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Luo H, Huang Z, Mo X, Long C, Wang K, Deng R, Zhu X, Zeng Z. Synthesis of fluorinated tubastatin A derivatives with bi-, tri-, and tetracyclic cap groups: molecular docking with HDAC6 and evaluation of in vitro antitumor activity. RSC Med Chem 2025:d4md00898g. [PMID: 40027347 PMCID: PMC11865918 DOI: 10.1039/d4md00898g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Accepted: 01/30/2025] [Indexed: 03/05/2025] Open
Abstract
Herein, we report the synthesis of 16 tubastatin A derivatives with fluorinated bi-, tri-, and tetracyclic cap groups. Most derivatives show strong in vitro antitumor activity, achieving micromolar or sub-micromolar efficacy. The most promising compound, 4-(6-bromo-3,3-difluoro-1,2,3,4-tetrahydro-9H-carbozol-9-yl)methyl)-N-hydroxybenzamide (14f), demonstrated potent anti-proliferative effects against human nasopharyngeal carcinoma cells (SUNE1) and human breast cancer cells (MDA-MB-231), with IC50 values of 0.51 μM and 0.52 μM, respectively. Notably, compound 4-((8-fluoroindeno[2,1-b]indol-5(6H)-yl)-N-hydroxybenzamide (13c) exhibited significant anti-proliferative activity against pancreatic cancer cells (SW1990), with an IC50 of 2.06 μM and low cytotoxicity to normal cells. Overall, variations in the cap group from bi- to tri-, then to tetracyclic, and the introduction of fluorinated groups enhance the antitumor activity of these derivatives. Among them, difluoromethyl-modified tricyclic derivatives show a broad spectrum in vitro antitumor effect. Molecular docking studies indicate that these derivatives bind to Histone Deacetylase 6 (HDAC6) at low binding energies, ranging from -6.54 to -9.84 kcal mol-1, through metal complexation, hydrogen bonding, π-π stacking, and π-cation interactions, which correlates with their good antitumor activity. Compound 4-((2-fluoro-5,6-dihydro-7H-benzo[c]carbazol-7-yl)methyl)-N-hydroxybenzamide (13a) with the lowest binding energy of -9.84 kcal mol-1 exhibited the best in vitro antitumor activity against MCF-7, with IC50 of 1.98 μM.
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Affiliation(s)
- Huaxin Luo
- School of Chemistry, South China Normal University Guangzhou 510006 People's Republic of China
| | - Zheng Huang
- School of Chemistry, South China Normal University Guangzhou 510006 People's Republic of China
| | - Xiangdong Mo
- School of Chemistry, South China Normal University Guangzhou 510006 People's Republic of China
| | - Chunmei Long
- School of Chemistry, South China Normal University Guangzhou 510006 People's Republic of China
| | - Kaiyuan Wang
- School of Chemistry, South China Normal University Guangzhou 510006 People's Republic of China
| | - Rong Deng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center Guangzhou 510060 China
| | - Xiaofeng Zhu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center Guangzhou 510060 China
| | - Zhuo Zeng
- School of Chemistry, South China Normal University Guangzhou 510006 People's Republic of China
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Lin C, Sniezek CM, McGann CD, Karki R, Giglio RM, Garcia BA, McFaline-Figeroa JL, Schweppe DK. Defining the heterogeneous molecular landscape of lung cancer cell responses to epigenetic inhibition. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.23.592075. [PMID: 38853901 PMCID: PMC11160595 DOI: 10.1101/2024.05.23.592075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2024]
Abstract
Epigenetic inhibitors exhibit powerful antiproliferative and anticancer activities. However, cellular responses to small-molecule epigenetic inhibition are heterogenous and dependent on factors such as the genetic background, metabolic state, and on-/off-target engagement of individual small-molecule compounds. The molecular study of the extent of this heterogeneity often measures changes in a single cell line or using a small number of compounds. To more comprehensively profile the effects of small-molecule perturbations and their influence on these heterogeneous cellular responses, we present a molecular resource based on the quantification of chromatin, proteome, and transcriptome remodeling due to histone deacetylase inhibitors (HDACi) in non-isogenic cell lines. Through quantitative molecular profiling of 10,621 proteins, these data reveal coordinated molecular remodeling of HDACi treated cancer cells. HDACi-regulated proteins differ greatly across cell lines with consistent (JUN, MAP2K3, CDKN1A) and divergent (CCND3, ASF1B, BRD7) cell-state effectors. Together these data provide valuable insight into cell-type driven and heterogeneous responses that must be taken into consideration when monitoring molecular perturbations in culture models.
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Affiliation(s)
- Chuwei Lin
- Genome Sciences, University of Washington, Seattle, WA 98105, USA
| | | | | | - Rashmi Karki
- Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Ross M. Giglio
- Biomedical Engineer, Columbia University, New York, NY 10027, USA
| | - Benjamin A. Garcia
- Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA
| | | | - Devin K. Schweppe
- Genome Sciences, University of Washington, Seattle, WA 98105, USA
- Brotman Baty Institute for Precision Medicine, Seattle, Washington, USA
- Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA
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Wu X, Cao J, Wan X, Du S. Programmed cell death in hepatocellular carcinoma: mechanisms and therapeutic prospects. Cell Death Discov 2024; 10:356. [PMID: 39117626 PMCID: PMC11310460 DOI: 10.1038/s41420-024-02116-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Revised: 07/26/2024] [Accepted: 07/29/2024] [Indexed: 08/10/2024] Open
Abstract
Hepatocellular Carcinoma (HCC), the most common primary liver cancer, ranks as the third most common cause of cancer-related deaths globally. A deeper understanding of the cell death mechanisms in HCC is essential for developing more effective treatment strategies. This review explores programmed cell death (PCD) pathways involved in HCC, including apoptosis, necroptosis, pyroptosis, ferroptosis, and immunogenic cell death (ICD). These mechanisms trigger specific cell death cascades that influence the development and progression of HCC. Although multiple PCD pathways are involved in HCC, shared cellular factors suggest a possible interplay between the different forms of cell death. However, the exact roles of different cell death pathways in HCC and which cell death pathway plays a major role remain unclear. This review also highlights how disruptions in cell death pathways are related to drug resistance in cancer therapy, promoting a combined approach of cell death induction and anti-tumor treatment to enhance therapeutic efficacy. Further research is required to unravel the complex interplay between cell death modalities in HCC, which may lead to innovative therapeutic breakthroughs.
