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Zhang L, Yang Y, Li Y, Wang C, Bian C, Wang H, Wang F. Epigenetic regulation of histone modifications in glioblastoma: recent advances and therapeutic insights. Biomark Res 2025; 13:80. [PMID: 40450300 DOI: 10.1186/s40364-025-00788-w] [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: 03/13/2025] [Accepted: 05/14/2025] [Indexed: 06/03/2025] Open
Abstract
Glioblastoma (GBM) is the most common primary malignant brain tumor, characterized by its aggressive behavior, limited treatment options, and poor prognosis. Despite advances in surgery, radiotherapy, and chemotherapy, the median survival of GBM patients remains disappointingly short. Recent studies have underscored the critical role of histone modifications in GBM malignant progression and therapy resistance. Histones, protein components of chromatin, undergo various modifications, including acetylation and methylation. These modifications significantly affect gene expression, thereby promoting tumorigenesis and resistance to therapy. Targeting histone modifications has emerged as a promising therapeutic approach. Numerous pre-clinical studies have evaluated histone modification agents in GBM, including histone deacetylase inhibitors and histone methyltransferase inhibitors. These studies demonstrate that modulating histone modifications can alter gene expression patterns, inhibit tumor growth, induce apoptosis, and sensitize tumor cells to conventional treatments. Some agents have advanced to clinical trials, aiming to translate preclinical efficacy into clinical benefit. However, clinical outcomes remain suboptimal, as many agents fail to significantly improve GBM patient prognosis. These challenges are attributed to the complexity of histone modification networks and the adaptive responses of the tumor microenvironment. This review provides a comprehensive overview of epigenetic regulation mechanisms involving histone modifications in GBM, covering their roles in tumor development, tumor microenvironment remodeling, and therapeutic resistance. Additionally, the review discusses current clinical trials targeting histone modifications in GBM, highlighting successes, limitations, and future perspectives.
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Affiliation(s)
- Li Zhang
- Division of Head & Neck Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yang Yang
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yanchu Li
- Division of Head & Neck Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Chenyu Wang
- Yuexiu District, First Affiliated Hospital of Sun Yat-Sen University, Zhongshan 2 Road, Guangzhou City, Guangdong Province, China
| | - Chenbin Bian
- Division of Head & Neck Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Hongbin Wang
- Division of Head & Neck Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Feng Wang
- Division of Head & Neck Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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Ghosh N, Chatterjee D, Datta A. Tumor heterogeneity and resistance in glioblastoma: the role of stem cells. Apoptosis 2025:10.1007/s10495-025-02123-y. [PMID: 40375039 DOI: 10.1007/s10495-025-02123-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] [Accepted: 04/25/2025] [Indexed: 05/18/2025]
Abstract
Glioblastoma multiforme (GBM) is one of the most aggressive and treatment-resistant brain tumor, characterized by its heterogeneity and the presence of glioblastoma stem cells (GSCs). GSCs are a subpopulation of cells within the tumor that possess self-renewal and differentiation capabilities, contributing to tumor initiation, progression, and recurrence. This review explores the unique biological properties of GSCs, including their molecular markers, signalling pathways, and interactions with the tumor microenvironment. We discuss the mechanisms by which GSCs evade conventional therapies, such as enhanced DNA repair and metabolic plasticity, which complicate treatment outcomes. Furthermore, we highlight recent advancements in identifying novel biomarkers and therapeutic targets that may improve the efficacy of treatments aimed at GSCs. The potential of targeted therapies, including immunotherapy and combination strategies, is also examined to overcome the challenges posed by GSCs. Ultimately, a deeper understanding of GSC biology is essential for developing personalized treatment approaches that can enhance patient outcomes in glioblastoma.
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Affiliation(s)
- Nikita Ghosh
- Department of Neuroscience Technology, School of Allied Health Sciences, Yenepoya, Mangalore, Karnataka, India
| | | | - Aparna Datta
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata, India.
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3
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Yakubov R, Kaloti R, Persaud P, McCracken A, Zadeh G, Bunda S. It's all downstream from here: RTK/Raf/MEK/ERK pathway resistance mechanisms in glioblastoma. J Neurooncol 2025; 172:327-345. [PMID: 39821893 PMCID: PMC11937199 DOI: 10.1007/s11060-024-04930-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 12/24/2024] [Indexed: 01/19/2025]
Abstract
BACKGROUND The receptor tyrosine kinase (RTK)/Ras/Raf/MEK/ERK signaling pathway is one of the most tumorigenic pathways in cancer, with its hyperactivation strongly linked to the aggressive nature of glioblastoma (GBM). Although extensive research has focused on developing therapeutics targeting this pathway, clinical success remains elusive due to the emergence of resistance mechanisms. OBJECTIVE This review investigates how inhibition of the RTK/Ras/Raf/MEK/ERK pathway alters transcription factors, contributing to acquired resistance mechanisms in GBM. It also highlights the critical role of transcription factor dysregulation in therapeutic resistance. METHODS & RESULTS Findings from key studies on the RTK/Ras/Raf/MEK/ERK pathway in GBM were synthesized to explore the role of transcription factor dysregulation in resistance to targeted therapies, radiation, and chemotherapy. The review highlights that transcription factors undergo significant dysregulation following RTK/Ras/Raf/MEK/ERK pathway inhibition, contributing to therapeutic resistance. CONCLUSION Transcription factors are promising targets for overcoming treatment resistance in GBM, with cotreatment strategies combining RTK/Ras/Raf/MEK/ERK pathway inhibitors and transcription factor-targeted therapies presenting a novel approach. Despite the challenges of targeting complex structures and interactions, advancements in drug development and precision technologies hold great potential. Continued research is essential to refine these strategies and improve outcomes for GBM and other aggressive cancers.
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Affiliation(s)
- Rebeca Yakubov
- MacFeeters Hamilton Neuro-Oncology Program, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, ON, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Ramneet Kaloti
- MacFeeters Hamilton Neuro-Oncology Program, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, ON, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Phooja Persaud
- MacFeeters Hamilton Neuro-Oncology Program, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, ON, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Anna McCracken
- MacFeeters Hamilton Neuro-Oncology Program, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, ON, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Gelareh Zadeh
- MacFeeters Hamilton Neuro-Oncology Program, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, ON, Canada.
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
- Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada.
| | - Severa Bunda
- MacFeeters Hamilton Neuro-Oncology Program, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, ON, Canada.
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
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4
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Oliveira LS, Oliveira-Silva JM, Almeida-Souza HO, Martins MM, Chiminazo CB, Fonseca R, Souza CVED, Aissa AF, Bastos LM, Ionta M, Almeida Lima GDD, Castro-Gamero AM. HDAC6 inhibition through WT161 synergizes with temozolomide, induces apoptosis, reduces cell motility, and decreases β-catenin levels in glioblastoma cells. Invest New Drugs 2025; 43:223-242. [PMID: 39954199 DOI: 10.1007/s10637-025-01508-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 01/28/2025] [Indexed: 02/17/2025]
Abstract
Glioblastoma multiforme (GBM) accounts for 70% of all primary malignancies of the central nervous system. Current treatment strategies involve surgery followed by chemotherapy with temozolomide (TMZ); however, the median survival after treatment is approximately 15 months. Many GBM cases develop resistance to TMZ, resulting in a poor prognosis for patients, which underscores the urgent need for novel therapeutic approaches. One promising avenue is the inhibition of histone deacetylase 6 (HDAC6), an enzyme that deacetylates α-tubulin and is increasingly recognized as a potential pharmacological target in cancer. In GBM specifically, HDAC6 overexpression has been linked to poor prognosis and chemoresistance. In this study, we demonstrate that HDAC6 protein levels are elevated in GBM and evaluate the effects of the novel selective HDAC6 inhibitor, WT161, on U251, U87, and T98G cells to assess its potential to revert the malignant phenotype. Our results show a significant increase in acetylated α-tubulin levels, suppression of cell growth, cell cycle arrest at the G2/M phase, and decreased clonogenicity of 2D-cultured GBM cells. Additionally, WT161 acted synergistically with TMZ, induced apoptosis and enhanced TMZ-induced apoptosis. Notably, HDAC6 inhibition resulted in reduced cell migration and invasion, associated with decreased β-catenin levels. When cultured in 3D conditions, WT161-treated T98G spheroids were sensitized to TMZ and exhibited reduced migration. Finally, HDAC6 inhibition altered the metabolome, particularly affecting metabolites associated with lipid peroxidation. In conclusion, our data reveal, for the first time, the efficacy of the selective HDAC6 inhibitor WT161 in a preclinical GBM setting.
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Affiliation(s)
- Leilane Sales Oliveira
- Human Genetics Laboratory, Institute of Natural Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
- Postgraduate Program in Biosciences Applied to Health (PPGB), Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
| | - João Marcos Oliveira-Silva
- Human Genetics Laboratory, Institute of Natural Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
- Postgraduate Program in Biosciences Applied to Health (PPGB), Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
| | - Hebreia Oliveira Almeida-Souza
- Laboratory of Nanobiotechnology Prof. Dr. Luiz Ricardo Goulart, Institute of Biotechnology, Federal University of Uberlândia, Uberlândia, MG, 38400-902, Brazil
| | - Mario Machado Martins
- Laboratory of Nanobiotechnology Prof. Dr. Luiz Ricardo Goulart, Institute of Biotechnology, Federal University of Uberlândia, Uberlândia, MG, 38400-902, Brazil
| | - Carolina Berraut Chiminazo
- Human Genetics Laboratory, Institute of Natural Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
| | - Rafael Fonseca
- Institute of Biomedical Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
| | | | - Alexandre Ferro Aissa
- Division of Genetics, Department of Morphology and Genetics, Federal University of São Paulo, São Paulo, Brazil
- Postgraduate Program in Biosciences Applied to Health (PPGB), Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
| | - Luciana Machado Bastos
- Laboratory of Nanobiotechnology Prof. Dr. Luiz Ricardo Goulart, Institute of Biotechnology, Federal University of Uberlândia, Uberlândia, MG, 38400-902, Brazil
| | - Marisa Ionta
- Institute of Biomedical Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
| | - Graziela Domingues de Almeida Lima
- Institute of Biomedical Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
- Postgraduate Program in Biosciences Applied to Health (PPGB), Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
| | - Angel Mauricio Castro-Gamero
- Human Genetics Laboratory, Institute of Natural Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil.
- Postgraduate Program in Biosciences Applied to Health (PPGB), Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil.
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Li C, Xie Q, Ghosh S, Cao B, Du Y, Vo GV, Huang TY, Spruck C, Carpenter RL, Wang YA, Lu QR, Nephew KP, Shen J. SUV39H1 maintains cancer stem cell chromatin state and properties in glioblastoma. JCI Insight 2025; 10:e186344. [PMID: 40059829 PMCID: PMC11949068 DOI: 10.1172/jci.insight.186344] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Accepted: 01/24/2025] [Indexed: 03/19/2025] Open
Abstract
Glioblastoma (GBM) is the most lethal brain cancer, with GBM stem cells (GSCs) driving therapeutic resistance and recurrence. Targeting GSCs offers a promising strategy for preventing tumor relapse and improving outcomes. We identify SUV39H1, a histone-3, lysine-9 methyltransferase, as critical for GSC maintenance and GBM progression. SUV39H1 is upregulated in GBM compared with normal brain tissues, with single-cell RNA-seq showing its expression predominantly in GSCs due to super-enhancer-mediated activation. Knockdown of SUV39H1 in GSCs impaired their proliferation and stemness. Whole-cell RNA-seq analysis revealed that SUV39H1 regulates G2/M cell cycle progression, stem cell maintenance, and cell death pathways in GSCs. By integrating the RNA-seq data with ATAC-seq data, we further demonstrated that knockdown of SUV39H1 altered chromatin accessibility in key genes associated with these pathways. Chaetocin, an SUV39H1 inhibitor, mimics the effects of SUV39H1 knockdown, reducing GSC stemness and sensitizing cells to temozolomide, a standard GBM chemotherapy. In a patient-derived xenograft model, targeting SUV39H1 inhibits GSC-driven tumor growth. Clinically, high SUV39H1 expression correlates with poor glioma prognosis, supporting its relevance as a therapeutic target. This study identifies SUV39H1 as a crucial regulator of GSC maintenance and a promising therapeutic target to improve GBM treatment and patient outcomes.
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Affiliation(s)
| | | | - Sugata Ghosh
- Medical Sciences Program, and
- Cell, Molecular, and Cancer Biology Graduate Program, Indiana University School of Medicine, Bloomington, Indiana, USA
| | | | | | | | | | - Charles Spruck
- Cancer Genome and Epigenetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA
| | - Richard L. Carpenter
- Medical Sciences Program, and
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana, USA
| | - Y. Alan Wang
- Brown Center for Immunotherapy and Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Q. Richard Lu
- Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
- Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, Ohio, USA
| | - Kenneth P. Nephew
- Medical Sciences Program, and
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana, USA
- Department of Anatomy, Cell Biology and Physiology, and
| | - Jia Shen
- Medical Sciences Program, and
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana, USA
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA
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Xiao D, Ran H, Chen L, Li Y, Cai Y, Zhang S, Qi Q, Wu H, Zhang C, Cao S, Mi L, Huang H, Qi J, Han Q, Tu H, Li H, Zhou T, Li F, Li A, Man J. FSD1 inhibits glioblastoma diffuse infiltration through restriction of HDAC6-mediated microtubule deacetylation. SCIENCE CHINA. LIFE SCIENCES 2025; 68:673-688. [PMID: 39808222 DOI: 10.1007/s11427-024-2616-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Accepted: 10/22/2024] [Indexed: 01/16/2025]
Abstract
The infiltration of glioblastoma multiforme (GBM) is predominantly characterized by diffuse spread, contributing significantly to therapy resistance and recurrence of GBM. In this study, we reveal that microtubule deacetylation, mediated through the downregulation of fibronectin type III and SPRY domain-containing 1 (FSD1), plays a pivotal role in promoting GBM diffuse infiltration. FSD1 directly interacts with histone deacetylase 6 (HDAC6) at its second catalytic domain, thereby impeding its deacetylase activity on α-tubulin and preventing microtubule deacetylation and depolymerization. This inhibitory interaction is disrupted upon phosphorylation of FSD1 at its Ser317 and Ser324 residues by activated CDK5, leading to FSD1 dissociation from microtubules and facilitating HDAC6-mediated α-tubulin deacetylation. Furthermore, increased expression of FSD1 or interference with FSD1 phosphorylation reduces microtubule deacetylation, suppresses invasion of GBM stem cells, and ultimately mitigates tumor infiltration in orthotopic GBM xenografts. Importantly, GBM tissues exhibit diminished levels of FSD1 expression, correlating with microtubule deacetylation and unfavorable clinical outcomes in GBM patients. These findings elucidate the mechanistic involvement of microtubule deacetylation in driving GBM cell invasion and offer potential avenues for managing GBM infiltration.
