Fazli
- Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, V6H 3Z6, Canada
- Department of Urologic Sciences, University of British Columbia, Vancouver, BC, V6H 3Z6, Canada
| | - Rui Wang
- Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Long Wang
- Department of Urology, the Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Xuesen Dong
- Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, V6H 3Z6, Canada
- Department of Urologic Sciences, University of British Columbia, Vancouver, BC, V6H 3Z6, Canada
| | - Wei Zhao
- Key Laboratory of Stem Cells and Tissue Engineering (Sun Yat-Sen University), Ministry of Education, Guangzhou, 510080, China
| | - Kaifu Chen
- Basic and Translational Research Division, Department of Cardiology, Boston Children's Hospital, Boston, MA, 02115, USA.
- Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA.
- Prostate Cancer Program, Dana-Farber Harvard Cancer Center, 450 Brookline Avenue, BP332A, Boston, MA, USA.
| | - Qi Cao
- Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
- Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX, 77030, USA.
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
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MicroRNA-101-3p Suppresses Cancer Cell Growth by Inhibiting the USP47-Induced Deubiquitination of RPL11. Cancers (Basel) 2022; 14:cancers14040964. [PMID: 35205710 PMCID: PMC8870143 DOI: 10.3390/cancers14040964] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 02/11/2022] [Accepted: 02/13/2022] [Indexed: 12/04/2022] Open
Abstract
Simple Summary An abnormal expression of microRNA is commonly observed in cancer. Since a single miRNA can target numerous genes, it is important to understand the exact mechanism for the regulation of cancer growth by miRNAs. Here, we show that miR-101-3p, which is downregulated in several cancers, regulates RPL11 ubiquitination by targeting USP47, thereby controlling p53 levels by affecting the localization of RPL11 and its interaction with MDM2. Our results provide a novel mechanism for the inhibition of cancer cell growth by miR-101-3p, and suggest that miR-101-3p could be a potential target as an anticancer agent. Abstract MicroRNAs (miRNAs) are a class of small non-coding RNA molecules that regulate a countless number of genes in the cell, and the aberrant expression of miRNA can lead to cancer. Here, we demonstrate that miR-101-3p regulates the RPL11–MDM2–p53 pathway by targeting ubiquitin-specific peptidase 47 (USP47), consequently inhibiting cancer cell proliferation. We confirm that miR-101-3p directly binds to the 3′-UTR region of the USP47 gene and inhibits USP47 expression. In addition, the overexpression of miR-101-3p suppresses cell proliferation in a p53-dependent manner. MiR-101-3p promotes interaction between RPL11 and MDM2 by inducing the translocation of RPL11 from the nucleolus to the nucleoplasm, thus preventing the MDM2-mediated proteasomal degradation of p53. However, these phenomena are restored by the overexpression of USP47, but not by its catalytically inactive form. Indeed, miR-101-3p regulates RPL11 localization and its interaction with MDM2 by inhibiting the USP47-induced deubiquitination of RPL11. Finally, the expression of miR-101-3p is downregulated in lung cancer patients, and the patients with low miR-101-3p expression exhibit a lower survival rate, indicating that miR-101-3p is associated with tumorigenesis. Together, our findings suggest that miR-101-3p functions as a tumor suppressor by targeting USP47 and could be a potential therapeutic target for cancers.
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Wong WK, Yin B, Lam CYK, Huang Y, Yan J, Tan Z, Wong SHD. The Interplay Between Epigenetic Regulation and CD8 + T Cell Differentiation/Exhaustion for T Cell Immunotherapy. Front Cell Dev Biol 2022; 9:783227. [PMID: 35087832 PMCID: PMC8787221 DOI: 10.3389/fcell.2021.783227] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Accepted: 12/20/2021] [Indexed: 12/15/2022] Open
Abstract
Effective immunotherapy treats cancers by eradicating tumourigenic cells by activated tumour antigen-specific and bystander CD8+ T-cells. However, T-cells can gradually lose cytotoxicity in the tumour microenvironment, known as exhaustion. Recently, DNA methylation, histone modification, and chromatin architecture have provided novel insights into epigenetic regulations of T-cell differentiation/exhaustion, thereby controlling the translational potential of the T-cells. Thus, developing strategies to govern epigenetic switches of T-cells dynamically is critical to maintaining the effector function of antigen-specific T-cells. In this mini-review, we 1) describe the correlation between epigenetic states and T cell phenotypes; 2) discuss the enzymatic factors and intracellular/extracellular microRNA imprinting T-cell epigenomes that drive T-cell exhaustion; 3) highlight recent advances in epigenetic interventions to rescue CD8+ T-cell functions from exhaustion. Finally, we express our perspective that regulating the interplay between epigenetic changes and transcriptional programs provides translational implications of current immunotherapy for cancer treatments.
