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Song Y, Hu L, Cheng J, Li Z, Zheng J. LncRNA SNHG5 induces CAFs-like phenotype and autophagy of AML-MSCs via PTBP1/ATG5 axis to confer chemoresistance of AML cells. Cell Signal 2025; 128:111625. [PMID: 39864537 DOI: 10.1016/j.cellsig.2025.111625] [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: 11/05/2024] [Revised: 01/21/2025] [Accepted: 01/22/2025] [Indexed: 01/28/2025]
Abstract
BACKGROUND Acute myeloid leukemia (AML) is still a threaten to human health due to its high occurrence and poor prognosis. Mesenchymal stem cells (MSCs) in bone marrow microenvironment (BMM) play a critical role in the development of AML. This study elucidated the interaction between MSCs and AML cells and its underlying mechanism. METHOD MSCs were isolated, identified, and co-cultured with AML cells. qRT-PCR, Western blotting and immunofluorescence were used to determine molecule expression. Cell viability and apoptosis were determined by CCK-8 and flow cytometry. Exosomes were isolated and characterized, and PKH26 was used for monitoring exosome internalization. RNA-FISH was used to determine the localization of SNHG5. RIP, RNA-pull down and ChIP assays were used to evaluate the molecular interaction. RESULTS SNHG5 expression was up-regulated and positively correlated with cancer-associated fibroblasts (CAFs)-related biomarkers in AML-MSCs. AML cells-derived exosomes delivered SNHG5 to enhance its expression in MSCs. SNHG5 overexpression induced CAFs-like phenotype and autophagy in HD-MSCs that led to daunorubicin resistance of AML cells. Mechanistically, SNHG5 stabilized autophagy related 5 (ATG5) mRNA by interaction with polypyrimidine tract-binding protein 1 (PTBP1). CONCLUSION AML cells-derived exosomal lncRNA SNHG5 triggered CAFs-like phenotype and autophagy of AML-MSCs via interaction with PTBP1 to increase ATG5 mRNA stability, thereby leading to chemoresistance of AML cells.
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MESH Headings
- Humans
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/metabolism
- Mesenchymal Stem Cells/metabolism
- Mesenchymal Stem Cells/pathology
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/pathology
- Leukemia, Myeloid, Acute/metabolism
- Leukemia, Myeloid, Acute/drug therapy
- Drug Resistance, Neoplasm/genetics
- Autophagy/genetics
- Autophagy-Related Protein 5/metabolism
- Autophagy-Related Protein 5/genetics
- Polypyrimidine Tract-Binding Protein/metabolism
- Polypyrimidine Tract-Binding Protein/genetics
- Heterogeneous-Nuclear Ribonucleoproteins/metabolism
- Heterogeneous-Nuclear Ribonucleoproteins/genetics
- Exosomes/metabolism
- Cell Line, Tumor
- Phenotype
- Apoptosis
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Affiliation(s)
- Yuan Song
- Department of Hematology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi Provincial Key Laboratory of Hematological Diseases, Nanchang 330006, Jiangxi Province, People's Republic of China
| | - Lili Hu
- Department of Nephrology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, People's Republic of China
| | - Jing Cheng
- Department of Hematology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi Provincial Key Laboratory of Hematological Diseases, Nanchang 330006, Jiangxi Province, People's Republic of China
| | - Zhenjiang Li
- Department of Hematology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi Provincial Key Laboratory of Hematological Diseases, Nanchang 330006, Jiangxi Province, People's Republic of China
| | - Jifu Zheng
- Department of Hematology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi Provincial Key Laboratory of Hematological Diseases, Nanchang 330006, Jiangxi Province, People's Republic of China.