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Affiliation(s)
- Dake Xiao
- Nanhu Laboratory, National Center of Biomedical Analysis, Beijing, 100850, China
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China
| | - Haowen Ran
- Nanhu Laboratory, National Center of Biomedical Analysis, Beijing, 100850, China
- Department of Neurosurgery, General Hospital of Central Theater Command of Chinese PLA, Wuhan, 430070, China
| | - Lishu Chen
- Nanhu Laboratory, National Center of Biomedical Analysis, Beijing, 100850, China
| | - Yuanyuan Li
- Nanhu Laboratory, National Center of Biomedical Analysis, Beijing, 100850, China
| | - Yan Cai
- Nanhu Laboratory, National Center of Biomedical Analysis, Beijing, 100850, China
| | - Songyang Zhang
- Nanhu Laboratory, National Center of Biomedical Analysis, Beijing, 100850, China
| | - Qinghui Qi
- Nanhu Laboratory, National Center of Biomedical Analysis, Beijing, 100850, China
| | - Huiran Wu
- Nanhu Laboratory, National Center of Biomedical Analysis, Beijing, 100850, China
| | - Cheng Zhang
- Nanhu Laboratory, National Center of Biomedical Analysis, Beijing, 100850, China
| | - Shuailiang Cao
- Nanhu Laboratory, National Center of Biomedical Analysis, Beijing, 100850, China
| | - Lanjuan Mi
- Nanhu Laboratory, National Center of Biomedical Analysis, Beijing, 100850, China
- School of Life and Health Sciences, Huzhou College, Huzhou, 313000, China
| | - Haohao Huang
- Nanhu Laboratory, National Center of Biomedical Analysis, Beijing, 100850, China
- Department of Neurosurgery, General Hospital of Central Theater Command of Chinese PLA, Wuhan, 430070, China
| | - Ji Qi
- Department of Neurosurgery, Beijing Fengtai Hospital, Beijing, 100070, China
| | - Qiuying Han
- Nanhu Laboratory, National Center of Biomedical Analysis, Beijing, 100850, China
| | - Haiqing Tu
- Nanhu Laboratory, National Center of Biomedical Analysis, Beijing, 100850, China
| | - Huiyan Li
- Nanhu Laboratory, National Center of Biomedical Analysis, Beijing, 100850, China
| | - Tao Zhou
- Nanhu Laboratory, National Center of Biomedical Analysis, Beijing, 100850, China
| | - Fangye Li
- Department of Neurosurgery, First Medical Center of PLA General Hospital, Beijing, 100853, China.
| | - Ailing Li
- Nanhu Laboratory, National Center of Biomedical Analysis, Beijing, 100850, China.
| | - Jianghong Man
- Nanhu Laboratory, National Center of Biomedical Analysis, Beijing, 100850, China.
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Emir SM, Karaoğlan BS, Kaşmer R, Şirin HB, Sarıyıldız B, Karakaş N. Hunting glioblastoma recurrence: glioma stem cells as retrospective targets. Am J Physiol Cell Physiol 2025; 328:C1045-C1061. [PMID: 39818986 DOI: 10.1152/ajpcell.00344.2024] [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: 05/21/2024] [Revised: 06/11/2024] [Accepted: 01/07/2025] [Indexed: 01/19/2025]
Abstract
Glioblastoma (GBM) remains one of the most aggressive and treatment-resistant brain malignancies in adults. Standard approaches, including surgical resection followed by adjuvant radio- and chemotherapy with temozolomide (TMZ), provide only transient control, as GBM frequently recurs due to its infiltrative nature and the presence of therapy-resistant subpopulations such as glioma stem cells (GSCs). GSCs, with their quiescent state and robust resistance mechanisms, evade conventional therapies, contributing significantly to relapse. Consequently, current treatment methods for GBM face significant limitations in effectively targeting GSCs. In this review, we emphasize the relationship between GBM recurrence and GSCs, discuss the current limitations, and provide future perspectives to overwhelm the challenges associated with targeting GSCs. Eliminating GSCs may suppress recurrence, achieve durable responses, and improve therapeutic outcomes for patients with GBM.
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Affiliation(s)
- Sümeyra Mengüç Emir
- Cancer Research Center, Research Institute for Health Sciences and Technologies (SABITA), İstanbul Medipol University, Istanbul, Türkiye
| | - Birnur Sinem Karaoğlan
- Cancer Research Center, Research Institute for Health Sciences and Technologies (SABITA), İstanbul Medipol University, Istanbul, Türkiye
| | - Ramazan Kaşmer
- Cancer Research Center, Research Institute for Health Sciences and Technologies (SABITA), İstanbul Medipol University, Istanbul, Türkiye
| | - Hilal Buse Şirin
- Cancer Research Center, Research Institute for Health Sciences and Technologies (SABITA), İstanbul Medipol University, Istanbul, Türkiye
| | - Batuhan Sarıyıldız
- Cancer Research Center, Research Institute for Health Sciences and Technologies (SABITA), İstanbul Medipol University, Istanbul, Türkiye
| | - Nihal Karakaş
- Cancer Research Center, Research Institute for Health Sciences and Technologies (SABITA), İstanbul Medipol University, Istanbul, Türkiye
- Department of Medical Biology, International School of Medicine, İstanbul Medipol University, Istanbul, Türkiye
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Asaad L, Pepperrell B, McErlean E, Furlong F. Regulation of HDAC6 Catalytic Activity in Cancer: The Role of Post-Translational Modifications and Protein-Protein Interactions. Int J Mol Sci 2025; 26:1274. [PMID: 39941046 PMCID: PMC11818932 DOI: 10.3390/ijms26031274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 01/20/2025] [Accepted: 01/26/2025] [Indexed: 02/16/2025] Open
Abstract
Histone deacetylase 6 (HDAC6) is a large multidomain protein that deacetylates lysine residues on cytoplasmic proteins, influencing numerous cellular processes. Both the catalytic and noncatalytic functions of HDAC6 have been implicated in cancer development and progression. Over a decade of research on catalytic domain inhibitors has shown that these drugs are well tolerated, exhibit anticancer activity, and can alleviate chemotherapy-induced peripheral neuropathies. However, their effectiveness in treating solid tumours remains uncertain. HDAC6 activity is regulated by protein-protein interactions and post-translational modifications, which may allosterically influence its catalytic domains. As a result, effective inhibition of HDAC6 in cancer using small molecule inhibitors requires a more sophisticated understanding of its role within tumour cells, including whether its expression correlates with deacetylase activity. A comprehensive understanding of cancer-specific HDAC6 expression, functional activity, and activation states will be critical for refining the use of HDAC6 inhibitors in cancer therapy.
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Affiliation(s)
- Leen Asaad
- School of Pharmacy, Queen’s University Belfast, Belfast BT7 1NN, UK
- Department of Pharmacology and Biomedical Sciences, Faculty of Pharmacy and Medical Sciences, University of Petra, Amman 11196, Jordan
| | | | - Emma McErlean
- School of Pharmacy, Queen’s University Belfast, Belfast BT7 1NN, UK
| | - Fiona Furlong
- School of Pharmacy, Queen’s University Belfast, Belfast BT7 1NN, UK
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9
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Oliveira-Silva JM, Oliveira LS, Chiminazo CB, Fonseca R, de Souza CVE, Aissa AF, de Almeida Lima GD, Ionta M, Castro-Gamero AM. WT161, a selective HDAC6 inhibitor, decreases growth, enhances chemosensitivity, promotes apoptosis, and suppresses motility of melanoma cells. Cancer Chemother Pharmacol 2025; 95:22. [PMID: 39821335 DOI: 10.1007/s00280-024-04731-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Accepted: 11/25/2024] [Indexed: 01/19/2025]
Abstract
PURPOSE Histone deacetylase 6 (HDAC6) plays a critical role in tumorigenesis and tumor progression, contributing to proliferation, chemoresistance, and cell motility by regulating microtubule architecture. Despite its upregulation in melanoma tissues and cell lines, the specific biological roles of HDAC6 in melanoma are not well understood. This study aims to explore the functional effects and underlying mechanisms of WT161, a selective HDAC6 inhibitor, in melanoma cell lines. METHODS Cell proliferation was assessed using both 2D and 3D cell culture systems, including MTT assays, spheroid growth analyses, and colony formation assays. The interaction between WT161 and the chemotherapeutic agents temozolomide (TMZ) or dacarbazine (DTIC) was evaluated using the Chou-Talalay method. Apoptotic cell death was analyzed through flow cytometry, while migration, adhesion, and invasion assays were conducted to evaluate the motility capacities of melanoma cells. Western blot assays quantified α-tubulin acetylation (Lys40), PARP cleavage, and protein levels of β-catenin and E-cadherin. RESULTS WT161 significantly reduced cell growth in both 2D and 3D cultures, decreased clonogenic capacity, and showed synergistic interactions with TMZ and DTIC. The inhibitor also induced apoptotic cell death and enhanced TMZ-induced apoptosis. Additionally, WT161 reduced cell migration and invasion while increasing cell adhesion. These effects were linked to changes in β-catenin and E-cadherin levels, depending on the specific cell type evaluated. CONCLUSION Our study underscores the pivotal role of HDAC6 in melanoma progression, establishing it as a promising therapeutic target. We provide the first comprehensive evidence of WT161's anti-melanoma effects, setting the stage for further research into HDAC6 inhibitors as a potential strategy for melanoma treatment.
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Affiliation(s)
- João Marcos Oliveira-Silva
- Human Genetics Laboratory, Institute of Natural Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
- Postgraduate Program in Biosciences Applied to Health (PPGB), Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
| | - Leilane Sales Oliveira
- Human Genetics Laboratory, Institute of Natural Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
- Postgraduate Program in Biosciences Applied to Health (PPGB), Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
| | - Carolina Berraut Chiminazo
- Human Genetics Laboratory, Institute of Natural Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
| | - Rafael Fonseca
- Institute of Biomedical Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
| | | | - Alexandre Ferro Aissa
- Institute of Biomedical Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
- Postgraduate Program in Biosciences Applied to Health (PPGB), Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
| | - Graziela Domingues de Almeida Lima
- Institute of Biomedical Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
- Postgraduate Program in Biosciences Applied to Health (PPGB), Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
| | - Marisa Ionta
- Institute of Biomedical Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
- Postgraduate Program in Biosciences Applied to Health (PPGB), Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
| | - Angel Mauricio Castro-Gamero
- Human Genetics Laboratory, Institute of Natural Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil.
- Postgraduate Program in Biosciences Applied to Health (PPGB), Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil.
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Masciale V, Banchelli F, Grisendi G, Samarelli AV, Raineri G, Rossi T, Zanoni M, Cortesi M, Bandini S, Ulivi P, Martinelli G, Stella F, Dominici M, Aramini B. The molecular features of lung cancer stem cells in dedifferentiation process-driven epigenetic alterations. J Biol Chem 2024; 300:107994. [PMID: 39547513 PMCID: PMC11714729 DOI: 10.1016/j.jbc.2024.107994] [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: 03/23/2024] [Revised: 10/30/2024] [Accepted: 11/05/2024] [Indexed: 11/17/2024] Open
Abstract
Cancer stem cells (CSCs) may be dedifferentiated somatic cells following oncogenic processes, representing a subpopulation of cells able to promote tumor growth with their capacities for proliferation and self-renewal, inducing lineage heterogeneity, which may be a main cause of resistance to therapies. It has been shown that the "less differentiated process" may have an impact on tumor plasticity, particularly when non-CSCs may dedifferentiate and become CSC-like. Bidirectional interconversion between CSCs and non-CSCs has been reported in other solid tumors, where the inflammatory stroma promotes cell reprogramming by enhancing Wnt signaling through nuclear factor kappa B activation in association with intracellular signaling, which may induce cells' pluripotency, the oncogenic transformation can be considered another important aspect in the acquisition of "new" development programs with oncogenic features. During cell reprogramming, mutations represent an initial step toward dedifferentiation, in which tumor cells switch from a partially or terminally differentiated stage to a less differentiated stage that is mainly manifested by re-entry into the cell cycle, acquisition of a stem cell-like phenotype, and expression of stem cell markers. This phenomenon typically shows up as a change in the form, function, and pattern of gene and protein expression, and more specifically, in CSCs. This review would highlight the main epigenetic alterations, major signaling pathways and driver mutations in which CSCs, in tumors and specifically, in lung cancer, could be involved, acting as key elements in the differentiation/dedifferentiation process. This would highlight the main molecular mechanisms which need to be considered for more tailored therapies.
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Affiliation(s)
- Valentina Masciale
- Laboratory of Cellular Therapies, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy
| | - Federico Banchelli
- Department of Statistical Sciences "Paolo Fortunati", Alma Mater Studiorum- University of Bologna, Bologna, Italy
| | - Giulia Grisendi
- Laboratory of Cellular Therapies, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy
| | - Anna Valeria Samarelli
- Laboratory of and Respiratory Medicine, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy
| | - Giulia Raineri
- Laboratory of Cellular Therapies, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy
| | - Tania Rossi
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Michele Zanoni
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Michela Cortesi
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Sara Bandini
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Paola Ulivi
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Giovanni Martinelli
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Franco Stella
- Thoracic Surgery Unit, Department of Medical and Surgical Sciences-DIMEC of the Alma Mater Studiorum, University of Bologna, G.B. Morgagni-L. Pierantoni Hospital, Forlì, Italy
| | - Massimo Dominici
- Laboratory of Cellular Therapies, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy; Division of Oncology, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena, Italy
| | - Beatrice Aramini
- Thoracic Surgery Unit, Department of Medical and Surgical Sciences-DIMEC of the Alma Mater Studiorum, University of Bologna, G.B. Morgagni-L. Pierantoni Hospital, Forlì, Italy.
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11
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Spallotta F, Illi B. The Role of HDAC6 in Glioblastoma Multiforme: A New Avenue to Therapeutic Interventions? Biomedicines 2024; 12:2631. [PMID: 39595195 PMCID: PMC11591585 DOI: 10.3390/biomedicines12112631] [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: 10/31/2024] [Revised: 11/14/2024] [Accepted: 11/15/2024] [Indexed: 11/28/2024] Open
Abstract
Despite the great advances in basic research results, glioblastoma multiforme (GBM) still remains an incurable tumour. To date, a GBM diagnosis is a death sentence within 15-18 months, due to the high recurrence rate and resistance to conventional radio- and chemotherapy approaches. The effort the scientific community is lavishing on the never-ending battle against GBM is reflected by the huge number of clinical trials launched, about 2003 on 10 September 2024. However, we are still far from both an in-depth comprehension of the biological and molecular processes leading to GBM onset and progression and, importantly, a cure. GBM is provided with high intratumoral heterogeneity, immunosuppressive capacity, and infiltrative ability due to neoangiogenesis. These features impact both tumour aggressiveness and therapeutic vulnerability, which is further limited by the presence in the tumour core of niches of glioblastoma stem cells (GSCs) that are responsible for the relapse of this brain neoplasm. Epigenetic alterations may both drive and develop along GBM progression and also rely on changes in the expression of the genes encoding histone-modifying enzymes, including histone deacetylases (HDACs). Among them, HDAC6-a cytoplasmic HDAC-has recently gained attention because of its role in modulating several biological aspects of GBM, including DNA repair ability, massive growth, radio- and chemoresistance, and de-differentiation through primary cilia disruption. In this review article, the available information related to HDAC6 function in GBM will be presented, with the aim of proposing its inhibition as a valuable therapeutic route for this deadly brain tumour.
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Affiliation(s)
- Francesco Spallotta
- Department of Biology and Biotechnology Charles Darwin, Sapienza University, 00185 Rome, Italy;
- Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University, 00185 Rome, Italy
| | - Barbara Illi
- Institute of Molecular Biology and Pathology, National Research Council (IBPM-CNR), 00185 Rome, Italy
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12
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Hu H, Wang Q, Zhang Y, Yang S, Shen A, Yan J, Zhao D, Hu B. Effects of a novel HDAC6-selective inhibitor's radiosensitization on cancer cells. Mol Biol Rep 2024; 51:1151. [PMID: 39537948 DOI: 10.1007/s11033-024-10084-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 10/31/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND The radiation sensitivity of tumor cells is a critical determinant of their therapeutic response to radiotherapy. Histone deacetylase 6 (HDAC6), beyond its known role in modulating tubulin acetylation and influencing cell motility, is also involved in the DNA damage response, potentially enhancing tumor cell radiosensitivity. Targeted HDAC6 inhibitors have shown substantial promise in preclinical studies aimed at increasing radiosensitivity and inhibiting cellular migration. METHODS A new HDAC inhibitor, named OXHA, was designed by substituting the phenyl cap of SAHA with an N,5-diphenyloxazole-2-carboxamide group. The inhibitory activity of OXHA was evaluated via in vitro enzymatic assays. Its effects on tumor cell migration and radiosensitization potential were assessed using scratch wound healing assays, micronucleus formation, and clonogenic survival assays. RESULT Enzymatic assays confirmed OXHA's selective inhibition of HDAC6. Compared to SAHA, OXHA significantly increased α-tubulin acetylation while minimally impacting histone H3 acetylation, indicating a high selectivity for HDAC6. In combination with X-ray irradiation, OXHA markedly impaired wound healing in A549 and HepG2 cells, enhanced micronucleus formation, and reduced clonogenic survival across multiple tumor lines. CONCLUSION OXHA exhibits potent and selective HDAC6 inhibition, effectively impeding tumor cell migration and enhancing radiosensitivity across multiple cell lines. These findings suggest that OXHA has strong potential as a therapeutic strategy to improve radiotherapy efficacy.