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Affiliation(s)
- Xiang'an Wu
- Department of Liver Surgery, Peking Union Medical College Hospital, PUMC and Chinese Academy of Medical Sciences, Dongcheng, Beijing, 100730, China
| | - Jingying Cao
- Zunyi Medical University, Zun Yi, Guizhou, 563000, China
| | - Xueshuai Wan
- Department of Liver Surgery, Peking Union Medical College Hospital, PUMC and Chinese Academy of Medical Sciences, Dongcheng, Beijing, 100730, China
| | - Shunda Du
- Department of Liver Surgery, Peking Union Medical College Hospital, PUMC and Chinese Academy of Medical Sciences, Dongcheng, Beijing, 100730, China.
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Chakraborty S, Nandi P, Mishra J, Niharika, Roy A, Manna S, Baral T, Mishra P, Mishra PK, Patra SK. Molecular mechanisms in regulation of autophagy and apoptosis in view of epigenetic regulation of genes and involvement of liquid-liquid phase separation. Cancer Lett 2024; 587:216779. [PMID: 38458592 DOI: 10.1016/j.canlet.2024.216779] [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: 01/13/2024] [Revised: 02/19/2024] [Accepted: 02/29/2024] [Indexed: 03/10/2024]
Abstract
Cellular physiology is critically regulated by multiple signaling nexuses, among which cell death mechanisms play crucial roles in controlling the homeostatic landscape at the tissue level within an organism. Apoptosis, also known as programmed cell death, can be induced by external and internal stimuli directing the cells to commit suicide in unfavourable conditions. In contrast, stress conditions like nutrient deprivation, infection and hypoxia trigger autophagy, which is lysosome-mediated processing of damaged cellular organelle for recycling of the degraded products, including amino acids. Apparently, apoptosis and autophagy both are catabolic and tumor-suppressive pathways; apoptosis is essential during development and cancer cell death, while autophagy promotes cell survival under stress. Moreover, autophagy plays dual role during cancer development and progression by facilitating the survival of cancer cells under stressed conditions and inducing death in extreme adversity. Despite having two different molecular mechanisms, both apoptosis and autophagy are interconnected by several crosslinking intermediates. Epigenetic modifications, such as DNA methylation, post-translational modification of histone tails, and miRNA play a pivotal role in regulating genes involved in both autophagy and apoptosis. Both autophagic and apoptotic genes can undergo various epigenetic modifications and promote or inhibit these processes under normal and cancerous conditions. Epigenetic modifiers are uniquely important in controlling the signaling pathways regulating autophagy and apoptosis. Therefore, these epigenetic modifiers of both autophagic and apoptotic genes can act as novel therapeutic targets against cancers. Additionally, liquid-liquid phase separation (LLPS) also modulates the aggregation of misfolded proteins and provokes autophagy in the cytosolic environment. This review deals with the molecular mechanisms of both autophagy and apoptosis including crosstalk between them; emphasizing epigenetic regulation, involvement of LLPS therein, and possible therapeutic approaches against cancers.
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Affiliation(s)
- Subhajit Chakraborty
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, India
| | - Piyasa Nandi
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, India
| | - Jagdish Mishra
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, India
| | - Niharika
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, India
| | - Ankan Roy
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, India
| | - Soumen Manna
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, India
| | - Tirthankar Baral
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, India
| | - Prahallad Mishra
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, India
| | - Pradyumna Kumar Mishra
- Department of Molecular Biology, ICMR-National Institute for Research in Environmental Health, Bypass Road, Bhauri, Bhopal, 462 030, MP, India
| | - Samir Kumar Patra
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, India.
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Pan J, Yu Q, Song Y, Cui Z, He Q, Cui M, Mei C, Cui H, Wang H, Li H, Chen S. Histone deacetylase 6 deficiency protects the liver against ischemia/reperfusion injury by activating PI3K/AKT/mTOR signaling. FASEB J 2024; 38:e23477. [PMID: 38334424 DOI: 10.1096/fj.202301445rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Revised: 01/14/2024] [Accepted: 01/26/2024] [Indexed: 02/10/2024]
Abstract
Liver transplantation (LT) is the only effective method to treat end-stage liver disease. Hepatic ischemia-reperfusion injury (IRI) continues to limit the prognosis of patients receiving LT. Histone deacetylase 6 (HDAC6) is a unique HDAC member involved in inflammation and apoptosis. However, its role and mechanism in hepatic IRI have not yet been reported. We examined HDAC6 levels in liver tissue from LT patients, mice challenged with liver IRI, and hepatocytes subjected to hypoxia/reoxygenation (H/R). In addition, HDAC6 global-knockout (HDAC6-KO) mice, adeno-associated virus-mediated liver-specific HDAC6 overexpressing (HDAC6-LTG) mice, and their corresponding controls were used to construct hepatic IRI models. Hepatic histology, inflammatory responses, and apoptosis were detected to assess liver injury. The molecular mechanisms of HDAC6 in hepatic IRI were explored in vivo and in vitro. Moreover, the HDAC6-selective inhibitor tubastatin A was used to detect the therapeutic effect of HDAC6 on liver IRI. Together, our results showed that HDAC6 expression was significantly upregulated in liver tissue from LT patients, mice subjected to hepatic I/R surgery, and hepatocytes challenged by hypoxia/reoxygenation (H/R) treatment. Compared with control mice, HDAC6 deficiency mitigated liver IRI by inhibiting inflammatory responses and apoptosis, whereas HDAC6-LTG mice displayed the opposite phenotype. Further molecular experiments show that HDAC6 bound to and deacetylated AKT and HDAC6 deficiency improved liver IRI by activating PI3K/AKT/mTOR signaling. In conclusion, HDAC6 is a key mediator of hepatic IRI that functions to promote inflammation and apoptosis via PI3K/AKT/mTOR signaling. Targeting hepatic HDAC6 inhibition may be a promising approach to attenuate liver IRI.