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Li M, Li J, Zhang S, Zhou L, Zhu Y, Li S, Li Q, Wang J, Song R. Progress in the study of autophagy-related proteins affecting resistance to chemotherapeutic drugs in leukemia. Front Cell Dev Biol 2024; 12:1394140. [PMID: 38887520 PMCID: PMC11180896 DOI: 10.3389/fcell.2024.1394140] [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: 03/01/2024] [Accepted: 05/17/2024] [Indexed: 06/20/2024] Open
Abstract
Leukemia is a life-threatening malignant tumor of the hematopoietic system. Currently, the main treatment modalities are chemotherapy and hematopoietic stem cell transplantation. However, increased drug resistance due to decreased sensitivity of leukemia cells to chemotherapeutic drugs presents a major challenge in current treatments. Autophagy-associated proteins involved in autophagy initiation have now been shown to be involved in the development of various types of leukemia cells and are associated with drug resistance. Therefore, this review will explore the roles of autophagy-related proteins involved in four key autophagic processes: induction of autophagy and phagophore formation, phagophore extension, and autophagosome formation, on the development of various types of leukemias as well as drug resistance. Autophagy may become a promising therapeutic target for treating leukemia.
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Affiliation(s)
- Meng Li
- Nursing Department, The Third People’s Hospital of Henan Province, Zhengzhou, China
| | - Jing Li
- Department of Pathophysiology, Sepsis Translational Medicine Key Laboratory of Hunan Province, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Shiming Zhang
- Clinical College, Xiamen Medical University, Xiamen, Fujian, China
| | - Linghan Zhou
- Nursing Department, The Third People’s Hospital of Henan Province, Zhengzhou, China
| | - Yuanyuan Zhu
- Nursing Department, The Third People’s Hospital of Henan Province, Zhengzhou, China
| | - Shen Li
- Rehabilitation Department, Henan Institute of Massage, Luoyang, Henan, China
| | - Qiong Li
- Nursing Department, Xinxiang Medical University, Xinxiang, China
| | - Junjie Wang
- Plastic Surgery, The Third People’s Hospital of Henan Province, Zhengzhou, China
| | - Ruipeng Song
- Endocrinology Department, The Third People’s Hospital of Henan Province, Zhengzhou, China
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Jiang M, Wu W, Xiong Z, Yu X, Ye Z, Wu Z. Targeting autophagy drug discovery: Targets, indications and development trends. Eur J Med Chem 2024; 267:116117. [PMID: 38295689 DOI: 10.1016/j.ejmech.2023.116117] [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: 11/20/2023] [Revised: 12/30/2023] [Accepted: 12/31/2023] [Indexed: 02/25/2024]
Abstract
Autophagy plays a vital role in sustaining cellular homeostasis and its alterations have been implicated in the etiology of many diseases. Drugs development targeting autophagy began decades ago and hundreds of agents were developed, some of which are licensed for the clinical usage. However, no existing intervention specifically aimed at modulating autophagy is available. The obstacles that prevent drug developments come from the complexity of the actual impact of autophagy regulators in disease scenarios. With the development and application of new technologies, several promising categories of compounds for autophagy-based therapy have emerged in recent years. In this paper, the autophagy-targeted drugs based on their targets at various hierarchical sites of the autophagic signaling network, e.g., the upstream and downstream of the autophagosome and the autophagic components with enzyme activities are reviewed and analyzed respectively, with special attention paid to those at preclinical or clinical trials. The drugs tailored to specific autophagy alone and combination with drugs/adjuvant therapies widely used in clinical for various diseases treatments are also emphasized. The emerging drug design and development targeting selective autophagy receptors (SARs) and their related proteins, which would be expected to arrest or reverse the progression of disease in various cancers, inflammation, neurodegeneration, and metabolic disorders, are critically reviewed. And the challenges and perspective in clinically developing autophagy-targeted drugs and possible combinations with other medicine are considered in the review.
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Affiliation(s)
- Mengjia Jiang
- Department of Pharmacology and Pharmacy, China Jiliang University, China
| | - Wayne Wu
- College of Osteopathic Medicine, New York Institute of Technology, USA
| | - Zijie Xiong
- Department of Pharmacology and Pharmacy, China Jiliang University, China
| | - Xiaoping Yu
- Department of Biology, China Jiliang University, China
| | - Zihong Ye
- Department of Biology, China Jiliang University, China
| | - Zhiping Wu
- Department of Pharmacology and Pharmacy, China Jiliang University, China.