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Affiliation(s)
- Huixiao Hu
- School of Public Health, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Zhejiang Engineering Research Center for Innovation and Application of Intelligent Radiotherapy Technology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Watershed Sciences and Health, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Wenzhou Key Laboratory of Basic Science and Translational Research of Radiation Oncology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Qi Wang
- School of Public Health, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Zhejiang Engineering Research Center for Innovation and Application of Intelligent Radiotherapy Technology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Watershed Sciences and Health, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Wenzhou Key Laboratory of Basic Science and Translational Research of Radiation Oncology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Yuni Zhang
- School of Public Health, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Zhejiang Engineering Research Center for Innovation and Application of Intelligent Radiotherapy Technology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Watershed Sciences and Health, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Wenzhou Key Laboratory of Basic Science and Translational Research of Radiation Oncology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Shuhua Yang
- School of Public Health, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Zhejiang Engineering Research Center for Innovation and Application of Intelligent Radiotherapy Technology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Watershed Sciences and Health, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Wenzhou Key Laboratory of Basic Science and Translational Research of Radiation Oncology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Aihua Shen
- School of Public Health, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Zhejiang Engineering Research Center for Innovation and Application of Intelligent Radiotherapy Technology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Watershed Sciences and Health, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Wenzhou Key Laboratory of Basic Science and Translational Research of Radiation Oncology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Junfang Yan
- School of Public Health, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Zhejiang Engineering Research Center for Innovation and Application of Intelligent Radiotherapy Technology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Watershed Sciences and Health, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Wenzhou Key Laboratory of Basic Science and Translational Research of Radiation Oncology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Denggao Zhao
- School of Pharmacy and Food Engineering, Wuyi University, Jiangmen, 529020, China.
| | - Burong Hu
- School of Public Health, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
- Zhejiang Engineering Research Center for Innovation and Application of Intelligent Radiotherapy Technology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
- Zhejiang Provincial Key Laboratory of Watershed Sciences and Health, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
- Wenzhou Key Laboratory of Basic Science and Translational Research of Radiation Oncology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
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13
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Dakal TC, Bhushan R, Xu C, Gadi BR, Cameotra SS, Yadav V, Maciaczyk J, Schmidt‐Wolf IGH, Kumar A, Sharma A. Intricate relationship between cancer stemness, metastasis, and drug resistance. MedComm (Beijing) 2024; 5:e710. [PMID: 39309691 PMCID: PMC11416093 DOI: 10.1002/mco2.710] [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: 03/13/2024] [Revised: 08/02/2024] [Accepted: 08/05/2024] [Indexed: 09/25/2024] Open
Abstract
Cancer stem cells (CSCs) are widely acknowledged as the drivers of tumor initiation, epithelial-mesenchymal transition (EMT) progression, and metastasis. Originating from both hematologic and solid malignancies, CSCs exhibit quiescence, pluripotency, and self-renewal akin to normal stem cells, thus orchestrating tumor heterogeneity and growth. Through a dynamic interplay with the tumor microenvironment (TME) and intricate signaling cascades, CSCs undergo transitions from differentiated cancer cells, culminating in therapy resistance and disease recurrence. This review undertakes an in-depth analysis of the multifaceted mechanisms underlying cancer stemness and CSC-mediated resistance to therapy. Intrinsic factors encompassing the TME, hypoxic conditions, and oxidative stress, alongside extrinsic processes such as drug efflux mechanisms, collectively contribute to therapeutic resistance. An exploration into key signaling pathways, including JAK/STAT, WNT, NOTCH, and HEDGEHOG, sheds light on their pivotal roles in sustaining CSCs phenotypes. Insights gleaned from preclinical and clinical studies hold promise in refining drug discovery efforts and optimizing therapeutic interventions, especially chimeric antigen receptor (CAR)-T cell therapy, cytokine-induced killer (CIK) cell therapy, natural killer (NK) cell-mediated CSC-targeting and others. Ultimately use of cell sorting and single cell sequencing approaches for elucidating the fundamental characteristics and resistance mechanisms inherent in CSCs will enhance our comprehension of CSC and intratumor heterogeneity, which ultimately would inform about tailored and personalized interventions.
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Affiliation(s)
- Tikam Chand Dakal
- Genome and Computational Biology LabDepartment of BiotechnologyMohanlal Sukhadia UniversityUdaipurRajasthanIndia
| | - Ravi Bhushan
- Department of ZoologyM.S. CollegeMotihariBiharIndia
| | - Caiming Xu
- Department of General SurgeryThe First Affiliated Hospital of Dalian Medical UniversityDalianChina
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research InstituteCity of HopeMonroviaCaliforniaUSA
| | - Bhana Ram Gadi
- Stress Physiology and Molecular Biology LaboratoryDepartment of BotanyJai Narain Vyas UniversityJodhpurRajasthanIndia
| | | | - Vikas Yadav
- School of Life SciencesJawaharlal Nehru UniversityNew DelhiIndia
| | - Jarek Maciaczyk
- Department of Stereotactic and Functional NeurosurgeryUniversity Hospital of BonnBonnGermany
| | - Ingo G. H. Schmidt‐Wolf
- Center for Integrated Oncology (CIO)Department of Integrated OncologyUniversity Hospital BonnBonnGermany
| | - Abhishek Kumar
- Manipal Academy of Higher EducationManipalKarnatakaIndia
- Institute of BioinformaticsInternational Technology ParkBangaloreIndia
| | - Amit Sharma
- Department of Stereotactic and Functional NeurosurgeryUniversity Hospital of BonnBonnGermany
- Center for Integrated Oncology (CIO)Department of Integrated OncologyUniversity Hospital BonnBonnGermany
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14
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Li C, Xie Q, Ghosh S, Cao B, Du Y, Vo GV, Huang TY, Spruck C, Wang YA, Nephew KP, Shen J. SUV39H1 Preserves Cancer Stem Cell Chromatin State and Properties in Glioblastoma. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.15.607856. [PMID: 39229036 PMCID: PMC11370334 DOI: 10.1101/2024.08.15.607856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/05/2024]
Abstract
Of the more than 100 types of brain cancer, glioblastoma (GBM) is the deadliest. As GBM stem cells (GSCs) are considered to be responsible for therapeutic resistance and tumor recurrence, effective targeting and elimination of GSCs could hold promise for preventing GBM recurrence and achieving potential cures. We show here that SUV39H1 , which encodes a histone-3, lysine-9 methyltransferase, plays a critical role in GSC maintenance and GBM progression. Upregulation of SUV39H1 was observed in GBM samples compared to normal brain tissues, and knockdown of SUV39H1 in patient-derived GSCs impaired their proliferation and stemness. Single-cell RNA-seq analysis demonstrated restricted expression of SUV39H1 is in GSCs relative to non-stem GBM cells, likely due to super-enhancer-mediated transcriptional activation, while whole cell RNA-seq analysis revealed that SUV39H1 regulates G2/M cell cycle progression, stem cell maintenance, and cell death pathways in GSCs. By integrating the RNA-seq data with ATAC-seq (assay for transposase-accessible chromatin followed by sequencing), we further demonstrated altered chromatin accessibility in key genes associated with these pathways following SUV39H1 knockdown. Treatment with chaetocin, a SUV39H1 inhibitor, mimicked the functional effects of SUV39H1 knockdown in GSCs and sensitized GSCs to the GBM chemotherapy drug temozolomide. Furthermore, targeting SUV39H1 in vivo using a patient-derived xenograft model for GBM inhibited GSC-driven tumor formation. This is the first report demonstrating a critical role for SUV39H1 in GSC maintenance. SUV39H1-mediated targeting of GSCs could enhance the efficacy of existing chemotherapy, presenting a promising strategy for improving GBM treatment and patient outcomes. Highlights SUV39H1 is upregulated in GBM, especially GSCsTargeting SUV39H1 disrupts GSC maintenance and sensitizes GSCs to TMZTargeting SUV39H1 alters chromatin accessibility at cell cycle and stemness genesTargeting SUV39H1 suppresses GSC-driven tumors in a patient-derived xenograft model.
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15
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Agosti E, Antonietti S, Ius T, Fontanella MM, Zeppieri M, Panciani PP. Glioma Stem Cells as Promoter of Glioma Progression: A Systematic Review of Molecular Pathways and Targeted Therapies. Int J Mol Sci 2024; 25:7979. [PMID: 39063221 PMCID: PMC11276876 DOI: 10.3390/ijms25147979] [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: 05/30/2024] [Revised: 07/16/2024] [Accepted: 07/17/2024] [Indexed: 07/28/2024] Open
Abstract
Gliomas' aggressive nature and resistance to therapy make them a major problem in oncology. Gliomas continue to have dismal prognoses despite significant advancements in medical science, and traditional treatments like surgery, radiation (RT), and chemotherapy (CT) frequently prove to be ineffective. After glioma stem cells (GSCs) were discovered, the traditional view of gliomas as homogeneous masses changed. GSCs are essential for tumor growth, treatment resistance, and recurrence. These cells' distinct capacities for differentiation and self-renewal are changing our knowledge of the biology of gliomas. This systematic literature review aims to uncover the molecular mechanisms driving glioma progression associated with GSCs. The systematic review adhered to PRISMA guidelines, with a thorough literature search conducted on PubMed, Ovid MED-LINE, and Ovid EMBASE. The first literature search was performed on 1 March 2024, and the search was updated on 15 May 2024. Employing MeSH terms and Boolean operators, the search focused on molecular mechanisms associated with GCSs-mediated glioma progression. Inclusion criteria encompassed English language studies, preclinical studies, and clinical trials. A number of 957 papers were initially identified, of which 65 studies spanning from 2005 to 2024 were finally included in the review. The main GSC model distribution is arranged in decreasing order of frequency: U87: 20 studies (32.0%); U251: 13 studies (20.0%); A172: 4 studies (6.2%); and T98G: 2 studies (3.17%). From most to least frequent, the distribution of the primary GSC pathway is as follows: Notch: 8 studies (12.3%); STAT3: 6 studies (9.2%); Wnt/β-catenin: 6 studies (9.2%); HIF: 5 studies (7.7%); and PI3K/AKT: 4 studies (6.2%). The distribution of molecular effects, from most to least common, is as follows: inhibition of differentiation: 22 studies (33.8%); increased proliferation: 18 studies (27.7%); enhanced invasive ability: 15 studies (23.1%); increased self-renewal: 5 studies (7.7%); and inhibition of apoptosis: 3 studies (4.6%). This work highlights GSC heterogeneity and the dynamic interplay within the glioblastoma microenvironment, underscoring the need for a tailored approach. A few key pathways influencing GSC behavior are JAK/STAT3, PI3K/AKT, Wnt/β-catenin, and Notch. Therapy may target these pathways. This research urges more study to fill in knowledge gaps in the biology of GSCs and translate findings into useful treatment approaches that could improve GBM patient outcomes.
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Affiliation(s)
- Edoardo Agosti
- Division of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Piazza Spedali Civili 1, 25123 Brescia, Italy; (E.A.); (P.P.P.)
| | - Sara Antonietti
- Division of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Piazza Spedali Civili 1, 25123 Brescia, Italy; (E.A.); (P.P.P.)
| | - Tamara Ius
- Neurosurgery Unit, Head-Neck and NeuroScience Department, University Hospital of Udine, p.le S. Maria della Misericordia 15, 33100 Udine, Italy
| | - Marco Maria Fontanella
- Division of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Piazza Spedali Civili 1, 25123 Brescia, Italy; (E.A.); (P.P.P.)
| | - Marco Zeppieri
- Department of Ophthalmology, University Hospital of Udine, p.le S. Maria della Misericordia 15, 33100 Udine, Italy
| | - Pier Paolo Panciani
- Division of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Piazza Spedali Civili 1, 25123 Brescia, Italy; (E.A.); (P.P.P.)
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Anraku T, Murata M, Kuroki H, Kazama A, Shirono Y, Tasaki M, Bilim V, Tomita Y. Selective HDAC6 Inhibition Has the Potential for Anti-Cancer Effect in Renal Cell Carcinoma. J Pers Med 2024; 14:704. [PMID: 39063958 PMCID: PMC11278056 DOI: 10.3390/jpm14070704] [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: 05/12/2024] [Revised: 06/24/2024] [Accepted: 06/27/2024] [Indexed: 07/28/2024] Open
Abstract
Despite significant advancements in systemic therapy for renal cell carcinoma (RCC), the prognosis for patients with metastatic RCC remains poor, as they are often incurable. Consequently, there is an urgent need for innovative therapeutic strategies to further enhance the efficacy of RCC treatment and improve patient outcomes. One such promising avenue lies in targeting histone deacetylase (HDAC) 6, a protein known to regulate numerous crucial biological processes implicated in cancer progression by modulating the acetylation status of various cytoplasmic proteins. To explore the therapeutic potential of HDAC6 inhibition in RCC, our study focused on investigating the effects of HDAC6 inhibitors on cultured RCC cells. Utilizing a panel of 12 small molecule selective HDAC6 inhibitors and employing genetic knockdown techniques, we examined the impact of HDAC6 inhibition on RCC cellular dynamics. Our findings revealed that HDAC6 inhibition exerted a profound effect on RCC cells, resulting in decreased cell viability and DNA replication. Importantly, this effect was attributed to the induction of apoptosis. Our study provides valuable insights into the mechanisms underlying the anticancer effects of selective HDAC6 inhibitors on RCC. A detailed understanding of the molecular mechanisms underlying the anticancer effects of HDAC6 inhibition is important to explore new therapeutic strategies for metastatic RCC.
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Affiliation(s)
- Tsutomu Anraku
- Department of Urology, Division of Molecular Oncology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan; (M.M.); (H.K.); (A.K.); (Y.S.); (M.T.); (V.B.); (Y.T.)
| | - Masaki Murata
- Department of Urology, Division of Molecular Oncology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan; (M.M.); (H.K.); (A.K.); (Y.S.); (M.T.); (V.B.); (Y.T.)
| | - Hiroo Kuroki
- Department of Urology, Division of Molecular Oncology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan; (M.M.); (H.K.); (A.K.); (Y.S.); (M.T.); (V.B.); (Y.T.)
| | - Akira Kazama
- Department of Urology, Division of Molecular Oncology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan; (M.M.); (H.K.); (A.K.); (Y.S.); (M.T.); (V.B.); (Y.T.)
| | - Yuko Shirono
- Department of Urology, Division of Molecular Oncology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan; (M.M.); (H.K.); (A.K.); (Y.S.); (M.T.); (V.B.); (Y.T.)
| | - Masayuki Tasaki
- Department of Urology, Division of Molecular Oncology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan; (M.M.); (H.K.); (A.K.); (Y.S.); (M.T.); (V.B.); (Y.T.)
| | - Vladimir Bilim
- Department of Urology, Division of Molecular Oncology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan; (M.M.); (H.K.); (A.K.); (Y.S.); (M.T.); (V.B.); (Y.T.)
- Department of Urology, Kameda Daiichi Hospital, Niigata 950-0165, Japan
| | - Yoshihiko Tomita
- Department of Urology, Division of Molecular Oncology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan; (M.M.); (H.K.); (A.K.); (Y.S.); (M.T.); (V.B.); (Y.T.)