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Affiliation(s)
- Jie Pan
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Qiwen Yu
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Emergency, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, China
- Henan Emergency and Trauma Medicine Engineering Research Center, Zhengzhou, China
| | - Yaodong Song
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Emergency, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, China
- Henan Emergency and Trauma Medicine Engineering Research Center, Zhengzhou, China
| | - Zongchao Cui
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Emergency, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, China
- Henan Emergency and Trauma Medicine Engineering Research Center, Zhengzhou, China
| | - Qianqian He
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Emergency, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, China
- Henan Emergency and Trauma Medicine Engineering Research Center, Zhengzhou, China
| | - Mengwei Cui
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Emergency, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, China
- Henan Emergency and Trauma Medicine Engineering Research Center, Zhengzhou, China
| | - Chaopeng Mei
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Emergency, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, China
- Henan Emergency and Trauma Medicine Engineering Research Center, Zhengzhou, China
| | - Huning Cui
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Emergency, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, China
- Henan Emergency and Trauma Medicine Engineering Research Center, Zhengzhou, China
| | - Haifeng Wang
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Emergency, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, China
- Henan Emergency and Trauma Medicine Engineering Research Center, Zhengzhou, China
| | - Huihui Li
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Emergency, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, China
- Henan Emergency and Trauma Medicine Engineering Research Center, Zhengzhou, China
| | - Sanyang Chen
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Emergency, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, China
- Henan Emergency and Trauma Medicine Engineering Research Center, Zhengzhou, China
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Zhang M, Wang W, Ye Q, Fu Y, Li X, Yang K, Gao F, Zhou A, Wei Y, Tian S, Li S, Wei F, Shi W, Li WD. Histone deacetylase inhibitors VPA and WT161 ameliorate the pathological features and cognitive impairments of the APP/PS1 Alzheimer's disease mouse model by regulating the expression of APP secretases. Alzheimers Res Ther 2024; 16:15. [PMID: 38245771 PMCID: PMC10799458 DOI: 10.1186/s13195-024-01384-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Accepted: 01/03/2024] [Indexed: 01/22/2024]
Abstract
BACKGROUND Alzheimer's disease (AD) is a degenerative neurological disorder. Recent studies have indicated that histone deacetylases (HDACs) are among the most prominent epigenetic therapy targets and that HDAC inhibitors have therapeutic effects on AD. Here, we identified sodium valproate (VPA), a pan-HDAC inhibitor, and WT161, a novel HDAC6 selective inhibitor, as potential therapeutic agents for AD. Underlying molecular mechanisms were investigated. METHODS A cellular model, N2a-APPswe, was established via lentiviral infection, and the APPswe/PSEN1dE9 transgenic mouse model was employed in the study. LC-MS/MS was applied to quantify the concentration of WT161 in the mouse brain. Western blotting, immunohistochemical staining, thioflavin-S staining and ELISA were applied to detect protein expression in cells, tissues, or serum. RNA interference was utilized to knockdown the expression of specific genes in cells. The cognitive function of mice was assessed via the nest-building test, novel object recognition test and Morris water maze test. RESULTS Previous studies have focused mainly on the impact of HDAC inhibitors on histone deacetylase activity. Our study discovered that VPA and WT161 can downregulate the expression of multiple HDACs, such as HDAC1 and HDAC6, in both AD cell and mouse models. Moreover, they also affect the expression of APP and APP secretases (BACE1, PSEN1, ADAM10). RNA interference and subsequent vitamin C induction further confirmed that the expression of APP and APP secretases is indeed regulated by HDAC1 and HDAC6, with the JNK pathway being the intermediate link in this regulatory process. Through the above pathways, VPA and WT161 effectively reduced Aβ deposition in both AD cell and mouse models and significantly improved cognitive function in AD mice. CONCLUSIONS In general, we have discovered that the HDAC6-JNK-APP secretases cascade is an important pathway for VPA and WT161 to exert their therapeutic effects on AD. Investigations into the safety and efficacy of VPA and WT161 were also conducted, providing essential preclinical evidence for assessing these two epigenetic drugs for the treatment of AD.
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Affiliation(s)
- Miaomiao Zhang
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
- Prenatal Diagnostic Center, Yiwu Maternity and Children Hospital, Yiwu, 322000, China
| | - Wanyao Wang
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Qun Ye
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Yun Fu
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
- College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Maternity and Child Health Hospital, Fujian Medical University, Fuzhou, 350000, China
| | - Xuemin Li
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Ke Yang
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Fan Gao
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - An Zhou
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Yonghui Wei
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Shuang Tian
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Shen Li
- Laboratory of Biological Psychiatry, Institute of Mental Health, Tianjin Anding Hospital, Mental Health Center of Tianjin Medical University, Tianjin, 300222, China
| | - Fengjiang Wei
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Wentao Shi
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.
| | - Wei-Dong Li
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.