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4
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Torres-López L, Dobrovinskaya O. Dissecting the Role of Autophagy-Related Proteins in Cancer Metabolism and Plasticity. Cells 2023; 12:2486. [PMID: 37887330 PMCID: PMC10605719 DOI: 10.3390/cells12202486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 10/11/2023] [Accepted: 10/16/2023] [Indexed: 10/28/2023] Open
Abstract
Modulation of autophagy as an anticancer strategy has been widely studied and evaluated in several cell models. However, little attention has been paid to the metabolic changes that occur in a cancer cell when autophagy is inhibited or induced. In this review, we describe how the expression and regulation of various autophagy-related (ATGs) genes and proteins are associated with cancer progression and cancer plasticity. We present a comprehensive review of how deregulation of ATGs affects cancer cell metabolism, where inhibition of autophagy is mainly reflected in the enhancement of the Warburg effect. The importance of metabolic changes, which largely depend on the cancer type and form part of a cancer cell's escape strategy after autophagy modulation, is emphasized. Consequently, pharmacological strategies based on a dual inhibition of metabolic and autophagy pathways emerged and are reviewed critically here.
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Affiliation(s)
- Liliana Torres-López
- Laboratory of Immunology and Ionic Transport Regulation, Biomedical Research Centre, University of Colima, Av. 25 de Julio #965, Villas de San Sebastián, Colima 28045, Mexico;
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Saulle E, Spinello I, Quaranta MT, Labbaye C. Advances in Understanding the Links between Metabolism and Autophagy in Acute Myeloid Leukemia: From Biology to Therapeutic Targeting. Cells 2023; 12:1553. [PMID: 37296673 PMCID: PMC10252746 DOI: 10.3390/cells12111553] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 05/24/2023] [Accepted: 06/01/2023] [Indexed: 06/12/2023] Open
Abstract
Autophagy is a highly conserved cellular degradation process that regulates cellular metabolism and homeostasis under normal and pathophysiological conditions. Autophagy and metabolism are linked in the hematopoietic system, playing a fundamental role in the self-renewal, survival, and differentiation of hematopoietic stem and progenitor cells, and in cell death, particularly affecting the cellular fate of the hematopoietic stem cell pool. In leukemia, autophagy sustains leukemic cell growth, contributes to survival of leukemic stem cells and chemotherapy resistance. The high frequency of disease relapse caused by relapse-initiating leukemic cells resistant to therapy occurs in acute myeloid leukemia (AML), and depends on the AML subtypes and treatments used. Targeting autophagy may represent a promising strategy to overcome therapeutic resistance in AML, for which prognosis remains poor. In this review, we illustrate the role of autophagy and the impact of its deregulation on the metabolism of normal and leukemic hematopoietic cells. We report updates on the contribution of autophagy to AML development and relapse, and the latest evidence indicating autophagy-related genes as potential prognostic predictors and drivers of AML. We review the recent advances in autophagy manipulation, combined with various anti-leukemia therapies, for an effective autophagy-targeted therapy for AML.
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Affiliation(s)
- Ernestina Saulle
- Correspondence: (E.S.); (C.L.); Tel.: +39-0649902422 (E.S.); +39-0649902418 (C.L.)
| | | | | | - Catherine Labbaye
- Correspondence: (E.S.); (C.L.); Tel.: +39-0649902422 (E.S.); +39-0649902418 (C.L.)