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17
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Obrador E, Moreno-Murciano P, Oriol-Caballo M, López-Blanch R, Pineda B, Gutiérrez-Arroyo JL, Loras A, Gonzalez-Bonet LG, Martinez-Cadenas C, Estrela JM, Marqués-Torrejón MÁ. Glioblastoma Therapy: Past, Present and Future. Int J Mol Sci 2024; 25:2529. [PMID: 38473776 PMCID: PMC10931797 DOI: 10.3390/ijms25052529] [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: 12/23/2023] [Revised: 02/10/2024] [Accepted: 02/16/2024] [Indexed: 03/14/2024] Open
Abstract
Glioblastoma (GB) stands out as the most prevalent and lethal form of brain cancer. Although great efforts have been made by clinicians and researchers, no significant improvement in survival has been achieved since the Stupp protocol became the standard of care (SOC) in 2005. Despite multimodality treatments, recurrence is almost universal with survival rates under 2 years after diagnosis. Here, we discuss the recent progress in our understanding of GB pathophysiology, in particular, the importance of glioma stem cells (GSCs), the tumor microenvironment conditions, and epigenetic mechanisms involved in GB growth, aggressiveness and recurrence. The discussion on therapeutic strategies first covers the SOC treatment and targeted therapies that have been shown to interfere with different signaling pathways (pRB/CDK4/RB1/P16ink4, TP53/MDM2/P14arf, PI3k/Akt-PTEN, RAS/RAF/MEK, PARP) involved in GB tumorigenesis, pathophysiology, and treatment resistance acquisition. Below, we analyze several immunotherapeutic approaches (i.e., checkpoint inhibitors, vaccines, CAR-modified NK or T cells, oncolytic virotherapy) that have been used in an attempt to enhance the immune response against GB, and thereby avoid recidivism or increase survival of GB patients. Finally, we present treatment attempts made using nanotherapies (nanometric structures having active anti-GB agents such as antibodies, chemotherapeutic/anti-angiogenic drugs or sensitizers, radionuclides, and molecules that target GB cellular receptors or open the blood-brain barrier) and non-ionizing energies (laser interstitial thermal therapy, high/low intensity focused ultrasounds, photodynamic/sonodynamic therapies and electroporation). The aim of this review is to discuss the advances and limitations of the current therapies and to present novel approaches that are under development or following clinical trials.
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Affiliation(s)
- Elena Obrador
- Scientia BioTech S.L., 46002 Valencia, Spain; (P.M.-M.); (M.O.-C.); (R.L.-B.); (J.M.E.)
- Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 46010 Valencia, Spain;
| | - Paz Moreno-Murciano
- Scientia BioTech S.L., 46002 Valencia, Spain; (P.M.-M.); (M.O.-C.); (R.L.-B.); (J.M.E.)
| | - María Oriol-Caballo
- Scientia BioTech S.L., 46002 Valencia, Spain; (P.M.-M.); (M.O.-C.); (R.L.-B.); (J.M.E.)
- Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 46010 Valencia, Spain;
| | - Rafael López-Blanch
- Scientia BioTech S.L., 46002 Valencia, Spain; (P.M.-M.); (M.O.-C.); (R.L.-B.); (J.M.E.)
- Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 46010 Valencia, Spain;
| | - Begoña Pineda
- Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 46010 Valencia, Spain;
| | - Julia Lara Gutiérrez-Arroyo
- Department of Medicine, Jaume I University of Castellon, 12071 Castellon, Spain; (J.L.G.-A.); (A.L.); (C.M.-C.)
| | - Alba Loras
- Department of Medicine, Jaume I University of Castellon, 12071 Castellon, Spain; (J.L.G.-A.); (A.L.); (C.M.-C.)
| | - Luis G. Gonzalez-Bonet
- Department of Neurosurgery, Castellon General University Hospital, 12004 Castellon, Spain;
| | - Conrado Martinez-Cadenas
- Department of Medicine, Jaume I University of Castellon, 12071 Castellon, Spain; (J.L.G.-A.); (A.L.); (C.M.-C.)
| | - José M. Estrela
- Scientia BioTech S.L., 46002 Valencia, Spain; (P.M.-M.); (M.O.-C.); (R.L.-B.); (J.M.E.)
- Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 46010 Valencia, Spain;
- Department of Physiology, Faculty of Pharmacy, University of Valencia, 46100 Burjassot, Spain
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18
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Zhang L, Zhang Y, Li K, Xue S. Hedgehog signaling and the glioma-associated oncogene in cancer radioresistance. Front Cell Dev Biol 2023; 11:1257173. [PMID: 38020914 PMCID: PMC10679362 DOI: 10.3389/fcell.2023.1257173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 10/31/2023] [Indexed: 12/01/2023] Open
Abstract
Tumor radioresistance remains a key clinical challenge. The Hedgehog (HH) signaling pathway and glioma-associated oncogene (GLI) are aberrantly activated in several cancers and are thought to contribute to cancer radioresistance by influencing DNA repair, reactive oxygen species production, apoptosis, autophagy, cancer stem cells, the cell cycle, and the tumor microenvironment. GLI is reported to activate the main DNA repair pathways, to interact with cell cycle regulators like Cyclin D and Cyclin E, to inhibit apoptosis via the activation of B-cell lymphoma-2, Forkhead Box M1, and the MYC proto-oncogene, to upregulate cell stemness related genes (Nanog, POU class 5 homeobox 1, SRY-box transcription factor 2, and the BMI1 proto-oncogene), and to promote cancer stem cell transformation. The inactivation of Patched, the receptor of HH, prevents caspase-mediated apoptosis. This causes some cancer cells to survive while others become cancer stem cells, resulting in cancer recurrence. Combination treatment using HH inhibitors (including GLI inhibitors) and conventional therapies may enhance treatment efficacy. However, the clinical use of HH signaling inhibitors is associated with toxic side effects and drug resistance. Nevertheless, selective HH agonists, which may relieve the adverse effects of inhibitors, have been developed in mouse models. Combination therapy with other pathway inhibitors or immunotherapy may effectively overcome resistance to HH inhibitors. A comprehensive cancer radiotherapy with HH or GLI inhibitor is more likely to enhance cancer treatment efficacy while further studies are still needed to overcome its adverse effects and drug resistance.
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Affiliation(s)
- Li Zhang
- Nephrology Department, The 1st Hospital of Jilin University, Changchun, China
| | - Yuhan Zhang
- General Surgery Center, Department of Thyroid Surgery, The 1st Hospital of Jilin University, Changchun, China
| | - Kaixuan Li
- General Surgery Center, Department of Thyroid Surgery, The 1st Hospital of Jilin University, Changchun, China
| | - Shuai Xue
- General Surgery Center, Department of Thyroid Surgery, The 1st Hospital of Jilin University, Changchun, China
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19
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Dewdney B, Jenkins MR, Best SA, Freytag S, Prasad K, Holst J, Endersby R, Johns TG. From signalling pathways to targeted therapies: unravelling glioblastoma's secrets and harnessing two decades of progress. Signal Transduct Target Ther 2023; 8:400. [PMID: 37857607 PMCID: PMC10587102 DOI: 10.1038/s41392-023-01637-8] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 08/29/2023] [Accepted: 09/07/2023] [Indexed: 10/21/2023] Open
Abstract
Glioblastoma, a rare, and highly lethal form of brain cancer, poses significant challenges in terms of therapeutic resistance, and poor survival rates for both adult and paediatric patients alike. Despite advancements in brain cancer research driven by a technological revolution, translating our understanding of glioblastoma pathogenesis into improved clinical outcomes remains a critical unmet need. This review emphasises the intricate role of receptor tyrosine kinase signalling pathways, epigenetic mechanisms, and metabolic functions in glioblastoma tumourigenesis and therapeutic resistance. We also discuss the extensive efforts over the past two decades that have explored targeted therapies against these pathways. Emerging therapeutic approaches, such as antibody-toxin conjugates or CAR T cell therapies, offer potential by specifically targeting proteins on the glioblastoma cell surface. Combination strategies incorporating protein-targeted therapy and immune-based therapies demonstrate great promise for future clinical research. Moreover, gaining insights into the role of cell-of-origin in glioblastoma treatment response holds the potential to advance precision medicine approaches. Addressing these challenges is crucial to improving outcomes for glioblastoma patients and moving towards more effective precision therapies.
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Affiliation(s)
- Brittany Dewdney
- Cancer Centre, Telethon Kids Institute, Nedlands, WA, 6009, Australia.
- Centre For Child Health Research, University of Western Australia, Perth, WA, 6009, Australia.
| | - Misty R Jenkins
- Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, 3052, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, 3010, Australia
| | - Sarah A Best
- Department of Medical Biology, University of Melbourne, Melbourne, 3010, Australia
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, 3052, Australia
| | - Saskia Freytag
- Department of Medical Biology, University of Melbourne, Melbourne, 3010, Australia
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, 3052, Australia
| | - Krishneel Prasad
- Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, 3052, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, 3010, Australia
| | - Jeff Holst
- School of Biomedical Sciences, University of New South Wales, Sydney, 2052, Australia
| | - Raelene Endersby
- Cancer Centre, Telethon Kids Institute, Nedlands, WA, 6009, Australia
- Centre For Child Health Research, University of Western Australia, Perth, WA, 6009, Australia
| | - Terrance G Johns
- Cancer Centre, Telethon Kids Institute, Nedlands, WA, 6009, Australia
- Centre For Child Health Research, University of Western Australia, Perth, WA, 6009, Australia
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20
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Shi P, Tian J, Mallinger JC, Ling D, Deleyrolle LP, McIntyre JC, Caspary T, Breunig JJ, Sarkisian MR. Increasing Ciliary ARL13B Expression Drives Active and Inhibitor-Resistant Smoothened and GLI into Glioma Primary Cilia. Cells 2023; 12:2354. [PMID: 37830570 PMCID: PMC10571910 DOI: 10.3390/cells12192354] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 09/14/2023] [Accepted: 09/20/2023] [Indexed: 10/14/2023] Open
Abstract
ADP-ribosylation factor-like protein 13B (ARL13B), a regulatory GTPase and guanine exchange factor (GEF), enriches in primary cilia and promotes tumorigenesis in part by regulating Smoothened (SMO), GLI, and Sonic Hedgehog (SHH) signaling. Gliomas with increased ARL13B, SMO, and GLI2 expression are more aggressive, but the relationship to cilia is unclear. Previous studies have showed that increasing ARL13B in glioblastoma cells promoted ciliary SMO accumulation, independent of exogenous SHH addition. Here, we show that SMO accumulation is due to increased ciliary, but not extraciliary, ARL13B. Increasing ARL13B expression promotes the accumulation of both activated SMO and GLI2 in glioma cilia. ARL13B-driven increases in ciliary SMO and GLI2 are resistant to SMO inhibitors, GDC-0449, and cyclopamine. Surprisingly, ARL13B-induced changes in ciliary SMO/GLI2 did not correlate with canonical changes in downstream SHH pathway genes. However, glioma cell lines whose cilia overexpress WT but not guanine exchange factor-deficient ARL13B, display reduced INPP5e, a ciliary membrane component whose depletion may favor SMO/GLI2 enrichment. Glioma cells overexpressing ARL13B also display reduced ciliary intraflagellar transport 88 (IFT88), suggesting that altered retrograde transport could further promote SMO/GLI accumulation. Collectively, our data suggest that factors increasing ARL13B expression in glioma cells may promote both changes in ciliary membrane characteristics and IFT proteins, leading to the accumulation of drug-resistant SMO and GLI. The downstream targets and consequences of these ciliary changes require further investigation.
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Affiliation(s)
- Ping Shi
- Department of Neuroscience, University of Florida College of Medicine, Gainesville, FL 32610, USA; (P.S.); (J.T.); (J.C.M.); (D.L.); (J.C.M.)
| | - Jia Tian
- Department of Neuroscience, University of Florida College of Medicine, Gainesville, FL 32610, USA; (P.S.); (J.T.); (J.C.M.); (D.L.); (J.C.M.)
| | - Julianne C. Mallinger
- Department of Neuroscience, University of Florida College of Medicine, Gainesville, FL 32610, USA; (P.S.); (J.T.); (J.C.M.); (D.L.); (J.C.M.)
| | - Dahao Ling
- Department of Neuroscience, University of Florida College of Medicine, Gainesville, FL 32610, USA; (P.S.); (J.T.); (J.C.M.); (D.L.); (J.C.M.)
| | - Loic P. Deleyrolle
- Preston A. Wells Jr. Center for Brain Tumor Therapy, University of Florida College of Medicine, Gainesville, FL 32610, USA;
- Department of Neurosurgery, University of Florida College of Medicine, Gainesville, FL 32610, USA
| | - Jeremy C. McIntyre
- Department of Neuroscience, University of Florida College of Medicine, Gainesville, FL 32610, USA; (P.S.); (J.T.); (J.C.M.); (D.L.); (J.C.M.)
| | - Tamara Caspary
- Department of Human Genetics, Emory School of Medicine, Atlanta, GA 30322, USA;
| | - Joshua J. Breunig
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA;
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Matthew R. Sarkisian
- Department of Neuroscience, University of Florida College of Medicine, Gainesville, FL 32610, USA; (P.S.); (J.T.); (J.C.M.); (D.L.); (J.C.M.)
- Preston A. Wells Jr. Center for Brain Tumor Therapy, University of Florida College of Medicine, Gainesville, FL 32610, USA;
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21
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Arechaga-Ocampo E. Epigenetics as a determinant of radiation response in cancer. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2023; 383:145-190. [PMID: 38359968 DOI: 10.1016/bs.ircmb.2023.07.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/17/2024]
Abstract
Radiation therapy is a cornerstone of modern cancer treatment. Treatment is based on depositing focal radiation to the tumor to inhibit cell growth, proliferation and metastasis, and to promote the death of cancer cells. In addition, radiation also affects non-tumor cells in the tumor microenvironmental (TME). Radiation resistance of the tumor cells is the most common cause of treatment failure, allowing survival of cancer cell and subsequent tumor growing. Molecular radioresistance comprises genetic and epigenetic characteristics inherent in cancer cells, or characteristics acquired after exposure to radiation. Furthermore, cancer stem cells (CSCs) and non-tumor cells into the TME as stromal and immune cells have a role in promoting and maintaining radioresistant tumor phenotypes. Different regulatory molecules and pathways distinctive of radiation resistance include DNA repair, survival signaling and cell death pathways. Epigenetic mechanisms are one of the most relevant events that occur after radiotherapy to regulate the expression and function of key genes and proteins in the differential radiation-response. This article reviews recent data on the main molecular mechanisms and signaling pathways related to the biological response to radiotherapy in cancer; highlighting the epigenetic control exerted by DNA methylation, histone marks, chromatin remodeling and m6A RNA methylation on gene expression and activation of signaling pathways related to radiation therapy response.
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Affiliation(s)
- Elena Arechaga-Ocampo
- Departamento de Ciencias Naturales, Unidad Cuajimalpa, Universidad Autonoma Metropolitana, Mexico City, Mexico.
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22
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Khan SU, Rayees S, Sharma P, Malik F. Targeting redox regulation and autophagy systems in cancer stem cells. Clin Exp Med 2023; 23:1405-1423. [PMID: 36473988 DOI: 10.1007/s10238-022-00955-5] [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] [Received: 10/24/2022] [Accepted: 11/16/2022] [Indexed: 12/12/2022]
Abstract
Cancer is a dysregulated cellular level pathological condition that results in tumor formation followed by metastasis. In the heterogeneous tumor architecture, cancer stem cells (CSCs) are essential to push forward the progression of tumors due to their strong pro-tumor properties such as stemness, self-renewal, plasticity, metastasis, and being poorly responsive to radiotherapy and chemotherapeutic agents. Cancer stem cells have the ability to withstand various stress pressures by modulating transcriptional and translational mechanisms, and adaptable metabolic changes. Owing to CSCs heterogeneity and plasticity, these cells display varied metabolic and redox profiles across different types of cancers. It has been established that there is a disparity in the levels of Reactive Oxygen Species (ROS) generated in CSCs vs Non-CSC and these differential levels are detected across different tumors. CSCs have unique metabolic demands and are known to change plasticity during metastasis by passing through the interchangeable epithelial and mesenchymal-like phenotypes. During the metastatic process, tumor cells undergo epithelial to mesenchymal transition (EMT) thus attaining invasive properties while leaving the primary tumor site, similarly during the course of circulation and extravasation at a distant organ, these cells regain their epithelial characteristics through Mesenchymal to Epithelial Transition (MET) to initiate micrometastasis. It has been evidenced that levels of Reactive Oxygen Species (ROS) and associated metabolic activities vary between the epithelial and mesenchymal states of CSCs. Similarly, the levels of oxidative and metabolic states were observed to get altered in CSCs post-drug treatments. As oxidative and metabolic changes guide the onset of autophagy in cells, its role in self-renewal, quiescence, proliferation and response to drug treatment is well established. This review will highlight the molecular mechanisms useful for expanding therapeutic strategies based on modulating redox regulation and autophagy activation to targets. Specifically, we will account for the mounting data that focus on the role of ROS generated by different metabolic pathways and autophagy regulation in eradicating stem-like cells hereafter referred to as cancer stem cells (CSCs).