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Vuletić A, Mirjačić Martinović K, Spasić J. Role of Histone Deacetylase 6 and Histone Deacetylase 6 Inhibition in Colorectal Cancer. Pharmaceutics 2023; 16:54. [PMID: 38258065 PMCID: PMC10818982 DOI: 10.3390/pharmaceutics16010054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 12/22/2023] [Accepted: 12/27/2023] [Indexed: 01/24/2024] Open
Abstract
Histone deacetylase 6 (HDAC6), by deacetylation of multiple substrates and association with interacting proteins, regulates many physiological processes that are involved in cancer development and invasiveness such as cell proliferation, apoptosis, motility, epithelial to mesenchymal transition, and angiogenesis. Due to its ability to remove misfolded proteins, induce autophagy, and regulate unfolded protein response, HDAC6 plays a protective role in responses to stress and enables tumor cell survival. The scope of this review is to discuss the roles of HDCA6 and its implications for the therapy of colorectal cancer (CRC). As HDAC6 is overexpressed in CRC, correlates with poor disease prognosis, and is not essential for normal mammalian development, it represents a good therapeutic target. Selective inhibition of HDAC6 impairs growth and progression without inducing major adverse events in experimental animals. In CRC, HDAC6 inhibitors have shown the potential to reduce tumor progression and enhance the therapeutic effect of other drugs. As HDAC6 is involved in the regulation of immune responses, HDAC6 inhibitors have shown the potential to improve antitumor immunity by increasing the immunogenicity of tumor cells, augmenting immune cell activity, and alleviating immunosuppression in the tumor microenvironment. Therefore, HDAC6 inhibitors may represent promising candidates to improve the effect of and overcome resistance to immunotherapy.
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Affiliation(s)
- Ana Vuletić
- Department of Experimental Oncology, Institute of Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia;
| | - Katarina Mirjačić Martinović
- Department of Experimental Oncology, Institute of Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia;
| | - Jelena Spasić
- Clinic for Medical Oncology, Institute of Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia;
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Wang B, Tang C, Lin E, Jia X, Xie G, Li P, Li D, Yang Q, Guo X, Cao C, Shi X, Zou B, Cai C, Tian J, Hu Z, Li J. NIR-II fluorescence-guided liver cancer surgery by a small molecular HDAC6 targeting probe. EBioMedicine 2023; 98:104880. [PMID: 38035463 PMCID: PMC10698675 DOI: 10.1016/j.ebiom.2023.104880] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Revised: 11/05/2023] [Accepted: 11/05/2023] [Indexed: 12/02/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the sixth most common malignancy globally and ranks third in terms of both mortality and incidence rates. Surgical resection holds potential as a curative approach for HCC. However, the residual disease contributes to a high 5-year recurrence rate of 70%. Due to their excellent specificity and optical properties, fluorescence-targeted probes are deemed effective auxiliary tools for addressing residual lesions, enabling precise surgical diagnosis and treatment. Research indicates histone deacetylase 6 (HDAC6) overexpression in HCC cells, making it a potential imaging biomarker. This study designed a targeted small-molecule fluorescent probe, SeCF3-IRDye800cw (SeCF3-IRD800), operating within the Second near-infrared window (NIR-II, 1000-1700 nm). The study confirms the biocompatibility of SeCF3-IRD800 and proceeds to demonstrate its applications in imaging in vivo, fluorescence-guided surgery (FGS) for liver cancer, liver fibrosis imaging, and clinical samples incubation, thereby preliminarily validating its utility in liver cancer. METHODS SeCF3-IRD800 was synthesized by combining the near-infrared fluorescent dye IRDye800cw-NHS with an improved HDAC6 inhibitor. Initially, a HepG2-Luc subcutaneous tumor model (n = 12) was constructed to investigate the metabolic differences between SeCF3-IRD800 and ICG in vivo. Subsequently, HepG2-Luc (n = 12) and HCCLM3-Luc (n = 6) subcutaneous xenograft mouse models were used to assess in vivo targeting by SeCF3-IRD800. The HepG2-Luc orthotopic liver cancer model (n = 6) was employed to showcase the application of SeCF3-IRD800 in FGS. Liver fibrosis (n = 6) and HepG2-Luc orthotopic (n = 6) model imaging results were used to evaluate the impact of different pathological backgrounds on SeCF3-IRD800 imaging. Three groups of fresh HCC and normal liver samples from patients with liver cancer were utilized for SeCF3-IRD800 incubation ex vivo, while preclinical experiments illustrated its potential for clinical application. FINDINGS The HDAC6 inhibitor 6 (SeCF3) modified with trifluoromethyl was labeled with IRDy800CW-NHS to synthesize the small-molecule targeted probe SeCF3-IRD800, with NIR-II fluorescence signals. SeCF3-IRD800 was rapidly metabolized by the kidneys and exhibited excellent biocompatibility. In vivo validation demonstrated that SeCF3-IRD800 achieved optimal imaging within 8 h, displaying high tumor fluorescence intensity (7658.41 ± 933.34) and high tumor-to-background ratio (5.20 ± 1.04). Imaging experiments with various expression levels revealed its capacity for HDAC6-specific targeting across multiple HCC tumor models, suitable for NIR-II intraoperative imaging. Fluorescence-guided surgery experiments were found feasible and capable of detecting sub-visible 2 mm tumor lesions under white light, aiding surgical decision-making. Further imaging of liver fibrosis mice showed that SeCF3-IRD800's imaging efficacy remained unaffected by liver pathological conditions. Correlations were observed between HDAC6 expression levels and corresponding fluorescence intensity (R2 = 0.8124) among normal liver, liver fibrosis, and HCC tissues. SeCF3-IRD800 identified HDAC6-positive samples from patients with HCC, holding advantages for perspective intraoperative identification in liver cancer. Thus, the rapidly metabolized HDAC6-targeted small-molecule NIR-II fluorescence probe SeCF3-IRD800 holds significant clinical translational value. INTERPRETATION The successful application of NIR-II fluorescence-guided surgery in liver cancer indicates that SeCF3-IRD800 has great potential to improve the clinical diagnosis and treatment of liver cancer, and could be used as an auxiliary tool for surgical treatment of liver cancer without being affected by liver pathology. FUNDING This paper is supported by the National Natural Science Foundation of China (NSFC) (92,059,207, 62,027,901, 81,930,053, 81,227,901, 82,272,105, U21A20386 and 81,971,773), CAS Youth Interdisciplinary Team (JCTD-2021-08), the Zhuhai High-level Health Personnel Team Project (Zhuhai HLHPTP201703), and Guangdong Basic and Applied Basic Research Foundation under Grant No. 2022A1515011244.