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Affiliation(s)
- Wai Ki Wong
- Department of Bioengineering, Imperial College London, London, United Kingdom
| | - Bohan Yin
- Department of Biomedical Engineering, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China
| | - Ching Ying Katherine Lam
- Department of Biomedical Engineering, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China
| | - Yingying Huang
- Department of Biomedical Engineering, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China
| | - Jiaxiang Yan
- Department of Biomedical Engineering, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China
| | - Zhiwu Tan
- AIDS Institute and Department of Microbiology, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Siu Hong Dexter Wong
- Department of Biomedical Engineering, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China
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Zhu B, Zhong W, Cao X, Pan G, Xu M, Zheng J, Chen H, Feng X, Luo C, Lu C, Xiao J, Lin W, Lai C, Li M, Du X, Yi Q, Yan D. Loss of miR-31-5p drives hematopoietic stem cell malignant transformation and restoration eliminates leukemia stem cells in mice. Sci Transl Med 2022; 14:eabh2548. [PMID: 35080912 DOI: 10.1126/scitranslmed.abh2548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Leukemia stem cells (LSCs) propagate leukemia and are responsible for the high frequency of relapse of treated patients. The ability to target LSCs remains elusive, indicating a need to understand the underlying mechanism of LSC formation. Here, we report that miR-31-5p is reduced or undetectable in human LSCs compared to hematopoietic stem progenitor cells (HSPCs). Inhibition of miR-31-5p in HSPCs promotes the expression of its target gene FIH, encoding FIH [factor inhibiting hypoxia-inducing factor 1α (HIF-1α)], to suppress HIF-1α signaling. Increased FIH resulted in a switch from glycolysis to oxidative phosphorylation (OXPHOS) as the predominant mode of energy metabolism and increased the abundance of the oncometabolite fumarate. Increased fumarate promoted the conversion of HSPCs to LSCs and initiated myeloid leukemia-like disease in NOD-Prkdcscid IL2rgtm1/Bcgen (B-NDG) mice. We further demonstrated that miR-31-5p inhibited long- and short-term hematopoietic stem cells with a high frequency of LSCs. In combination with the chemotherapeutic agent Ara-C (cytosine arabinoside), restoration of miR-31-5p using G7 poly (amidoamine) nanosized dendriplex encapsulating miR-31-5p eliminated LSCs and inhibited acute myeloid leukemia (AML) progression in patient-derived xenograft mouse models. These results demonstrated a mechanism of HSC malignant transformation through altered energy metabolism and provided a potential therapeutic strategy to treat patients with AML.
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Affiliation(s)
- Biying Zhu
- MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou 510632, China
| | - Wenbin Zhong
- MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou 510632, China
| | - Xiuye Cao
- MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou 510632, China
| | - Guoping Pan
- MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou 510632, China
| | - Mengyang Xu
- MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou 510632, China
| | - Jie Zheng
- MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou 510632, China
| | - Huanzhao Chen
- MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou 510632, China
| | - Xiaoqin Feng
- Hematology and Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Chengwei Luo
- Department of Hematology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510000, China
| | - Chen Lu
- MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou 510632, China
| | - Jie Xiao
- MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou 510632, China
| | - Weize Lin
- MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou 510632, China
| | - Chaofeng Lai
- MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou 510632, China
| | - Mingchuan Li
- MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou 510632, China
| | - Xin Du
- Department of Hematology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510000, China
| | - Qing Yi
- Cancer Center, Houston Methodist Research Institute, Houston, TX 77030, USA
| | - Daoguang Yan
- MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou 510632, China
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Epi-miRNAs: Regulators of the Histone Modification Machinery in Human Cancer. JOURNAL OF ONCOLOGY 2022; 2022:4889807. [PMID: 35087589 PMCID: PMC8789461 DOI: 10.1155/2022/4889807] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 12/14/2021] [Indexed: 12/18/2022]
Abstract
Cancer is a leading cause of death and disability worldwide. Epigenetic deregulation is one of the most critical mechanisms in carcinogenesis and can be classified into effects on DNA methylation and histone modification. MicroRNAs are small noncoding RNAs involved in fine-tuning their target genes after transcription. Various microRNAs control the expression of histone modifiers and are involved in a variety of cancers. Therefore, overexpression or downregulation of microRNAs can alter cell fate and cause malignancies. In this review, we discuss the role of microRNAs in regulating the histone modification machinery in various cancers, with a focus on the histone-modifying enzymes such as acetylases, deacetylases, methyltransferases, demethylases, kinases, phosphatases, desumoylases, ubiquitinases, and deubiquitinases. Understanding of microRNA-related aberrations underlying histone modifiers in pathogenesis of different cancers can help identify novel therapeutic targets or early detection approaches that allow better management of patients or monitoring of treatment response.