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Affiliation(s)
- Sameer Ullah Khan
- Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Srinagar, 190005, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Sheikh Rayees
- PK PD Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India
| | - Pankaj Sharma
- Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Srinagar, 190005, India
| | - Fayaz Malik
- Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Srinagar, 190005, India.
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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23
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Bahia RK, Hao X, Hassam R, Cseh O, Bozek DA, Luchman HA, Weiss S. Epigenetic and molecular coordination between HDAC2 and SMAD3-SKI regulates essential brain tumour stem cell characteristics. Nat Commun 2023; 14:5051. [PMID: 37598220 PMCID: PMC10439933 DOI: 10.1038/s41467-023-40776-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 08/10/2023] [Indexed: 08/21/2023] Open
Abstract
Histone deacetylases are important epigenetic regulators that have been reported to play essential roles in cancer stem cell functions and are promising therapeutic targets in many cancers including glioblastoma. However, the functionally relevant roles of specific histone deacetylases, in the maintenance of key self-renewal and growth characteristics of brain tumour stem cell (BTSC) sub-populations of glioblastoma, remain to be fully resolved. Here, using pharmacological inhibition and genetic loss and gain of function approaches, we identify HDAC2 as the most relevant histone deacetylase for re-organization of chromatin accessibility resulting in maintenance of BTSC growth and self-renewal properties. Furthermore, its specific interaction with the transforming growth factor-β pathway related proteins, SMAD3 and SKI, is crucial for the maintenance of tumorigenic potential in BTSCs in vitro and in orthotopic xenograft models. Inhibition of HDAC2 activity and disruption of the coordinated mechanisms regulated by the HDAC2-SMAD3-SKI axis are thus promising therapeutic approaches for targeting BTSCs.
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Affiliation(s)
- Ravinder K Bahia
- Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Department of Cell Biology and Anatomy, University of Calgary, Calgary, AB, Canada
| | - Xiaoguang Hao
- Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Department of Cell Biology and Anatomy, University of Calgary, Calgary, AB, Canada
| | - Rozina Hassam
- Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Department of Cell Biology and Anatomy, University of Calgary, Calgary, AB, Canada
| | - Orsolya Cseh
- Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Department of Cell Biology and Anatomy, University of Calgary, Calgary, AB, Canada
| | - Danielle A Bozek
- Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Department of Cell Biology and Anatomy, University of Calgary, Calgary, AB, Canada
| | - H Artee Luchman
- Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
- Department of Cell Biology and Anatomy, University of Calgary, Calgary, AB, Canada.
| | - Samuel Weiss
- Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
- Department of Cell Biology and Anatomy, University of Calgary, Calgary, AB, Canada.
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24
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Lin S, Li K, Qi L. Cancer stem cells in brain tumors: From origin to clinical implications. MedComm (Beijing) 2023; 4:e341. [PMID: 37576862 PMCID: PMC10412776 DOI: 10.1002/mco2.341] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 06/24/2023] [Accepted: 07/04/2023] [Indexed: 08/15/2023] Open
Abstract
Malignant brain tumors are highly heterogeneous tumors with a poor prognosis and a high morbidity and mortality rate in both children and adults. The cancer stem cell (CSC, also named tumor-initiating cell) model states that tumor growth is driven by a subset of CSCs. This model explains some of the clinical observations of brain tumors, including the almost unavoidable tumor recurrence after initial successful chemotherapy and/or radiotherapy and treatment resistance. Over the past two decades, strategies for the identification and characterization of brain CSCs have improved significantly, supporting the design of new diagnostic and therapeutic strategies for brain tumors. Relevant studies have unveiled novel characteristics of CSCs in the brain, including their heterogeneity and distinctive immunobiology, which have provided opportunities for new research directions and potential therapeutic approaches. In this review, we summarize the current knowledge of CSCs markers and stemness regulators in brain tumors. We also comprehensively describe the influence of the CSCs niche and tumor microenvironment on brain tumor stemness, including interactions between CSCs and the immune system, and discuss the potential application of CSCs in brain-based therapies for the treatment of brain tumors.
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Affiliation(s)
- Shuyun Lin
- Institute of Digestive DiseaseThe Sixth Affiliated Hospital of Guangzhou Medical UniversityQingyuan People's HospitalQingyuanGuangdongChina
| | - Kaishu Li
- Institute of Digestive DiseaseThe Sixth Affiliated Hospital of Guangzhou Medical UniversityQingyuan People's HospitalQingyuanGuangdongChina
| | - Ling Qi
- Institute of Digestive DiseaseThe Sixth Affiliated Hospital of Guangzhou Medical UniversityQingyuan People's HospitalQingyuanGuangdongChina
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25
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Pezzotta A, Brioschi L, Carbone S, Mazzoleni B, Bontempi V, Monastra F, Mauri L, Marozzi A, Mione M, Pistocchi A, Viani P. Combined Inhibition of Hedgehog and HDAC6: In Vitro and In Vivo Studies Reveal a New Role for Lysosomal Stress in Reducing Glioblastoma Cell Viability. Int J Mol Sci 2023; 24:ijms24065771. [PMID: 36982845 PMCID: PMC10051748 DOI: 10.3390/ijms24065771] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/03/2023] [Accepted: 03/07/2023] [Indexed: 03/22/2023] Open
Abstract
Glioblastoma multiforme (GBM) is the most common and malignant brain tumor in adults. The invasiveness and the rapid progression that characterize GBM negatively impact patients’ survival. Temozolomide (TMZ) is currently considered the first-choice chemotherapeutic agent. Unfortunately, over 50% of patients with GBM do not respond to TMZ treatment, and the mutation-prone nature of GBM enables the development of resistance mechanisms. Therefore, efforts have been devoted to the dissection of aberrant pathways involved in GBM insurgence and resistance in order to identify new therapeutic targets. Among them, sphingolipid signaling, Hedgehog (Hh) pathway, and the histone deacetylase 6 (HDAC6) activity are frequently dysregulated and may represent key targets to counteract GBM progression. Given the positive correlation between Hh/HDAC6/sphingolipid metabolism in GBM, we decided to perform a dual pharmacological inhibition of Hh and HDAC6 through cyclopamine and tubastatin A, respectively, in a human GMB cell line and zebrafish embryos. The combined administration of these compounds elicited a more significant reduction of GMB cell viability than did single treatments in vitro and in cells orthotopically transplanted in the zebrafish hindbrain ventricle. We demonstrated, for the first time, that the inhibition of these pathways induces lysosomal stress which results in an impaired fusion of lysosomes with autophagosomes and a block of sphingolipid degradation in GBM cell lines. This condition, which we also recapitulated in zebrafish embryos, suggests an impairment of lysosome-dependent processes involving autophagy and sphingolipid homeostasis and might be instrumental in the reduction of GBM progression.
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Affiliation(s)
- Alex Pezzotta
- Department of Medical Biotechnology and Translational Medicine, University of Milan, L.I.T.A., Via Fratelli Cervi 93, Segrate, 20054 Milano, Italy
| | - Loredana Brioschi
- Department of Medical Biotechnology and Translational Medicine, University of Milan, L.I.T.A., Via Fratelli Cervi 93, Segrate, 20054 Milano, Italy
| | - Sabrina Carbone
- Department of Medical Biotechnology and Translational Medicine, University of Milan, L.I.T.A., Via Fratelli Cervi 93, Segrate, 20054 Milano, Italy
| | - Beatrice Mazzoleni
- Department of Medical Biotechnology and Translational Medicine, University of Milan, L.I.T.A., Via Fratelli Cervi 93, Segrate, 20054 Milano, Italy
- Molecular Mechanisms Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Via Giacomo Venezian, 1, 20133 Milano, Italy
| | - Vittorio Bontempi
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento, Italy
| | - Federica Monastra
- Department of Medical Biotechnology and Translational Medicine, University of Milan, L.I.T.A., Via Fratelli Cervi 93, Segrate, 20054 Milano, Italy
| | - Laura Mauri
- Department of Medical Biotechnology and Translational Medicine, University of Milan, L.I.T.A., Via Fratelli Cervi 93, Segrate, 20054 Milano, Italy
| | - Anna Marozzi
- Department of Medical Biotechnology and Translational Medicine, University of Milan, L.I.T.A., Via Fratelli Cervi 93, Segrate, 20054 Milano, Italy
| | - Marina Mione
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento, Italy
| | - Anna Pistocchi
- Department of Medical Biotechnology and Translational Medicine, University of Milan, L.I.T.A., Via Fratelli Cervi 93, Segrate, 20054 Milano, Italy
- Correspondence: (A.P.); (P.V.)
| | - Paola Viani
- Department of Medical Biotechnology and Translational Medicine, University of Milan, L.I.T.A., Via Fratelli Cervi 93, Segrate, 20054 Milano, Italy
- Correspondence: (A.P.); (P.V.)
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27
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Nasrolahi A, Azizidoost S, Radoszkiewicz K, Najafi S, Ghaedrahmati F, Anbiyaee O, Khoshnam SE, Farzaneh M, Uddin S. Signaling pathways governing glioma cancer stem cells behavior. Cell Signal 2023; 101:110493. [PMID: 36228964 DOI: 10.1016/j.cellsig.2022.110493] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 10/03/2022] [Accepted: 10/05/2022] [Indexed: 11/30/2022]
Abstract
Glioma is the most common malignant brain tumor that develops in the glial tissue. Several studies have identified that glioma cancer stem cells (GCSCs) play important roles in tumor-initiating features in malignant gliomas. GCSCs are a small population in the brain that presents an essential role in the metastasis of glioma cells to other organs. These cells can self-renew and differentiate, which are thought to be involved in the pathogenesis of glioma. Therefore, targeting GCSCs might be a novel strategy for the treatment of glioma. Accumulating evidence revealed that several signaling pathways, including Notch, TGF-β, Wnt, STAT3, AKT, and EGFR mediated GCSC growth, proliferation, migration, and invasion. Besides, non-coding RNAs (ncRNAs), including miRNAs, circular RNAs, and long ncRNAs have been found to play pivotal roles in the regulation of GCSC pathogenesis and drug resistance. Therefore, targeting these pathways could open a new avenue for glioma management. In this review, we summarized critical signaling pathways involved in the stimulation or prevention of GCSCs tumorigenesis and invasiveness.
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Affiliation(s)
- Ava Nasrolahi
- Infectious Ophthalmologic Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Shirin Azizidoost
- Atherosclerosis Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Klaudia Radoszkiewicz
- Translational Platform for Regenerative Medicine, Mossakowski Medical Research Institute, Polish Academy of Sciences, Poland
| | - Sajad Najafi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farhoodeh Ghaedrahmati
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Omid Anbiyaee
- Cardiovascular Research Center, Nemazi Hospital, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyed Esmaeil Khoshnam
- Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Maryam Farzaneh
- Fertility, Infertility and Perinatology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
| | - Shahab Uddin
- Translational Research Institute and Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.
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Kaur S, Rajoria P, Chopra M. HDAC6: A unique HDAC family member as a cancer target. Cell Oncol (Dordr) 2022; 45:779-829. [PMID: 36036883 DOI: 10.1007/s13402-022-00704-6] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/10/2022] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND HDAC6, a structurally and functionally distinct member of the HDAC family, is an integral part of multiple cellular functions such as cell proliferation, apoptosis, senescence, DNA damage and genomic stability, all of which when deregulated contribute to carcinogenesis. Among several HDAC family members known so far, HDAC6 holds a unique position. It differs from the other HDAC family members not only in terms of its subcellular localization, but also in terms of its substrate repertoire and hence cellular functions. Recent findings have considerably expanded the research related to the substrate pool, biological functions and regulation of HDAC6. Studies in HDAC6 knockout mice highlighted the importance of HDAC6 as a cell survival player in stressful situations, making it an important anticancer target. There is ample evidence stressing the importance of HDAC6 as an anti-cancer synergistic partner of many chemotherapeutic drugs. HDAC6 inhibitors have been found to enhance the effectiveness of conventional chemotherapeutic drugs such as DNA damaging agents, proteasome inhibitors and microtubule inhibitors, thereby highlighting the importance of combination therapies involving HDAC6 inhibitors and other anti-cancer agents. CONCLUSIONS Here, we present a review on HDAC6 with emphasis on its role as a critical regulator of specific physiological cellular pathways which when deregulated contribute to tumorigenesis, thereby highlighting the importance of HDAC6 inhibitors as important anticancer agents alone and in combination with other chemotherapeutic drugs. We also discuss the synergistic anticancer effect of combination therapies of HDAC6 inhibitors with conventional chemotherapeutic drugs.
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Affiliation(s)
- Sumeet Kaur
- Laboratory of Molecular Modeling and Anticancer Drug Development, Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110007, India
| | - Prerna Rajoria
- Laboratory of Molecular Modeling and Anticancer Drug Development, Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110007, India
| | - Madhu Chopra
- Laboratory of Molecular Modeling and Anticancer Drug Development, Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110007, India.
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Wang H, Lai Q, Wang D, Pei J, Tian B, Gao Y, Gao Z, Xu X. Hedgehog signaling regulates the development and treatment of glioblastoma. Oncol Lett 2022; 24:294. [PMID: 35949611 PMCID: PMC9353242 DOI: 10.3892/ol.2022.13414] [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: 04/05/2022] [Accepted: 06/14/2022] [Indexed: 11/12/2022] Open
Abstract
Glioblastoma (GBM) is the most common and fatal malignant tumor type of the central nervous system. GBM affects public health and it is important to identify biomarkers to improve diagnosis, reduce drug resistance and improve prognosis (e.g., personalized targeted therapies). Hedgehog (HH) signaling has an important role in embryonic development, tissue regeneration and stem cell renewal. A large amount of evidence indicates that both normative and non-normative HH signals have an important role in GBM. The present study reviewed the role of the HH signaling pathway in the occurrence and progression of GBM. Furthermore, the effectiveness of drugs that target different components of the HH pathway was also examined. The HH pathway has an important role in reversing drug resistance after GBM conventional treatment. The present review highlighted the relevance of HH signaling in GBM and outlined that this pathway has a key role in the occurrence, development and treatment of GBM.