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Affiliation(s)
- Bo Wang
- Department of Hepatobiliary Surgery and Liver Transplantation, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, 519000, China; CAS Key Laboratory of Molecular Imaging, Beijing Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China
| | - Chu Tang
- Engineering Research Center of Molecular and Neuro Imaging of Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, 710071, China
| | - En Lin
- Department of Hepatobiliary Surgery and Liver Transplantation, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, 519000, China; CAS Key Laboratory of Molecular Imaging, Beijing Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China
| | - Xiaohua Jia
- CAS Key Laboratory of Molecular Imaging, Beijing Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China; School of Artificial Intelligence, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Ganyuan Xie
- Department of Hepatobiliary Surgery and Liver Transplantation, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, 519000, China
| | - Peiping Li
- Department of Hepatobiliary Surgery and Liver Transplantation, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, 519000, China
| | - Decheng Li
- Department of Hepatobiliary Surgery and Liver Transplantation, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, 519000, China
| | - Qiyue Yang
- Key Laboratory of Digital Hepatobiliary Surgery, PLA, Institute of Hepatobiliary Surgery of Chinese PLA, Beijing, 100048, China
| | - Xiaoyong Guo
- CAS Key Laboratory of Molecular Imaging, Beijing Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China; Clinical College of Armed Police General Hospital of Anhui Medical University, Department of Gastroenterology of The Third Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Caiguang Cao
- CAS Key Laboratory of Molecular Imaging, Beijing Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China; School of Artificial Intelligence, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xiaojing Shi
- CAS Key Laboratory of Molecular Imaging, Beijing Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China; School of Artificial Intelligence, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Baojia Zou
- Department of Hepatobiliary Surgery and Liver Transplantation, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, 519000, China
| | - Chaonong Cai
- Department of Hepatobiliary Surgery and Liver Transplantation, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, 519000, China
| | - Jie Tian
- CAS Key Laboratory of Molecular Imaging, Beijing Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China; School of Artificial Intelligence, University of Chinese Academy of Sciences, Beijing, 100049, China; Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, School of Engineering Medicine, Beihang University, Beijing, 100191, China; Engineering Research Center of Molecular and Neuro Imaging of Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, 710071, China.
| | - Zhenhua Hu
- CAS Key Laboratory of Molecular Imaging, Beijing Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China; School of Artificial Intelligence, University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Jian Li
- Department of Hepatobiliary Surgery and Liver Transplantation, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, 519000, China.
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9
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Nguyen TH, Nguyen TM, Ngoc DTM, You T, Park MK, Lee CH. Unraveling the Janus-Faced Role of Autophagy in Hepatocellular Carcinoma: Implications for Therapeutic Interventions. Int J Mol Sci 2023; 24:16255. [PMID: 38003445 PMCID: PMC10671265 DOI: 10.3390/ijms242216255] [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: 09/07/2023] [Revised: 11/02/2023] [Accepted: 11/08/2023] [Indexed: 11/26/2023] Open
Abstract
This review aims to provide a comprehensive understanding of the molecular mechanisms underlying autophagy and mitophagy in hepatocellular carcinoma (HCC). Autophagy is an essential cellular process in maintaining cell homeostasis. Still, its dysregulation is associated with the development of liver diseases, including HCC, which is one of leading causes of cancer-related death worldwide. We focus on elucidating the dual role of autophagy in HCC, both in tumor initiation and progression, and highlighting the complex nature involved in the disease. In addition, we present a detailed analysis of a small subset of autophagy- and mitophagy-related molecules, revealing their specific functions during tumorigenesis and the progression of HCC cells. By understanding these mechanisms, we aim to provide valuable insights into potential therapeutic strategies to manipulate autophagy effectively. The goal is to improve the therapeutic response of liver cancer cells and overcome drug resistance, providing new avenues for improved treatment options for HCC patients. Overall, this review serves as a valuable resource for researchers and clinicians interested in the complex role of autophagy in HCC and its potential as a target for innovative therapies aimed to combat this devastating disease.