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6
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Tan Z, Kan C, Wong M, Sun M, Liu Y, Yang F, Wang S, Zheng H. Regulation of Malignant Myeloid Leukemia by Mesenchymal Stem Cells. Front Cell Dev Biol 2022; 10:857045. [PMID: 35756991 PMCID: PMC9213747 DOI: 10.3389/fcell.2022.857045] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 04/25/2022] [Indexed: 11/13/2022] Open
Abstract
Bone marrow microenvironment (BMM) has been proven to have benefits for both normal hematopoietic stem cell niche and pathological leukemic stem cell niche. In fact, the pathological leukemia microenvironment reprograms bone marrow niche cells, especially mesenchymal stem cells for leukemia progression, chemoresistance and relapse. The growth and differentiation of MSCs are modulated by leukemia stem cells. Moreover, chromatin abnormality of mesenchymal stem cells is sufficient for leukemia initiation. Here, we summarize the detailed relationship between MSC and leukemia. MSCs can actively and passively regulate the progression of myelogenous leukemia through cell-to-cell contact, cytokine-receptor interaction, and exosome communication. These behaviors benefit LSCs proliferation and survival and inhibit physiological hematopoiesis. Finally, we describe the recent advances in therapy targeting MSC hoping to provide new perspectives and therapeutic strategies for leukemia.
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Affiliation(s)
- Zhenya Tan
- Department of Pathophysiology, Anhui Medical University, Hefei, China
| | - Chen Kan
- Department of Pathophysiology, Anhui Medical University, Hefei, China
| | - Mandy Wong
- Department of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, United States
| | - Minqiong Sun
- Department of Pathophysiology, Anhui Medical University, Hefei, China
| | - Yakun Liu
- Department of Pathophysiology, Anhui Medical University, Hefei, China
| | - Fan Yang
- Department of Pathophysiology, Anhui Medical University, Hefei, China
| | - Siying Wang
- Department of Pathophysiology, Anhui Medical University, Hefei, China
| | - Hong Zheng
- Department of Pathophysiology, Anhui Medical University, Hefei, China
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7
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Seo W, Silwal P, Song IC, Jo EK. The dual role of autophagy in acute myeloid leukemia. J Hematol Oncol 2022; 15:51. [PMID: 35526025 PMCID: PMC9077970 DOI: 10.1186/s13045-022-01262-y] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 04/14/2022] [Indexed: 01/18/2023] Open
Abstract
Acute myeloid leukemia (AML) is a severe hematologic malignancy prevalent in older patients, and the identification of potential therapeutic targets for AML is problematic. Autophagy is a lysosome-dependent catabolic pathway involved in the tumorigenesis and/or treatment of various cancers. Mounting evidence has suggested that autophagy plays a critical role in the initiation and progression of AML and anticancer responses. In this review, we describe recent updates on the multifaceted functions of autophagy linking to genetic alterations of AML. We also summarize the latest evidence for autophagy-related genes as potential prognostic predictors and drivers of AML tumorigenesis. We then discuss the crosstalk between autophagy and tumor cell metabolism into the impact on both AML progression and anti-leukemic treatment. Moreover, a series of autophagy regulators, i.e., the inhibitors and activators, are described as potential therapeutics for AML. Finally, we describe the translation of autophagy-modulating therapeutics into clinical practice. Autophagy in AML is a double-edged sword, necessitating a deeper understanding of how autophagy influences dual functions in AML tumorigenesis and anti-leukemic responses.
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Affiliation(s)
- Wonhyoung Seo
- Infection Control Convergence Research Center, Chungnam National University College of Medicine, Daejeon, 35015, Korea.,Department of Microbiology, Chungnam National University College of Medicine, Daejeon, 35015, Korea.,Department of Medical Science, Chungnam National University College of Medicine, Daejeon, 35015, Korea
| | - Prashanta Silwal
- Infection Control Convergence Research Center, Chungnam National University College of Medicine, Daejeon, 35015, Korea.,Department of Microbiology, Chungnam National University College of Medicine, Daejeon, 35015, Korea
| | - Ik-Chan Song
- Division of Hematology/Oncology, Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, 35015, Korea
| | - Eun-Kyeong Jo
- Infection Control Convergence Research Center, Chungnam National University College of Medicine, Daejeon, 35015, Korea. .,Department of Microbiology, Chungnam National University College of Medicine, Daejeon, 35015, Korea. .,Department of Medical Science, Chungnam National University College of Medicine, Daejeon, 35015, Korea.