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Affiliation(s)
- Hongping Wang
- Department of Neurosurgery, Tangshan Gongren Hospital of Hebei Medical University, Tangshan, Hebei 063000, P.R. China
| | - Qun Lai
- Department of Hematology and Oncology, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Dayong Wang
- Department of Neurosurgery, Tangshan Gongren Hospital of Hebei Medical University, Tangshan, Hebei 063000, P.R. China
| | - Jian Pei
- Department of Neurosurgery, Tangshan Gongren Hospital of Hebei Medical University, Tangshan, Hebei 063000, P.R. China
| | - Baogang Tian
- Department of Neurosurgery, Tangshan Gongren Hospital of Hebei Medical University, Tangshan, Hebei 063000, P.R. China
| | - Yunhe Gao
- Department of Neurosurgery, Tangshan Gongren Hospital of Hebei Medical University, Tangshan, Hebei 063000, P.R. China
| | - Zhaoguo Gao
- Department of Neurosurgery, Tangshan Gongren Hospital of Hebei Medical University, Tangshan, Hebei 063000, P.R. China
| | - Xiang Xu
- Department of Neurosurgery, Tangshan Gongren Hospital of Hebei Medical University, Tangshan, Hebei 063000, P.R. China
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Safa AR. Drug and apoptosis resistance in cancer stem cells: a puzzle with many pieces. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2022; 5:850-872. [PMID: 36627897 PMCID: PMC9771762 DOI: 10.20517/cdr.2022.20] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 05/10/2022] [Accepted: 05/26/2022] [Indexed: 01/13/2023]
Abstract
Resistance to anticancer agents and apoptosis results in cancer relapse and is associated with cancer mortality. Substantial data have provided convincing evidence establishing that human cancers emerge from cancer stem cells (CSCs), which display self-renewal and are resistant to anticancer drugs, radiation, and apoptosis, and express enhanced epithelial to mesenchymal progression. CSCs represent a heterogeneous tumor cell population and lack specific cellular targets, which makes it a great challenge to target and eradicate them. Similarly, their close relationship with the tumor microenvironment creates greater complexity in developing novel treatment strategies targeting CSCs. Several mechanisms participate in the drug and apoptosis resistance phenotype in CSCs in various cancers. These include enhanced expression of ATP-binding cassette membrane transporters, activation of various cytoprotective and survival signaling pathways, dysregulation of stemness signaling pathways, aberrant DNA repair mechanisms, increased quiescence, autophagy, increased immune evasion, deficiency of mitochondrial-mediated apoptosis, upregulation of anti-apoptotic proteins including c-FLIP [cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein], Bcl-2 family members, inhibitors of apoptosis proteins, and PI3K/AKT signaling. Studying such mechanisms not only provides mechanistic insights into these cells that are unresponsive to drugs, but may lead to the development of targeted and effective therapeutics to eradicate CSCs. Several studies have identified promising strategies to target CSCs. These emerging strategies may help target CSC-associated drug resistance and metastasis in clinical settings. This article will review the CSCs drug and apoptosis resistance mechanisms and how to target CSCs.
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Affiliation(s)
- Ahmad R. Safa
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Kundu S, Nandhu MS, Longo SL, Longo JA, Rai S, Chin LS, Richardson TE, Viapiano MS. The scaffolding protein DLG5 promotes glioblastoma growth by controlling Sonic Hedgehog signaling in tumor stem cells. Neuro Oncol 2022; 24:1230-1242. [PMID: 34984467 PMCID: PMC9340653 DOI: 10.1093/neuonc/noac001] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Tumor invasion, a hallmark of malignant gliomas, involves reorganization of cell polarity and changes in the expression and distribution of scaffolding proteins associated with polarity complexes. The scaffolding proteins of the DLG family are usually downregulated in invasive tumors and regarded as tumor suppressors. Despite their important role in regulating neurodevelopmental signaling, the expression and functions of DLG proteins have remained almost entirely unexplored in malignant gliomas. METHODS Western blot, immunohistochemistry, and analysis of gene expression were used to quantify DLG members in glioma specimens and cancer datasets. Over-expression and knockdown of DLG5, the highest-expressed DLG member in glioblastoma, were used to investigate its effects on tumor stem cells and tumor growth. qRT-PCR, Western blotting, and co-precipitation assays were used to investigate DLG5 signaling mechanisms. RESULTS DLG5 was upregulated in malignant gliomas compared to other solid tumors, being the predominant DLG member in all glioblastoma molecular subtypes. DLG5 promoted glioblastoma stem cell invasion, viability, and self-renewal. Knockdown of this protein in vivo disrupted tumor formation and extended survival. At the molecular level, DLG5 regulated Sonic Hedgehog (Shh) signaling, making DLG5-deficient cells insensitive to Shh ligand. Loss of DLG5 increased the proteasomal degradation of Gli1, underlying the loss of Shh signaling and tumor stem cell sensitization. CONCLUSIONS The high expression and pro-tumoral functions of DLG5 in glioblastoma, including its dominant regulation of Shh signaling in tumor stem cells, reveal a novel role for this protein that is strikingly different from its proposed tumor-suppressor role in other solid tumors.
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Affiliation(s)
- Somanath Kundu
- Department of Neuroscience & Physiology, SUNY Upstate Medical University, Syracuse, New York, USA
| | - Mohan S Nandhu
- Department of Neuroscience & Physiology, SUNY Upstate Medical University, Syracuse, New York, USA
| | - Sharon L Longo
- Department of Neurosurgery, SUNY Upstate Medical University, Syracuse, New York, USA
| | - John A Longo
- Department of Neuroscience & Physiology, SUNY Upstate Medical University, Syracuse, New York, USA
| | - Shawn Rai
- Department of Neurosurgery, SUNY Upstate Medical University, Syracuse, New York, USA
| | - Lawrence S Chin
- Department of Neurosurgery, SUNY Upstate Medical University, Syracuse, New York, USA
| | - Timothy E Richardson
- Department of Pathology, University of Texas Health Science Center, San Antonio, Texas, USA
| | - Mariano S Viapiano
- Department of Neurosurgery, SUNY Upstate Medical University, Syracuse, New York, USA
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Bian C, Su J, Zheng Z, Wei J, Wang H, Meng L, Xin Y, Jiang X. ARTS, an unusual septin, regulates tumorigenesis by promoting apoptosis. Biomed Pharmacother 2022; 152:113281. [PMID: 35714512 DOI: 10.1016/j.biopha.2022.113281] [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: 05/18/2022] [Revised: 06/04/2022] [Accepted: 06/08/2022] [Indexed: 11/02/2022] Open
Abstract
Apoptosis plays particularly important roles in tumorigenesis through various mechanisms. Apoptosis can be initiated by both extrinsic and intrinsic signals centered in and coming from the mitochondria. Antiapoptotic proteins promote tumor progression, and the occurrence and progression of tumors are closely related to antiapoptotic protein expression. As the only member of the septin gene family with proapoptotic function, apoptosis-related proteins in the TGF-β signaling pathway (ARTS) has received extensive attention for its unique structure. In contrast, unlike other known inhibitors of apoptosis protein (IAP) antagonists, ARTS exhibits a stronger tumor suppressor potential. Recent research has shown that ARTS can bind and inhibit XIAP and Bcl-2 directly or assist p53 in the degradation of Bcl-XL. Here, we review recent advances in the molecular mechanisms by which the proapoptotic protein ARTS, with its unique structure, inhibits tumorigenesis. We also discuss the possibility of mimicking ARTS to develop small-molecule drugs.
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Affiliation(s)
- Chenbin Bian
- Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun 130021, China; Department of Radiation Oncology, The First Hospital of Jilin University, Changchun 130021, China; NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun 130021, China.
| | - Jing Su
- Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun 130021, China; Department of Radiation Oncology, The First Hospital of Jilin University, Changchun 130021, China; NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun 130021, China.
| | - Zhuangzhuang Zheng
- Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun 130021, China; Department of Radiation Oncology, The First Hospital of Jilin University, Changchun 130021, China; NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun 130021, China.
| | - Jinlong Wei
- Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun 130021, China; Department of Radiation Oncology, The First Hospital of Jilin University, Changchun 130021, China; NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun 130021, China.
| | - Huanhuan Wang
- Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun 130021, China; Department of Radiation Oncology, The First Hospital of Jilin University, Changchun 130021, China; NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun 130021, China.
| | - Lingbin Meng
- Department of Hematology and Medical Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA.
| | - Ying Xin
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun 130021, China.
| | - Xin Jiang
- Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun 130021, China; Department of Radiation Oncology, The First Hospital of Jilin University, Changchun 130021, China; NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun 130021, China.
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Hersh AM, Gaitsch H, Alomari S, Lubelski D, Tyler BM. Molecular Pathways and Genomic Landscape of Glioblastoma Stem Cells: Opportunities for Targeted Therapy. Cancers (Basel) 2022; 14:3743. [PMID: 35954407 PMCID: PMC9367289 DOI: 10.3390/cancers14153743] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 07/26/2022] [Accepted: 07/27/2022] [Indexed: 02/01/2023] Open
Abstract
Glioblastoma (GBM) is an aggressive tumor of the central nervous system categorized by the World Health Organization as a Grade 4 astrocytoma. Despite treatment with surgical resection, adjuvant chemotherapy, and radiation therapy, outcomes remain poor, with a median survival of only 14-16 months. Although tumor regression is often observed initially after treatment, long-term recurrence or progression invariably occurs. Tumor growth, invasion, and recurrence is mediated by a unique population of glioblastoma stem cells (GSCs). Their high mutation rate and dysregulated transcriptional landscape augment their resistance to conventional chemotherapy and radiation therapy, explaining the poor outcomes observed in patients. Consequently, GSCs have emerged as targets of interest in new treatment paradigms. Here, we review the unique properties of GSCs, including their interactions with the hypoxic microenvironment that drives their proliferation. We discuss vital signaling pathways in GSCs that mediate stemness, self-renewal, proliferation, and invasion, including the Notch, epidermal growth factor receptor, phosphatidylinositol 3-kinase/Akt, sonic hedgehog, transforming growth factor beta, Wnt, signal transducer and activator of transcription 3, and inhibitors of differentiation pathways. We also review epigenomic changes in GSCs that influence their transcriptional state, including DNA methylation, histone methylation and acetylation, and miRNA expression. The constituent molecular components of the signaling pathways and epigenomic regulators represent potential sites for targeted therapy, and representative examples of inhibitory molecules and pharmaceuticals are discussed. Continued investigation into the molecular pathways of GSCs and candidate therapeutics is needed to discover new effective treatments for GBM and improve survival.
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Affiliation(s)
- Andrew M. Hersh
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; (A.M.H.); (H.G.); (S.A.); (D.L.)
| | - Hallie Gaitsch
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; (A.M.H.); (H.G.); (S.A.); (D.L.)
- NIH Oxford-Cambridge Scholars Program, Wellcome—MRC Cambridge Stem Cell Institute and Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 1TN, UK
| | - Safwan Alomari
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; (A.M.H.); (H.G.); (S.A.); (D.L.)
| | - Daniel Lubelski
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; (A.M.H.); (H.G.); (S.A.); (D.L.)
| | - Betty M. Tyler
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; (A.M.H.); (H.G.); (S.A.); (D.L.)
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Thakur A, Faujdar C, Sharma R, Sharma S, Malik B, Nepali K, Liou JP. Glioblastoma: Current Status, Emerging Targets, and Recent Advances. J Med Chem 2022; 65:8596-8685. [PMID: 35786935 PMCID: PMC9297300 DOI: 10.1021/acs.jmedchem.1c01946] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
![]()
Glioblastoma (GBM) is a highly malignant
brain tumor characterized
by a heterogeneous population of genetically unstable and highly infiltrative
cells that are resistant to chemotherapy. Although substantial efforts
have been invested in the field of anti-GBM drug discovery in the
past decade, success has primarily been confined to the preclinical
level, and clinical studies have often been hampered due to efficacy-,
selectivity-, or physicochemical property-related issues. Thus, expansion
of the list of molecular targets coupled with a pragmatic design of
new small-molecule inhibitors with central nervous system (CNS)-penetrating
ability is required to steer the wheels of anti-GBM drug discovery
endeavors. This Perspective presents various aspects of drug discovery
(challenges in GBM drug discovery and delivery, therapeutic targets,
and agents under clinical investigation). The comprehensively covered
sections include the recent medicinal chemistry campaigns embarked
upon to validate the potential of numerous enzymes/proteins/receptors
as therapeutic targets in GBM.
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Affiliation(s)
- Amandeep Thakur
- School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei 11031, Taiwan
| | - Chetna Faujdar
- Department of Biotechnology, Jaypee Institute of Information Technology, Noida 201307, India
| | - Ram Sharma
- School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei 11031, Taiwan
| | - Sachin Sharma
- School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei 11031, Taiwan
| | - Basant Malik
- Department of Sterile Product Development, Research and Development-Unit 2, Jubiliant Generics Ltd., Noida 201301, India
| | - Kunal Nepali
- School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei 11031, Taiwan
| | - Jing Ping Liou
- School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei 11031, Taiwan
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Tavares MO, Milan TM, Bighetti-Trevisan RL, Leopoldino AM, de Almeida LO. Pharmacological inhibition of HDAC6 overcomes cisplatin chemoresistance by targeting cancer stem cells in oral squamous cell carcinoma. J Oral Pathol Med 2022; 51:529-537. [PMID: 35678235 DOI: 10.1111/jop.13326] [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: 03/29/2022] [Accepted: 06/01/2022] [Indexed: 11/30/2022]
Abstract
BACKGROUND Chemoresistance is associated with recurrence and metastasis in oral squamous cell carcinoma (OSCC). The cancer stem cell (CSC) subpopulation is highly resistant to therapy, and they are regulated by epigenetic mechanisms. HDACs are histone deacetylase enzymes that epigenetically regulate gene expression. HDAC6 acts on several physiological processes, including oxidative stress, autophagy and DNA damage response, and its accumulation is associated with cancer. Here, we investigate the role of HDAC6 in CSC-mediated chemoresistance in oral carcinoma in addition to its application as a therapeutic target to reverse chemoresistance. METHODS Wild-type oral carcinoma cell lines (CAL27 WT and SCC9 WT), cisplatin-resistant (CAL27 CisR and SCC9 CisR), and the subpopulations of cancer stem cells (CSC+) and non-stem (CSC-) derived from CisR cells were investigated. HDAC6 accumulation was analyzed by Western blot and immunofluorescence; DNA damage was evaluated by immunofluorescence of phospho-H2A.X; the qPCR for PRDX2, PRDX6, SOD2, and TXN and ROS assay assessed oxidative stress. Apoptosis and CSC accumulation were investigated by flow cytometry. RESULTS We identified the accumulation of HDAC6 in CisR cell lines and CSC. Cisplatin-resistant cell lines and CSC demonstrated a reduction in DNA damage and ROS and elevated expression of PRDX2. The administration of tubastatin A (a specific HDAC6 inhibitor) increased oxidative stress and DNA damage and decreased PRDX2. Tubastatin A as a monotherapy induced apoptosis in CisR and CSC and reduced the stemness phenotype. CONCLUSION High levels of HDAC6 sustain CSC subpopulation and chemoresistance in OSCC, suggesting HDAC6 as a pharmacological target to overcome resistance and perhaps prevent recurrence in OSCC.
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Affiliation(s)
- Marcela Oliveira Tavares
- Department of Basic and Oral Biology, School of Dentistry, University of São Paulo, Ribeirão Preto, Brazil
| | - Thaís Moré Milan
- Department of Basic and Oral Biology, School of Dentistry, University of São Paulo, Ribeirão Preto, Brazil.,School of Pharmaceutical Sciences of Ribeirão Preto, Graduate Program in Biosciences and Biotechnology, University of São Paulo, Ribeirão Preto, Brazil
| | | | - Andréia Machado Leopoldino
- Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
| | - Luciana Oliveira de Almeida
- Department of Basic and Oral Biology, School of Dentistry, University of São Paulo, Ribeirão Preto, Brazil.,School of Pharmaceutical Sciences of Ribeirão Preto, Graduate Program in Biosciences and Biotechnology, University of São Paulo, Ribeirão Preto, Brazil
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MicroRNA-22 represses glioma development via activation of macrophage-mediated innate and adaptive immune responses. Oncogene 2022; 41:2444-2457. [PMID: 35279703 DOI: 10.1038/s41388-022-02236-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 01/18/2022] [Accepted: 02/07/2022] [Indexed: 01/29/2023]
Abstract
Macrophage-mediated tumor cell phagocytosis and subsequent neoantigen presentation are critical for generating anti-tumor immunity. This study aimed to uncover the potential clinical value and molecular mechanisms of miRNA-22 (miR-22) in tumor cell phagocytosis via macrophages and more efficient T cell priming. We found that miR-22 expression was markedly downregulated in primary macrophages from glioma tissue samples compared to adjacent tissues. miR-22-overexpressing macrophages inhibited glioma cell proliferation and migration, respectively. miR-22 upregulation stimulated the phagocytic ability of macrophages, enhanced tumor cell phagocytosis, antigen presentation, and efficient T cell priming. Additionally, our data revealed that miR-22-overexpressing macrophages inhibited glioma formation in vivo, HDAC6 was a target, and NF-κB signaling was a pathway closely associated with miR-22 in tumor-associated macrophages (TAMs) of glioma. Our findings revealed the essential roles of miR-22 in tumor cell phagocytosis by macrophages and more efficient T cell priming, facilitating further research on phagocytic regulation to enhance the response to tumor immunotherapy.