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Affiliation(s)
- Thi Ha Nguyen
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea
| | - Tuan Minh Nguyen
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea
| | | | - Taesik You
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea
| | - Mi Kyung Park
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy National Cance Center, Goyang 10408, Republic of Korea
- Department of Bio-Healthcare, Hwasung Medi-Science University, Hwaseong-si 18274, Republic of Korea
| | - Chang Hoon Lee
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea
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10
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Sofi FA, Tabassum N. Natural product inspired leads in the discovery of anticancer agents: an update. J Biomol Struct Dyn 2023; 41:8605-8628. [PMID: 36255181 DOI: 10.1080/07391102.2022.2134212] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 10/03/2022] [Indexed: 10/24/2022]
Abstract
Natural products have emerged as major leads for the discovery and development of new anti-cancer drugs. The plant-derived anti-cancer drugs account for approximately 60% and the quest for new anti-cancer agents is in progress. Anti-cancer leads have been isolated from plants, animals, marine organisms, and microorganisms from time immemorial. The process of semisynthetic modifications of the parent lead has led to the generation of new anti-cancer agents with improved therapeutic efficacy and minimal side effects. The various chemo-informatics tools, bioinformatics, high-throughput screening, and combinatorial synthesis are able to deliver the new natural product lead molecules. Plant-derived anticancer agents in either late preclinical development or early clinical trials include taxol, vincristine, vinblastine, topotecan, irinotecan, etoposide, paclitaxel, and docetaxel. Similarly, anti-cancer agents from microbial sources include dactinomycin, bleomycin, mitomycin C, and doxorubicin. In this review, we highlighted the importance of natural products leads in the discovery and development of novel anti-cancer agents. The semisynthetic modifications of the parent lead to the new anti-cancer agent are also presented. Further, the leads in the preclinical settings with the potential to become effective anticancer agents are also reviewed.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Firdoos Ahmad Sofi
- Department of Pharmaceutical Sciences, School of Applied Sciences and Technology, University of Kashmir, Srinagar, Jammu & Kashmir, India
| | - Nahida Tabassum
- Department of Pharmaceutical Sciences, School of Applied Sciences and Technology, University of Kashmir, Srinagar, Jammu & Kashmir, India
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11
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Xu J, Li Y, Kang M, Chang C, Wei H, Zhang C, Chen Y. Multiple forms of cell death: A focus on the PI3K/AKT pathway. J Cell Physiol 2023; 238:2026-2038. [PMID: 37565518 DOI: 10.1002/jcp.31087] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 07/10/2023] [Accepted: 07/17/2023] [Indexed: 08/12/2023]
Abstract
Cell death is a natural biological process that occurs in living organisms. Since 1963, extensive research has shed light on the occurrence, progress, and final outcome of cell death. According to different cell phenotypes, it is classified into different types, including apoptosis, pyroptosis, necroptosis, autophagy, ferroptosis, cuproptosis, and so on. However, regardless of the form of cell death, what we ultimately expect is the disappearance of abnormal cells, such as tumor cells, while normal cells survive. As a result, it is vital to investigate the details of cell death, including death triggers, potent regulators, and executioners. Although significant progress has been made in understanding molecular pathways of cell death, many aspects remain unclear because of the complex regulatory networks in cells. Among them, the phosphoinositide-3-kinase (PI3K)/protein kinase B(AKT) pathway is discovered to be a crucial regulator of the cell death process. AKT, as a proto-oncogene, has become a major focus of attention in the medical community due to its role in regulating a multiplicity of cellular functions counting metabolism, immunity, proliferation, survival, transcription, and protein synthesis. Here, we explored the connection between the PI3K/AKT pathway and cell death, aiming to enhance our comprehension of the mechanism underlying this process. Such knowledge may pave the way for the subsequent development of more effective disease treatments, such as finding suitable targets for drug intervention.
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Affiliation(s)
- Jiawei Xu
- Department of Medical Science Research Center, Peihua University, Xi'an, Shaanxi, China
| | - Yu Li
- Department of Medical Science Research Center, Peihua University, Xi'an, Shaanxi, China
| | - Meili Kang
- Department of Medical Science Research Center, Peihua University, Xi'an, Shaanxi, China
| | - Cuicui Chang
- Department of Medical Science Research Center, Peihua University, Xi'an, Shaanxi, China
| | - Hong Wei
- Department of Rehabilitation Teaching and Research, Xi'an Siyuan University, Xi'an, China
| | - Chi Zhang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
- The Institute of Skull Base Surgery and Neurooncology at Hunan Province, Changsha, China
| | - Yuhua Chen
- Department of Neurosurgery, Life Science Research Laboratory, Bijie Traditional Chinese Medicine Hospital, Bijie, China
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12
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Dey DK, Sharma C, Vadlamudi Y, Kang SC. CopA3 peptide inhibits MDM2-p53 complex stability in colorectal cancers and activates p53 mediated cell death machinery. Life Sci 2023; 318:121476. [PMID: 36758667 DOI: 10.1016/j.lfs.2023.121476] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 01/23/2023] [Accepted: 02/02/2023] [Indexed: 02/10/2023]
Abstract
The diverse expression patterns of the tumor suppressor p53 in cancer cells reflect the regulatory efficiency of multiple cellular pathways. By contrast, many human tumors are reported to develop in the presence of wild-type p53. Recently, several oncogene inhibitors have been used clinically to suppress tumor development by functionally reactivating other oncoproteins. On the other hand, p53 reactivation therapies have not been well established, as few of the p53-MDM2 complex inhibitors such as Nutlin-3 induces mutation in p53 gene upon prolonged usage. Therefore, in this study CopA3, a 9-mer dimeric D-type peptide with anticancer activity against the human colorectal cancer cells, was used to explore the efficacy of p53 reactivation in-vitro and in-vivo. The anticancer activity of CopA3 was more selective towards the wild-type p53 expressing cells than the p53 deficient or mutant colorectal cancer cells. In response to this, this study investigated the signaling pathway in vitro and validated its anti-tumor activity in-vivo. The protein-peptide interaction and molecular docking efficiently provided insight into the specific binding affinity of CopA3 to the p53-binding pocket of the MDM2 protein, which efficiently blocked the p53 and MDM2 interaction. CopA3 plays a crucial role in the binding with MDM2 and enhanced the nuclear translocation of the p53 protein, which sequentially activated the downstream targets to trigger the autophagic mediated cell death machinery through the JNK/Beclin-1 mediated pathway. Collectively, CopA3 affected the MDM2-p53 interaction, which suppressed tumor development. This study may provide a novel inhibitor candidate for the MDM2-p53 complex, which could ultimately suppress the growth of colorectal cancer cells without being cytotoxic to the healthy neighboring cells present around the tumor microenvironment.
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Affiliation(s)
- Debasish Kumar Dey
- Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Biotechnology, Daegu University, Gyeongsan, Gyeongbuk 38453, Republic of Korea
| | - Chanchal Sharma
- Department of Biotechnology, Daegu University, Gyeongsan, Gyeongbuk 38453, Republic of Korea
| | - Yellamandayya Vadlamudi
- Department of Biotechnology, Daegu University, Gyeongsan, Gyeongbuk 38453, Republic of Korea
| | - Sun Chul Kang
- Department of Biotechnology, Daegu University, Gyeongsan, Gyeongbuk 38453, Republic of Korea.