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8
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Ruiz-Aparicio PF, Vernot JP. Bone Marrow Aging and the Leukaemia-Induced Senescence of Mesenchymal Stem/Stromal Cells: Exploring Similarities. J Pers Med 2022; 12:jpm12050716. [PMID: 35629139 PMCID: PMC9147878 DOI: 10.3390/jpm12050716] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/20/2022] [Accepted: 04/27/2022] [Indexed: 12/17/2022] Open
Abstract
Bone marrow aging is associated with multiple cellular dysfunctions, including perturbed haematopoiesis, the propensity to haematological transformation, and the maintenance of leukaemia. It has been shown that instructive signals from different leukemic cells are delivered to stromal cells to remodel the bone marrow into a supportive leukemic niche. In particular, cellular senescence, a physiological program with both beneficial and deleterious effects on the health of the organisms, may be responsible for the increased incidence of haematological malignancies in the elderly and for the survival of diverse leukemic cells. Here, we will review the connection between BM aging and cellular senescence and the role that these processes play in leukaemia progression. Specifically, we discuss the role of mesenchymal stem cells as a central component of the supportive niche. Due to the specificity of the genetic defects present in leukaemia, one would think that bone marrow alterations would also have particular changes, making it difficult to envisage a shared therapeutic use. We have tried to summarize the coincident features present in BM stromal cells during aging and senescence and in two different leukaemias, acute myeloid leukaemia, with high frequency in the elderly, and B-acute lymphoblastic leukaemia, mainly a childhood disease. We propose that mesenchymal stem cells are similarly affected in these different leukaemias, and that the changes that we observed in terms of cellular function, redox balance, genetics and epigenetics, soluble factor repertoire and stemness are equivalent to those occurring during BM aging and cellular senescence. These coincident features may be used to explore strategies useful to treat various haematological malignancies.
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Affiliation(s)
- Paola Fernanda Ruiz-Aparicio
- Grupo de Investigación Fisiología Celular y Molecular, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá 111321, Colombia;
| | - Jean-Paul Vernot
- Grupo de Investigación Fisiología Celular y Molecular, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá 111321, Colombia;
- Instituto de Investigaciones Biomédicas, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá 111321, Colombia
- Correspondence:
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Xie S, Jiang X, Qin R, Song S, Lu Y, Wang L, Chen Y, Lu D. miR-1307 promotes hepatocarcinogenesis by CALR-OSTC-endoplasmic reticulum protein folding pathway. iScience 2021; 24:103271. [PMID: 34761190 PMCID: PMC8567365 DOI: 10.1016/j.isci.2021.103271] [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: 05/17/2021] [Revised: 08/27/2021] [Accepted: 10/12/2021] [Indexed: 12/20/2022] Open
Abstract
miR-1307 is highly expressed in liver cancer and inhibits methyltransferase protein8. Thereby, miR-1307 inhibits the expression of KDM3A and KDM3B and increases the methylation modification of histone H3 lysine 9, which enhances the expression of endoplasmic-reticulum-related gene CALR. Of note, miR-1307 weakens the binding ability of OSTC to CDK2, CDK4, CyclinD1, and cyclinE and enhances the binding ability of CALR to CDK2, CDK4, CyclinD1, and cyclinE, decreasing of p21WAF1/CIP1, GADD45, pRB, and p18, and decreasing of ppRB. Furthermore, miR-1307 increases the activity of H-Ras, PKM2, and PLK1. Strikingly, miR-1307 reduces the binding ability of OSTC to ATG4 and enhances the binding ability of CALR to ATG4. Therefore, miR-1307 reduces the occurrence of autophagy based on ATG4-LC3-ATG3-ATG7-ATG5-ATG16L1-ATG12-ATG9- Beclin1. In particular, miR-1307 enhances the expression of PAK2, PLK1, PRKAR2A, MYBL1, and Trim44 and inhibits the expression of Sash1 and Smad5 via autophagy. Our observations suggest that miR-1307 promotes hepatocarcinogenesis by CALR-OSTC-endoplasmic reticulum protein folding pathway.