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Salimi-Jeda A, Ghabeshi S, Gol Mohammad Pour Z, Jazaeri EO, Araiinejad M, Sheikholeslami F, Abdoli M, Edalat M, Abdoli A. Autophagy Modulation and Cancer Combination Therapy: A Smart Approach in Cancer Therapy. Cancer Treat Res Commun 2022; 30:100512. [PMID: 35026533 DOI: 10.1016/j.ctarc.2022.100512] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 12/03/2021] [Accepted: 01/04/2022] [Indexed: 12/15/2022]
Abstract
The autophagy pathway is the process whereby cells keep cellular homeostasis and respond to stress via recycling their damaged cellular proteins, organelles, and other cellular components. In the context of cancer, autophagy is a dual-edge sword pro- and anti-tumorigenic role depending on the oncogenic context and stage of tumorigenesis. Cancer cells have a higher dependency on autophagy compared with normal cells because of cellular damages and high demands for energy. The carbon, nitrogen, and molecular oxygen are building blocks for highly proliferative cancer cells which extremely depend on glutaminolysis and aerobic glycolysis; when a cancer cell is restricted to glucose and glutamine, it initiates to activate a stress response pathway using autophagy. Oncogenic tyrosine kinases (OncTKs) and receptor tyrosine kinases (RTKs) activation result in autophagy modulation through activation of the PI3K/AKT/mTORC1 and RAS/MAPK signaling pathways. Targeted inhibition of tyrosine kinases (TKs) and RTKs have recently been considered as cancer therapy but drug resistance and cancer relapse continue to be a major limitation of tyrosine kinase inhibitors (TKIs). Manipulation of autophagy pathway along with TKIs may be a promising strategy to circumvent unknown existing drug-resistance mechanisms that may emerge in a treated patient. In this way, clinical trials are ongoing to modulate autophagy to treat cancer. This review aims to summarize the combination therapy of autophagy affecting compounds with anticancer drugs which target cell signaling pathways, metabolism mechanisms, and epigenetics modification to improve therapeutic efficacy against cancers.
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Affiliation(s)
- Ali Salimi-Jeda
- Department of Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Soad Ghabeshi
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Ehsan Ollah Jazaeri
- Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, 13169-43551, Iran
| | - Mehrdad Araiinejad
- WHO Collaborating Center for Reference and Research on Rabies, Pasteur Institute of Iran Iran
| | - Farzaneh Sheikholeslami
- WHO Collaborating Center for Reference and Research on Rabies, Pasteur Institute of Iran Iran
| | - Mohsen Abdoli
- Antimicrobial Resistance Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahdi Edalat
- Department of medical laboratory sciences, Paramedical Sciences, Tabriz University of medical sciences, Tabriz, Iran
| | - Asghar Abdoli
- Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, 13169-43551, Iran.
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Carlos-Reyes A, Muñiz-Lino MA, Romero-Garcia S, López-Camarillo C, Hernández-de la Cruz ON. Biological Adaptations of Tumor Cells to Radiation Therapy. Front Oncol 2021; 11:718636. [PMID: 34900673 PMCID: PMC8652287 DOI: 10.3389/fonc.2021.718636] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 10/28/2021] [Indexed: 12/15/2022] Open
Abstract
Radiation therapy has been used worldwide for many decades as a therapeutic regimen for the treatment of different types of cancer. Just over 50% of cancer patients are treated with radiotherapy alone or with other types of antitumor therapy. Radiation can induce different types of cell damage: directly, it can induce DNA single- and double-strand breaks; indirectly, it can induce the formation of free radicals, which can interact with different components of cells, including the genome, promoting structural alterations. During treatment, radiosensitive tumor cells decrease their rate of cell proliferation through cell cycle arrest stimulated by DNA damage. Then, DNA repair mechanisms are turned on to alleviate the damage, but cell death mechanisms are activated if damage persists and cannot be repaired. Interestingly, some cells can evade apoptosis because genome damage triggers the cellular overactivation of some DNA repair pathways. Additionally, some surviving cells exposed to radiation may have alterations in the expression of tumor suppressor genes and oncogenes, enhancing different hallmarks of cancer, such as migration, invasion, and metastasis. The activation of these genetic pathways and other epigenetic and structural cellular changes in the irradiated cells and extracellular factors, such as the tumor microenvironment, is crucial in developing tumor radioresistance. The tumor microenvironment is largely responsible for the poor efficacy of antitumor therapy, tumor relapse, and poor prognosis observed in some patients. In this review, we describe strategies that tumor cells use to respond to radiation stress, adapt, and proliferate after radiotherapy, promoting the appearance of tumor radioresistance. Also, we discuss the clinical impact of radioresistance in patient outcomes. Knowledge of such cellular strategies could help the development of new clinical interventions, increasing the radiosensitization of tumor cells, improving the effectiveness of these therapies, and increasing the survival of patients.
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Affiliation(s)
- Angeles Carlos-Reyes
- Department of Chronic-Degenerative Diseases, National Institute of Respiratory Diseases “Ismael Cosío Villegas”, Mexico City, Mexico
| | - Marcos A. Muñiz-Lino
- Laboratorio de Patología y Medicina Bucal, Universidad Autónoma Metropolitana Unidad Xochimilco, Mexico City, Mexico
| | - Susana Romero-Garcia
- Department of Chronic-Degenerative Diseases, National Institute of Respiratory Diseases “Ismael Cosío Villegas”, Mexico City, Mexico
| | - César López-Camarillo
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, Mexico, Mexico City
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Karagiannis D, Rampias T. HDAC Inhibitors: Dissecting Mechanisms of Action to Counter Tumor Heterogeneity. Cancers (Basel) 2021; 13:3575. [PMID: 34298787 PMCID: PMC8307174 DOI: 10.3390/cancers13143575] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 07/09/2021] [Accepted: 07/13/2021] [Indexed: 12/17/2022] Open
Abstract
Intra-tumoral heterogeneity presents a major obstacle to cancer therapeutics, including conventional chemotherapy, immunotherapy, and targeted therapies. Stochastic events such as mutations, chromosomal aberrations, and epigenetic dysregulation, as well as micro-environmental selection pressures related to nutrient and oxygen availability, immune infiltration, and immunoediting processes can drive immense phenotypic variability in tumor cells. Here, we discuss how histone deacetylase inhibitors, a prominent class of epigenetic drugs, can be leveraged to counter tumor heterogeneity. We examine their effects on cellular processes that contribute to heterogeneity and provide insights on their mechanisms of action that could assist in the development of future therapeutic approaches.
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Affiliation(s)
- Dimitris Karagiannis
- Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA
| | - Theodoros Rampias
- Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece
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Yuan Y, Cao W, Zhou H, Qian H, Wang H. CLTRN, Regulated by NRF1/RAN/DLD Protein Complex, Enhances Radiation Sensitivity of Hepatocellular Carcinoma Cells Through Ferroptosis Pathway. Int J Radiat Oncol Biol Phys 2021; 110:859-871. [PMID: 33508374 DOI: 10.1016/j.ijrobp.2020.12.062] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 12/10/2020] [Accepted: 12/17/2020] [Indexed: 12/24/2022]
Abstract
PURPOSE Radiation therapy is a viable treatment option for patients with unresectable hepatocellular carcinoma (HCC). However, radiation resistance and adverse effects are issues that needs to be addressed. Herein, for the first time, we investigated the ability of collectrin (CLTRN) to enhance radiosensitivity in patients with HCC. METHODS AND MATERIALS Transcriptome sequencing technology (RNA-seq technology) was used to analyze the transcription-level changes in the genes in HepG2 cells before and after x-ray irradiation. Combining the results with the HCC tissue RNA-seq data, we determined the ultimate target gene through bioinformatics analysis and cellular verification. A series of cellular and molecular biology techniques were applied in vitro and in vivo to confirm whether CLTRN can enhance radiosensitivity in HCC cells. Subsequently, the downstream action mechanism, the upstream transcription factor, and the interaction proteins of CLTRN were determined. RESULTS First, we confirmed that CLTRN is the target gene for radiation therapy and verified the association between CLTRN and radiosensitivity. In vivo and in vitro experiments were performed. Investigation of the gene regulatory mechanism revealed that the genes analyzed at the transcriptome level after CLTRN overexpression were mostly enriched in the glutathione metabolic pathway. As glutathione metabolism forms a vital link in ferroptosis, we surmised that CLTRN is associated with ferroptosis. This was confirmed through detection of cellular iron, determination of reactive oxygen species levels, use of transmission electron microscopy, and monitoring of ferroptosis-related protein indicators. Lastly, we investigated whether nuclear respiratory factor 1 is the upstream transcription factor of CLTRN and whether dihydrolipoamide dehydrogenase and members of the RAS oncogene family are its interacting proteins. CONCLUSIONS CLTRN is a vital regulator of radiation sensitivity and could serve as a novel therapeutic target or prognostic marker in HCC treatment.
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Affiliation(s)
- Yin Yuan
- Department of General Surgery, First Affiliated Hospital of Suzhou University, Suzhou, China; Department of Hepatobiliary Surgery, Fifth Affiliated Hospital of Medical School of Nantong University, Taizhou, China
| | - Wen Cao
- Department of Liver Disease, Fifth Affiliated Hospital of Medical School of Nantong University, Taizhou, China
| | - Hongbing Zhou
- Department of Hepatobiliary Surgery, Fifth Affiliated Hospital of Medical School of Nantong University, Taizhou, China
| | - Haixin Qian
- Department of General Surgery, First Affiliated Hospital of Suzhou University, Suzhou, China.
| | - Honggang Wang
- Department of General Surgery, Fifth Affiliated Hospital of Medical School of Nantong University, Taizhou, China.
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An Insight into Pathophysiological Features and Therapeutic Advances on Ependymoma. Cancers (Basel) 2021; 13:cancers13133221. [PMID: 34203272 PMCID: PMC8269186 DOI: 10.3390/cancers13133221] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/21/2021] [Accepted: 06/23/2021] [Indexed: 12/21/2022] Open
Abstract
Simple Summary Although biological information and the molecular classification of ependymoma have been studied, the treatment systems for ependymoma are still insufficient. In addition, because the disease occurs infrequently, it is difficult to obtain sufficient data to conduct large-scale or randomized clinical trials. Therefore, this study is intended to emphasize the importance of understanding its pathological characteristics and prognosis as well as developing treatments for ependymoma through multilateral studies. Abstract Glial cells comprise the non-sensory parts of the central nervous system as well as the peripheral nervous system. Glial cells, also known as neuroglia, constitute a significant portion of the mammalian nervous system and can be viewed simply as a matrix of neural cells. Despite being the “Nervenkitt” or “glue of the nerves”, they aptly serve multiple roles, including neuron repair, myelin sheath formation, and cerebrospinal fluid circulation. Ependymal cells are one of four kinds of glial cells that exert distinct functions. Tumorigenesis of a glial cell is termed a glioma, and in the case of an ependymal cell, it is called an ependymoma. Among the various gliomas, an ependymoma in children is one of the more challenging brain tumors to cure. Children are afflicted more severely by ependymal tumors than adults. It has appeared from several surveys that ependymoma comprises approximately six to ten percent of all tumors in children. Presently, the surgical removal of the tumor is considered a standard treatment for ependymomas. It has been conspicuously evident that a combination of irradiation therapy and surgery is much more efficacious in treating ependymomas. The main purpose of this review is to present the importance of both a deep understanding and ongoing research into histopathological features and prognoses of ependymomas to ensure that effective diagnostic methods and treatments can be developed.
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Mandhair HK, Novak U, Radpour R. Epigenetic regulation of autophagy: A key modification in cancer cells and cancer stem cells. World J Stem Cells 2021; 13:542-567. [PMID: 34249227 PMCID: PMC8246247 DOI: 10.4252/wjsc.v13.i6.542] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 05/02/2021] [Accepted: 06/04/2021] [Indexed: 02/06/2023] Open
Abstract
Aberrant epigenetic alterations play a decisive role in cancer initiation and propagation via the regulation of key tumor suppressor genes and oncogenes or by modulation of essential signaling pathways. Autophagy is a highly regulated mechanism required for the recycling and degradation of surplus and damaged cytoplasmic constituents in a lysosome dependent manner. In cancer, autophagy has a divergent role. For instance, autophagy elicits tumor promoting functions by facilitating metabolic adaption and plasticity in cancer stem cells (CSCs) and cancer cells. Moreover, autophagy exerts pro-survival mechanisms to these cancerous cells by influencing survival, dormancy, immunosurveillance, invasion, metastasis, and resistance to anti-cancer therapies. In addition, recent studies have demonstrated that various tumor suppressor genes and oncogenes involved in autophagy, are tightly regulated via different epigenetic modifications, such as DNA methylation, histone modifications and non-coding RNAs. The impact of epigenetic regulation of autophagy in cancer cells and CSCs is not well-understood. Therefore, uncovering the complex mechanism of epigenetic regulation of autophagy provides an opportunity to improve and discover novel cancer therapeutics. Subsequently, this would aid in improving clinical outcome for cancer patients. In this review, we provide a comprehensive overview of the existing knowledge available on epigenetic regulation of autophagy and its importance in the maintenance and homeostasis of CSCs and cancer cells.
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Affiliation(s)
- Harpreet K Mandhair
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Urban Novak
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Ramin Radpour
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
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Keyvani-Ghamsari S, Khorsandi K, Rasul A, Zaman MK. Current understanding of epigenetics mechanism as a novel target in reducing cancer stem cells resistance. Clin Epigenetics 2021; 13:120. [PMID: 34051847 PMCID: PMC8164819 DOI: 10.1186/s13148-021-01107-4] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 05/19/2021] [Indexed: 12/13/2022] Open
Abstract
At present, after extensive studies in the field of cancer, cancer stem cells (CSCs) have been proposed as a major factor in tumor initiation, progression, metastasis, and recurrence. CSCs are a subpopulation of bulk tumors, with stem cell-like properties and tumorigenic capabilities, having the abilities of self-renewal and differentiation, thereby being able to generate heterogeneous lineages of cancer cells and lead to resistance toward anti-tumor treatments. Highly resistant to conventional chemo- and radiotherapy, CSCs have heterogeneity and can migrate to different organs and metastasize. Recent studies have demonstrated that the population of CSCs and the progression of cancer are increased by the deregulation of different epigenetic pathways having effects on gene expression patterns and key pathways connected with cell proliferation and survival. Further, epigenetic modifications (DNA methylation, histone modifications, and RNA methylations) have been revealed to be key drivers in the formation and maintenance of CSCs. Hence, identifying CSCs and targeting epigenetic pathways therein can offer new insights into the treatment of cancer. In the present review, recent studies are addressed in terms of the characteristics of CSCs, the resistance thereof, and the factors influencing the development thereof, with an emphasis on different types of epigenetic changes in genes and main signaling pathways involved therein. Finally, targeted therapy for CSCs by epigenetic drugs is referred to, which is a new approach in overcoming resistance and recurrence of cancer.