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13
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Kakoty V, Kc S, Kumari S, Yang CH, Dubey SK, Sahebkar A, Kesharwani P, Taliyan R. Brain insulin resistance linked Alzheimer's and Parkinson's disease pathology: An undying implication of epigenetic and autophagy modulation. Inflammopharmacology 2023; 31:699-716. [PMID: 36952096 DOI: 10.1007/s10787-023-01187-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Accepted: 02/25/2023] [Indexed: 03/24/2023]
Abstract
In metabolic syndrome, dysregulated signalling activity of the insulin receptor pathway in the brain due to persistent insulin resistance (IR) condition in the periphery may lead to brain IR (BIR) development. BIR causes an upsurge in the activity of glycogen synthase kinase-3 beta, increased amyloid beta (Aβ) accumulation, hyperphosphorylation of tau, aggravated formation of Aβ oligomers and simultaneously neurofibrillary tangle formation, all of which are believed to be direct contributors in Alzheimer's Disease (AD) pathology. Likewise, for Parkinson's Disease (PD), BIR is associated with alpha-synuclein alterations, dopamine loss in brain areas which ultimately succumbs towards the appearance of classical motor symptoms corresponding to the typical PD phenotype. Modulation of the autophagy process for clearing misfolded proteins and alteration in histone proteins to alleviate disease progression in BIR-linked AD and PD have recently evolved as a research hotspot, as the majority of the autophagy-related proteins are believed to be regulated by histone posttranslational modifications. Hence, this review will provide a timely update on the possible mechanism(s) converging towards BIR induce AD and PD. Further, emphasis on the potential epigenetic regulation of autophagy that can be effectively targeted for devising a complete therapeutic cure for BIR-induced AD and PD will also be reviewed.
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Affiliation(s)
- Violina Kakoty
- School of Pharmaceutical Sciences, Lovely Professional University, Punjab, India, Jalandhar-Delhi G.T Road, Phagwara
- Neuropsychopharmacology Division, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Pilani Campus, Pilani, Rajasthan, India
| | - Sarathlal Kc
- Neuropsychopharmacology Division, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Pilani Campus, Pilani, Rajasthan, India
- Department of Non-Communicable Disease, Translational Health Science and Technology Institute, Faridabad, India
| | - Shobha Kumari
- Neuropsychopharmacology Division, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Pilani Campus, Pilani, Rajasthan, India
| | - Chih-Hao Yang
- Department of Pharmacology, Taipei Medical University, Taipei, Taiwan
| | - Sunil Kumar Dubey
- Medical Research, R&D Healthcare Division, Emami Ltd, 13, BT Road, Belgharia, Kolkata, India
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India.
- Center for Transdisciplinary Research, Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Science, Chennai, India.
- University Institute of Pharma Sciences, Chandigarh University, Mohali, Punjab, India.
| | - Rajeev Taliyan
- Neuropsychopharmacology Division, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Pilani Campus, Pilani, Rajasthan, India.
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14
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HDAC6 promotes aggressive development of liver cancer by improving egfr mRNA stability. Neoplasia 2022; 35:100845. [PMID: 36334332 PMCID: PMC9640351 DOI: 10.1016/j.neo.2022.100845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 10/12/2022] [Indexed: 11/07/2022] Open
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15
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Liu YF, Chiang Y, Hsu FM, Tsai CL, Cheng JCH. Radiosensitization effect by HDAC inhibition improves NKG2D-dependent natural killer cytotoxicity in hepatocellular carcinoma. Front Oncol 2022; 12:1009089. [PMID: 36185276 PMCID: PMC9520006 DOI: 10.3389/fonc.2022.1009089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 08/26/2022] [Indexed: 01/27/2023] Open
Abstract
Background Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Radiotherapy (RT) controls HCC unsatisfactorily and temporarily. Histone deacetylase inhibitor (HDACi) is a heterogeneous group of epigenetic therapeutics with promising anticancer effects and synergism in combination with RT. HDACi modulates natural killer (NK) cell ligand expression on tumor cells, and leads to immune evasion of cancer cells. Expressions of NK group 2D (NKG2D) ligands on cancer cells determine the cytotoxic effect by interacting with NKG2D receptor on NK cells. However, the role of NKG2D signaling in HCC upon combined RT and HDACi remains unclear. Method In vitro co-culture system with NK cells was tested for human and murine HCC cell lines. Pan-HDACi (panobinostat) and specific HDAC4 knockdown (HDAC4-KD) were used for HDAC inhibition. Clonogenic assay and flow cytometry examined HCC cell survival and NKG2D ligand expression, respectively. Syngeneic mouse model was used to validate the radiosensitizing effect in vivo. Results Combined RT and HDACi/HDAC4-KD significantly enhanced NK cell-related cytotoxicity and increased NKG2D ligands, MICA/MICB expressions in human and RAE-1/H60 expressions in murine HCC cells. Delayed tumor growth in vivo by the combinational treatment of RT and HDACi/HDAC4-KD was shown with the associated NKG2D ligand expressions. However, NKG2D receptor did not significantly change among tumors. Conclusion Radiosensitizing effect with combined RT and HDAC inhibition increased the expression of NKG2D ligands in HCC cells and enhanced their susceptibility to NK cell-mediated cytotoxicity. These findings imply the potential use of combined RT/HDACi and NK cell-directed immunotherapy.