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Affiliation(s)
- Sijie Xie
- Shanghai Putuo People's Hospital, School of Life Science and Technology, Tongji University, 200092 Shanghai, China
| | - Xiaoxue Jiang
- Shanghai Putuo People's Hospital, School of Life Science and Technology, Tongji University, 200092 Shanghai, China
| | - Rushi Qin
- Shanghai Putuo People's Hospital, School of Life Science and Technology, Tongji University, 200092 Shanghai, China
| | - Shuting Song
- Shanghai Putuo People's Hospital, School of Life Science and Technology, Tongji University, 200092 Shanghai, China
| | - Yanan Lu
- Shanghai Putuo People's Hospital, School of Life Science and Technology, Tongji University, 200092 Shanghai, China
| | - Liyan Wang
- Shanghai Putuo People's Hospital, School of Life Science and Technology, Tongji University, 200092 Shanghai, China
| | - Yingjie Chen
- Shanghai Putuo People's Hospital, School of Life Science and Technology, Tongji University, 200092 Shanghai, China
| | - Dongdong Lu
- Shanghai Putuo People's Hospital, School of Life Science and Technology, Tongji University, 200092 Shanghai, China
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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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Wang C, Li L, Li M, Wang W, Liu Y, Wang S. Silencing long non-coding RNA XIST suppresses drug resistance in acute myeloid leukemia through down-regulation of MYC by elevating microRNA-29a expression. Mol Med 2020; 26:114. [PMID: 33228517 PMCID: PMC7685636 DOI: 10.1186/s10020-020-00229-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 10/20/2020] [Indexed: 12/14/2022] Open
Abstract
Background Long non-coding RNAs (lncRNAs) are biomarkers participating in multiple disease development including acute myeloid leukemia (AML). Here, we investigated molecular mechanism of X Inactive-Specific Transcript (XIST) in regulating cellular viability, apoptosis and drug resistance in AML. Methods XIST, miR-29a and myelocytomatosis oncogene (MYC) expression in AML bone marrow cells collected from 62 patients was evaluated by RT-qPCR and Western blot analysis. Besides, the relationship among XIST, miR-29a and MYC was analyzed by dual luciferase reporter assay, RIP, and RNA pull down assays. AML KG-1 cells were treated with anti-tumor drug Adriamycin. The role of XIST/miR-29a/MYC in cellular viability, apoptosis and drug resistance in AML was accessed via gain- and loss-of-function approaches. At last, we evaluated role of XIST/miR-29a/MYC on tumorigenesis in vivo. Results XIST and MYC were up-regulated, and miR-29a was down-regulated in AML bone marrow cells. Silencing XIST inhibited cellular activity and drug resistance but promoted cellular apoptosis of KG-1 cells by down-regulating MYC. XIST inhibited miR-29a expression to up-regulate MYC. Moreover, silencing XIST inhibited tumorigenesis of AML cells in vivo. Conclusions Overall, down-regulation of XIST decreased MYC expression through releasing the inhibition on miR-29a, thereby reducing drug resistance, inhibiting viability and promoting apoptosis of AML cells.
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Affiliation(s)
- Chong Wang
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou, 450052, Henan, P. R. China.
| | - Lingling Li
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou, 450052, Henan, P. R. China
| | - Mengya Li
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou, 450052, Henan, P. R. China
| | - Weiqiong Wang
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou, 450052, Henan, P. R. China
| | - Yanfang Liu
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou, 450052, Henan, P. R. China
| | - Shujuan Wang
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou, 450052, Henan, P. R. China
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