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Affiliation(s)
| | - Khatereh Khorsandi
- Department of Photodynamic, Medical Laser Research Center, Yara Institute, ACECR, Tehran, Iran.
| | - Azhar Rasul
- Department of Zoology, Government College University Faisalabad, Faisalabad, 38000, Pakistan
| | - Muhammad Khatir Zaman
- Department of Biotechnology, Abdul Wali Khan University Mardan (AWKUM), Mardan, 23200, Pakistan
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Silencing of Histone Deacetylase 6 Decreases Cellular Malignancy and Contributes to Primary Cilium Restoration, Epithelial-to-Mesenchymal Transition Reversion, and Autophagy Inhibition in Glioblastoma Cell Lines. BIOLOGY 2021; 10:biology10060467. [PMID: 34073238 PMCID: PMC8228543 DOI: 10.3390/biology10060467] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 05/20/2021] [Accepted: 05/23/2021] [Indexed: 12/25/2022]
Abstract
Simple Summary Glioblastoma multiforme (GBM) is the most common as well as the most aggressive malignant brain tumor, with an overall survival of almost 15 months. Histone deacetylase 6 (HDAC6), an enzyme related to the deacetylation of α-tubulin, is overexpressed in GBM. The aim of our research was to study the effects of HDAC6 silencing in GBM cells. We first confirmed the overexpression of HDAC6 in GBM tissue (n = 40) against control brain (n = 10). Treatment with siHDAC6 diminished viability, clonogenic potential, and migration ability in GBM-derived cell lines. HDAC6 inhibition also reverted the mesenchymal phenotype, inhibited the Sonic Hedgehog pathway, restored primary cilium structure, and decreased autophagy. Thus, we confirm that HDAC6 is a good therapeutic target for GBM treatment. Abstract Glioblastoma multiforme, the most common type of malignant brain tumor as well as the most aggressive one, lacks an effective therapy. Glioblastoma presents overexpression of mesenchymal markers Snail, Slug, and N-Cadherin and of the autophagic marker p62. Glioblastoma cell lines also present increased autophagy, overexpression of mesenchymal markers, Shh pathway activation, and lack of primary cilia. In this study, we aimed to evaluate the role of HDAC6 in the pathogenesis of glioblastoma, as HDAC6 is the most overexpressed of all HDACs isoforms in this tumor. We treated glioblastoma cell lines with siHDAC6. HDAC6 silencing inhibited proliferation, migration, and clonogenicity of glioblastoma cell lines. They also reversed the mesenchymal phenotype, decreased autophagy, inhibited Shh pathway, and recovered the expression of primary cilia in glioblastoma cell lines. These results demonstrate that HDAC6 might be a good target for glioblastoma treatment.
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HDAC6 Signaling at Primary Cilia Promotes Proliferation and Restricts Differentiation of Glioma Cells. Cancers (Basel) 2021; 13:cancers13071644. [PMID: 33915983 PMCID: PMC8036575 DOI: 10.3390/cancers13071644] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 03/22/2021] [Accepted: 03/25/2021] [Indexed: 12/26/2022] Open
Abstract
Simple Summary Glioblastoma is the most common and lethal brain tumor in adults because it becomes resistant to virtually every treatment. Histone deacetylase 6 (HDAC6), which is located primarily in the cytoplasm, has a unique role in promoting the disassembly of cells’ primary cilium, a non-motile “antenna” that must be broken down before cells can progress through the cell cycle. The role of HDAC6 and its function in gliomas have not been investigated with respect to tumor cell cilia. We have found that inhibitors of HDAC6 cause rapid and specific changes inside glioma cilia, reducing tumor cell proliferative capacity and promoting cell differentiation. Importantly, the HDAC6 inhibitors did not affect the proliferation or differentiation of glioma cells that we genetically modified unable to grow cilia. Our findings reveal a conserved and critical role for HDAC6 in glioma growth that is dependent on cilia. Abstract Histone deacetylase 6 (HDAC6) is an emerging therapeutic target that is overexpressed in glioblastoma when compared to other HDACs. HDAC6 catalyzes the deacetylation of alpha-tubulin and mediates the disassembly of primary cilia, a process required for cell cycle progression. HDAC6 inhibition disrupts glioma proliferation, but whether this effect is dependent on tumor cell primary cilia is unknown. We found that HDAC6 inhibitors ACY-1215 (1215) and ACY-738 (738) inhibited the proliferation of multiple patient-derived and mouse glioma cells. While both inhibitors triggered rapid increases in acetylated alpha-tubulin (aaTub) in the cytosol and led to increased frequencies of primary cilia, they unexpectedly reduced the levels of aaTub in the cilia. To test whether the antiproliferative effects of HDAC6 inhibitors are dependent on tumor cell cilia, we generated patient-derived glioma lines devoid of cilia through depletion of ciliogenesis genes ARL13B or KIF3A. At low concentrations, 1215 or 738 did not decrease the proliferation of cilia-depleted cells. Moreover, the differentiation of glioma cells that was induced by HDAC6 inhibition did not occur after the inhibition of cilia formation. These data suggest HDAC6 signaling at primary cilia promotes the proliferation of glioma cells by restricting their ability to differentiate. Surprisingly, overexpressing HDAC6 did not reduce cilia length or the frequency of ciliated glioma cells, suggesting other factors are required to control HDAC6-mediated cilia disassembly in glioma cells. Collectively, our findings suggest that HDAC6 promotes the proliferation of glioma cells through primary cilia.
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Cabrera-Licona A, Pérez-Añorve IX, Flores-Fortis M, Moral-Hernández OD, González-de la Rosa CH, Suárez-Sánchez R, Chávez-Saldaña M, Aréchaga-Ocampo E. Deciphering the epigenetic network in cancer radioresistance. Radiother Oncol 2021; 159:48-59. [PMID: 33741468 DOI: 10.1016/j.radonc.2021.03.012] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 02/15/2021] [Accepted: 03/09/2021] [Indexed: 12/16/2022]
Abstract
Radiotherapy, in addition to surgery and systemic chemotherapy, remains the core of the current clinical management of cancer. Radioresistance is one of the major causes of disease progression and mortality in cancer; therefore, it is a significant challenge in the treatment of locally advanced, recurrent and metastatic cancer. Epigenetic mechanisms that control hallmarks of cancer have a key role in the development of radiation resistance of cancer cells. Recent advances in DNA methylation, histone modification, chromatin remodeling and non-coding RNAs identified in the control of signal transduction pathways in cancer and cancer stem cells have provided even greater promise in the improvement of understanding cancer radioresistance. Many epigenetic drugs that target epigenetic enzymes revert the radioresistant phenotypes decreasing the possibility that resistant cancer cells will develop refractory tumors to radiotherapy. Epigenetic profiles identified as regulators of DNA damage repair, hypoxia, cell survival, apoptosis and invasion are determinants in the development of tumor radioresistance; hence, they also are promising in personalized medicine to develop novel targeted therapies or biomarkers to follow-up the effectiveness of radiotherapy. Now, it is clear that radiotherapy can influence a complex epigenetic network for transcriptional reprogramming, enabling the cells to adapt and avoid the effect of radiotherapy. This review aims to highlight the epigenetic modifications identified in cancer radioresistance and to discuss approaches to disable epigenetic networks to increase the sensitivity and specificity of radiotherapy.
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Affiliation(s)
- Ariana Cabrera-Licona
- Departamento de Ciencias Naturales, Unidad Cuajimalpa, Universidad Autonoma Metropolitana, Ciudad de Mexico, Mexico; Posgrado en Ciencias Naturales e Ingenieria, Unidad Cuajimalpa, Universidad Autonoma Metropolitana, Ciudad de Mexico, Mexico
| | - Isidro X Pérez-Añorve
- Departamento de Ciencias Naturales, Unidad Cuajimalpa, Universidad Autonoma Metropolitana, Ciudad de Mexico, Mexico
| | - Mauricio Flores-Fortis
- Departamento de Ciencias Naturales, Unidad Cuajimalpa, Universidad Autonoma Metropolitana, Ciudad de Mexico, Mexico; Posgrado en Ciencias Naturales e Ingenieria, Unidad Cuajimalpa, Universidad Autonoma Metropolitana, Ciudad de Mexico, Mexico
| | - Oscar Del Moral-Hernández
- Laboratorio de Virologia y Epigenetica del Cancer, Facultad de Ciencias Quimico Biologicas, Universidad Autonoma de Guerrero, Chilpancingo, Mexico
| | | | - Rocio Suárez-Sánchez
- Laboratorio de Medicina Genomica, Departamento de Genetica, Instituto Nacional de Rehabilitacion LGII, Ciudad de Mexico, Mexico
| | - Margarita Chávez-Saldaña
- Laboratorio de Biologia de la Reproduccion, Instituto Nacional de Pediatria, Ciudad de Mexico, Mexico
| | - Elena Aréchaga-Ocampo
- Departamento de Ciencias Naturales, Unidad Cuajimalpa, Universidad Autonoma Metropolitana, Ciudad de Mexico, Mexico.
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Castresana J, Urdiciain A, Bermúdez-Lekerika P, Meléndez B, Rey J, Idoate M, Riobo-Del Galdo N. Inhibition of histone deacetylase 6 by tubastatin A as an experimental therapeutic strategy against glioblastoma. GLIOMA 2021. [DOI: 10.4103/glioma.glioma_5_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Ribeiro Reily Rocha C, Reily Rocha A, Molina Silva M, Rodrigues Gomes L, Teatin Latancia M, Andrade Tomaz M, de Souza I, Karolynne Seregni Monteiro L, Frederico Martins Menck C. Revealing Temozolomide Resistance Mechanisms via Genome-Wide CRISPR Libraries. Cells 2020; 9:cells9122573. [PMID: 33271924 PMCID: PMC7760831 DOI: 10.3390/cells9122573] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 11/15/2020] [Accepted: 11/23/2020] [Indexed: 12/13/2022] Open
Abstract
Glioblastoma is a severe type of brain tumor with a poor prognosis and few therapy options. Temozolomide (TMZ) is one of these options, however, with limited success, and failure is mainly due to tumor resistance. In this work, genome-wide CRISPR-Cas9 lentiviral screen libraries for gene knockout or activation were transduced in the human glioblastoma cell line, aiming to identify genes that modulate TMZ resistance. The sgRNAs enriched in both libraries in surviving cells after TMZ treatment were identified by next-generation sequencing (NGS). Pathway analyses of gene candidates on knockout screening revealed several enriched pathways, including the mismatch repair and the Sonic Hedgehog pathways. Silencing three genes ranked on the top 10 list (MSH2, PTCH2, and CLCA2) confirm cell protection from TMZ-induced death. In addition, a CRISPR activation library revealed that NRF2 and Wnt pathways are involved in TMZ resistance. Consistently, overexpression of FZD6, CTNNB1, or NRF2 genes significantly increased cell survival upon TMZ treatment. Moreover, NRF2 and related genes detected in this screen presented a robust negative correlation with glioblastoma patient survival rates. Finally, several gene candidates from knockout or activation screening are targetable by inhibitors or small molecules, and some of them have already been used in the clinic.
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Affiliation(s)
- Clarissa Ribeiro Reily Rocha
- Department of Clinical and Experimental Oncology, Federal University of São Paulo (UNIFESP), São Paulo 04037-003, Brazil; (C.R.R.R.); (M.A.T.); (I.d.S.); (L.K.S.M.)
| | - Alexandre Reily Rocha
- Institute of Theoretical Physics, State University of São Paulo (UNESP), São Paulo 01140-070, Brazil;
| | - Matheus Molina Silva
- Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo 05508-000, Brazil; (M.M.S.); (M.T.L.)
| | - Luciana Rodrigues Gomes
- Laboratory of Cell Cycle, Center of Toxins, Immune Response and Cell Signaling (CeTICS), Butantan Institute, São Paulo 05503-001, Brazil;
| | - Marcela Teatin Latancia
- Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo 05508-000, Brazil; (M.M.S.); (M.T.L.)
| | - Marina Andrade Tomaz
- Department of Clinical and Experimental Oncology, Federal University of São Paulo (UNIFESP), São Paulo 04037-003, Brazil; (C.R.R.R.); (M.A.T.); (I.d.S.); (L.K.S.M.)
| | - Izadora de Souza
- Department of Clinical and Experimental Oncology, Federal University of São Paulo (UNIFESP), São Paulo 04037-003, Brazil; (C.R.R.R.); (M.A.T.); (I.d.S.); (L.K.S.M.)
| | - Linda Karolynne Seregni Monteiro
- Department of Clinical and Experimental Oncology, Federal University of São Paulo (UNIFESP), São Paulo 04037-003, Brazil; (C.R.R.R.); (M.A.T.); (I.d.S.); (L.K.S.M.)
| | - Carlos Frederico Martins Menck
- Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo 05508-000, Brazil; (M.M.S.); (M.T.L.)
- Correspondence: ; Tel.: +55-1130917499
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New Avenues in Radiotherapy of Glioblastoma: from Bench to Bedside. Curr Treat Options Neurol 2020. [DOI: 10.1007/s11940-020-00654-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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50
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Chi F, Liu J, Brady SW, Cosgrove PA, Nath A, McQuerry JA, Majumdar S, Moos PJ, Chang JT, Kahn M, Bild AH. A `one-two punch' therapy strategy to target chemoresistance in estrogen receptor positive breast cancer. Transl Oncol 2020; 14:100946. [PMID: 33221681 PMCID: PMC7689336 DOI: 10.1016/j.tranon.2020.100946] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 11/02/2020] [Accepted: 11/04/2020] [Indexed: 12/12/2022] Open
Abstract
Patient tumor subclones that survive chemotherapy acquire primitive cell traits. HDAC inhibitors can reverse chemo-acquired stemness states and abolish self-renewal abilities. Belinostat promotes stem cell differentiation and inhibits HDAC and MYC pathways. A ‘one-two punch’, chemotherapy-HDAC inhibitor combination strategy reverses chemo-induced resistant phenotypes. Cancer cell phenotypes evolve during a tumor's treatment. In some cases, tumor cells acquire cancer stem cell-like (CSL) traits such as resistance to chemotherapy and diminished differentiation; therefore, targeting these cells may be therapeutically beneficial. In this study we show that in progressive estrogen receptor positive (ER+) metastatic breast cancer tumors, resistant subclones that emerge following chemotherapy have increased CSL abundance. Further, in vitro organoid growth of ER+ patient cancer cells also shows that chemotherapy treatment leads to increased abundance of ALDH+/CD44+ CSL cells. Chemotherapy induced CSL abundance is blocked by treatment with a pan-HDAC inhibitor, belinostat. Belinostat treatment diminished both mammosphere formation and size following chemotherapy, indicating a decrease in progenitor CSL traits. HDAC inhibitors specific to class IIa (HDAC4, HDAC5) and IIb (HDAC6) were shown to primarily reverse the chemo-resistant CSL state. Single-cell RNA sequencing analysis with patient samples showed that HDAC targets and MYC signaling were promoted by chemotherapy and inhibited upon HDAC inhibitor treatment. In summary, HDAC inhibition can block chemotherapy-induced drug resistant phenotypes with ‘one-two punch’ strategy in refractory breast cancer cells.
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Affiliation(s)
- Feng Chi
- Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, United States
| | - Jiayi Liu
- Department of Integrative Biology and Pharmacology, School of Medicine, School of Biomedical Informatics, UT Health Sciences Center at Houston, Houston, TX 77030, United States
| | - Samuel W Brady
- Department of Oncological Sciences, School of Medicine, University of Utah, 2000 Circle of Hope Drive, Salt Lake City, UT 84112, United States
| | - Patrick A Cosgrove
- Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, United States
| | - Aritro Nath
- Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, United States
| | - Jasmine A McQuerry
- Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, United States; Department of Oncological Sciences, School of Medicine, University of Utah, 2000 Circle of Hope Drive, Salt Lake City, UT 84112, United States; Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, 30 South 2000 East, Salt Lake City, UT 84112, United States
| | - Sumana Majumdar
- Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, United States
| | - Philip J Moos
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, 30 South 2000 East, Salt Lake City, UT 84112, United States
| | - Jeffrey T Chang
- Department of Integrative Biology and Pharmacology, School of Medicine, School of Biomedical Informatics, UT Health Sciences Center at Houston, Houston, TX 77030, United States
| | - Michael Kahn
- Department of Molecular Medicine, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, United States
| | - Andrea H Bild
- Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, United States.
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