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Liu LC, Chien YC, Wu GW, Hua CH, Tsai IC, Hung CC, Wu TK, Pan YR, Yang SF, Yu YL. Analysis of EZH2 Genetic Variants on Triple-Negative Breast Cancer Susceptibility and Pathology. Int J Med Sci 2022; 19:1023-1028. [PMID: 35813302 PMCID: PMC9254368 DOI: 10.7150/ijms.71931] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 05/15/2022] [Indexed: 11/16/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is the third most common female cancer in Taiwan. EZH2 plays an important role in cancer development through transcriptional repression by chromatin remodeling. However, the expression of EZH2 in breast cancer is highly correlated with tumorigenesis, and patient survival is not matched to TNBC. Furthermore, it has not been determined if specific EZH2 genetic variants are associated with breast cancer risk. In this paper, we evaluated the survival of different types of breast cancer. The results indicated that a lower expression of EZH2 led to poor survival of TNBC patients. Therefore, we aimed at studying the relationship between genetic polymorphisms of EZH2 and susceptibility to TNBC in Taiwan. Four single-nucleotide polymorphisms (SNPs) of EZH2 (rs6950683, rs2302427, rs3757441, and rs41277434) were analyzed by real-time PCR genotyping in 176 patients with TNBC and 1000 cancer-free controls. The results showed that TNBC patients under 60 years old who carried a TC or CC genotype at EZH2 rs6950683 and re3757441 had a tumor size of 20 mm or smaller (T1). Thus, this study is the first to examine the age and mutant genes associated with EZH2 SNPs in TNBC progression and development in Taiwan.
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Affiliation(s)
- Liang-Chih Liu
- School of Medicine, College of Medicine, China Medical University, Taichung 40402, Taiwan.,Department of Surgery, China Medical University Hospital, Taichung 40402, Taiwan
| | - Yi-Chung Chien
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan.,Ph.D. Program for Translational Medicine, China Medical University, Taichung 40402, Taiwan.,Institute of New Drug Development, China Medical University, Taichung 40402, Taiwan.,Drug Development Center, Research Center for Cancer Biology, China Medical University, Taichung 40402, Taiwan.,Center for Molecular Medicine, China Medical University Hospital, Taichung 40402, Taiwan
| | - Guo-Wei Wu
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan.,Center for Molecular Medicine, China Medical University Hospital, Taichung 40402, Taiwan
| | - Chun-Hung Hua
- Department of Otorhinolaryngology Head and Neck Surgery, China Medical University Hospital, Taichung 40402, Taiwan
| | - I-Chen Tsai
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan.,Division of Breast Surgery, Department of Surgery, Taichung Veterans General Hospital, Taichung 40705, Taiwan
| | - Chih-Chiang Hung
- Division of Breast Surgery, Department of Surgery, Taichung Veterans General Hospital, Taichung 40705, Taiwan.,Department of Applied Cosmetology, College of Human Science and Social Innovation, Hungkuang University, Taichung 43302, Taiwan
| | - Tsai-Kun Wu
- Division of Renal Medicine, Tungs' Taichung MetroHarbor Hospital, Taichung 43503, Taiwan.,College of Medicine, National Chung Hsing University, Taichung 402204, Taiwan
| | - Ying-Ru Pan
- Department of Medical Research, Tungs' Taichung Metroharbor Hospital, Taichung, Taiwan
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan.,Department of Medical Research, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
| | - Yung-Luen Yu
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan.,Ph.D. Program for Translational Medicine, China Medical University, Taichung 40402, Taiwan.,Institute of New Drug Development, China Medical University, Taichung 40402, Taiwan.,Drug Development Center, Research Center for Cancer Biology, China Medical University, Taichung 40402, Taiwan.,Center for Molecular Medicine, China Medical University Hospital, Taichung 40402, Taiwan.,Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung 41354, Taiwan
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Gong Y, Wei C, Cheng L, Ma F, Lu S, Peng Q, Liu L, Wang Y. Tracking the Dynamic Histone Methylation of H3K27 in Live Cancer Cells. ACS Sens 2021; 6:4369-4378. [PMID: 34878766 PMCID: PMC9013700 DOI: 10.1021/acssensors.1c01670] [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] [Indexed: 01/18/2023]
Abstract
Histone methylations play a crucial role in chromatin remodeling and genome regulations. However, there is a lack of tools to visualize these histone modifications with high spatiotemporal resolutions in live cells. We have developed a biosensor based on fluorescence resonance energy transfer (FRET) and incorporated it into nucleosomes, capable of monitoring the trimethylation of H3K27 (H3K27me3) in live cells. We also revealed that the performance of the FRET biosensor can be significantly improved by adjusting the linkers within the biosensor. An improved biosensor enables the live-cell imaging of different histone methylation status, induced by the suppressive H3.3K27M or existing in breast cancer cells with varying genetic backgrounds. We have further applied the biosensor to reveal the dynamic coupling between H3K27me3 changes and caspase activity representing the initiation of apoptosis in cancer cells by imaging both H3K27me3 and caspase activity simultaneously in the same live cells. Thus, this new FRET biosensor can provide a powerful tool to visualize the epigenetic regulation in live cells with high spatial temporal resolutions.
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Affiliation(s)
- Ya Gong
- Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, La Jolla, California 92093-0435, United States
| | - Chujun Wei
- Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, La Jolla, California 92093-0435, United States
| | - Leonardo Cheng
- Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, La Jolla, California 92093-0435, United States
| | - Fengyi Ma
- Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, La Jolla, California 92093-0435, United States
| | - Shaoying Lu
- Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, La Jolla, California 92093-0435, United States
| | - Qin Peng
- Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, La Jolla, California 92093-0435, United States
| | - Longwei Liu
- Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, La Jolla, California 92093-0435, United States
| | - Yingxiao Wang
- Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, La Jolla, California 92093-0435, United States
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Slabáková E, Kahounová Z, Procházková J, Souček K. Regulation of Neuroendocrine-like Differentiation in Prostate Cancer by Non-Coding RNAs. Noncoding RNA 2021; 7:ncrna7040075. [PMID: 34940756 PMCID: PMC8704250 DOI: 10.3390/ncrna7040075] [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: 09/07/2021] [Revised: 11/18/2021] [Accepted: 11/29/2021] [Indexed: 12/21/2022] Open
Abstract
Neuroendocrine prostate cancer (NEPC) represents a variant of prostate cancer that occurs in response to treatment resistance or, to a much lesser extent, de novo. Unravelling the molecular mechanisms behind transdifferentiation of cancer cells to neuroendocrine-like cancer cells is essential for development of new treatment opportunities. This review focuses on summarizing the role of small molecules, predominantly microRNAs, in this phenomenon. A published literature search was performed to identify microRNAs, which are reported and experimentally validated to modulate neuroendocrine markers and/or regulators and to affect the complex neuroendocrine phenotype. Next, available patients’ expression datasets were surveyed to identify deregulated microRNAs, and their effect on NEPC and prostate cancer progression is summarized. Finally, possibilities of miRNA detection and quantification in body fluids of prostate cancer patients and their possible use as liquid biopsy in prostate cancer monitoring are discussed. All the addressed clinical and experimental contexts point to an association of NEPC with upregulation of miR-375 and downregulation of miR-34a and miR-19b-3p. Together, this review provides an overview of different roles of non-coding RNAs in the emergence of neuroendocrine prostate cancer.
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