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Affiliation(s)
- Yu-Fan Liu
- Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yun Chiang
- Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Feng-Ming Hsu
- Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chiao-Ling Tsai
- Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan
- *Correspondence: Jason Chia-Hsien Cheng, ; Chiao-Ling Tsai,
| | - Jason Chia-Hsien Cheng
- Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
- *Correspondence: Jason Chia-Hsien Cheng, ; Chiao-Ling Tsai,
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16
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Rahmati A, Homayouni Tabrizi M, Karimi E, Zarei B. Fabrication and assessment of folic acid conjugated-chitosan modified PLGA nanoparticle for delivery of alpha terpineol in colon cancer. JOURNAL OF BIOMATERIALS SCIENCE. POLYMER EDITION 2022; 33:1289-1307. [PMID: 35260045 DOI: 10.1080/09205063.2022.2051693] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
The objective of this study was to fabrication of α-terpineol-PLGA nanoparticles coated with folic acid-chitosan (αT-PCF-NPs) as well as evaluates their anticancer effects. αT-PCF-NPs were synthesized using the nanoprecipitation method and characterized by Dynamic light scattering (DLS), zeta potential (ZP), scanning electron microscope (SEM), Fourier transform infrared spectroscopy (FTIR) analysis. Folic acid (FA) binding rate and entrapment efficiency of α-T were assessed by HPLC method. MTT assay was performed for cytotoxicity assessment. Quantitative polymerase chain reaction (qPCR) analysis, acridine orange and propodium iodide (AO/PI) staining and cell cycle analysis were done to assess the pro-apoptotic properties of αT-PCF-NPs. Molecular analysis for angiogenesis and antioxidant properties and murine colon cancer model for antitumor effects of αT-PCF-NPs were used. The % FA-binding and encapsulation efficiency of α-T in αT-PCF-NPs (particle size of 263.95 nm, polydispersity index (PDI) of 0.25, and surface charge of +38.20 mV) was reported to be 67% and 88.1% respectively. The higher inhibitory effect of αT-PCF-NPs on cancer cells compared to HFF cells was confirmed. The pro-apoptotic effect of αT-PCF-NPs was showed by increased SubG1 phase cells, AO/PI staining results and up and down regulation Bax and Bcl-2 as pro and anti-apoptotic genes in HT-29 cells. Antioxidant (SOD) and angiogenesis genes (VEGF and VEGF-R) were inhibited by αT-PCF-NPs exposure in HT-29 cells and also decreased the size of murine tumors was confirmed in exposure of αT-PCF-NPs. αT-PCF-NPs can be considered as a promising anticancer drug for colon cancer.
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Affiliation(s)
- Amir Rahmati
- Department of Biology, Mashhad Branch, Islamic Azad University, Mashhad, Iran
| | | | - Ehsan Karimi
- Department of Biology, Mashhad Branch, Islamic Azad University, Mashhad, Iran
| | - Bahar Zarei
- Department of Biology, Mashhad Branch, Islamic Azad University, Mashhad, Iran
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17
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Liu J, Liu B, Diao G, Zhang Z. Tissue factor promotes HCC carcinogenesis by inhibiting BCL2-dependent autophagy. Bull Cancer 2022; 109:795-804. [DOI: 10.1016/j.bulcan.2022.04.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 03/23/2022] [Accepted: 04/05/2022] [Indexed: 10/18/2022]
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18
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Phorl S, Memon A, Seo Y, Thi Oanh H, Trung Nghia T, Nguyen LMT, Lee CH, Lee WK, Lee JY. Opposing roles of HDAC6 in liver regeneration and hepatocarcinogenesis. Cancer Sci 2022; 113:2311-2322. [PMID: 35534985 PMCID: PMC9277267 DOI: 10.1111/cas.15391] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 04/20/2022] [Accepted: 04/30/2022] [Indexed: 11/30/2022] Open
Abstract
Histone deacetylase 6 (HDAC6), a deacetylase of p53, has emerged as a privileged inhibitory target for cancer therapy because of its deacetylating activity for p53 at K120 and K373/382. However, intricate roles of HDAC6 in hepatocellular carcinogenesis have been suggested by recent evidence, namely that HDAC6 ablation suppresses innate immunity, which plays critical roles in tumor immunosurveillance and antitumor immune responses. Therefore, it is valuable to determine whether HDAC6 ablation inhibits hepatocellular carcinogenesis using in vivo animal models. Here, we firstly showed that HDAC6 ablation increased K320 acetylation of p53, known as pro‐survival acetylation, in all tested animal models but did not always increase K120 and K373/382 acetylation of p53, known as pro‐apoptotic acetylation. HDAC6 ablation induced cellular senescence in primary MEFs and inhibited cell proliferation in HepG2 cells and liver regeneration after two‐thirds partial hepatectomy. However, the genetic ablation of HDAC6 did not inhibit hepatocarcinogenesis, but instead slightly enhanced it in two independent mouse models (DEN + HFD and DEN + TAA). Notably, HDAC6 ablation significantly promoted hepatocarcinogenesis in a multiple DEN treatment hepatocellular carcinoma (HCC) mouse model, mimicking chronic DNA damage in the liver, which correlated with hyperacetylation at K320 of p53 and a decrease in inflammatory cytokines and chemokines. Our data from three independent in vivo animal HCC models emphasize the importance of the complex roles of HDAC6 ablation in hepatocellular carcinogenesis, highlighting its immunosuppressive effects. We provide the first evidence that HDAC6 is a p53 deacetylase at K320, which is especially important for cancer cell survival in chronic DNA damage conditions. Contrary to the general assumption that HDAC6 inhibition leads to hyperacetylation of p53 at K120, resulting in tumor suppression, our findings from in vivo animal HCC modelsemphasize the importance of the opposing roles of HDAC6 ablation in hepatocellular carcinogenesis by highlighting the K320 acetylation of p53 and immunosuppressive effects.
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Affiliation(s)
- Sophors Phorl
- Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, 305-764, Republic of Korea
| | - Azra Memon
- Department of Biomedical Sciences, School of Medicine, Inha University, Incheon, 22212, Republic of Korea
| | - Yuri Seo
- Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, 305-764, Republic of Korea
| | - Hoang Thi Oanh
- Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, 305-764, Republic of Korea
| | - Tran Trung Nghia
- Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, 305-764, Republic of Korea
| | - Le Minh Tri Nguyen
- Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, 305-764, Republic of Korea
| | - Chang Hoon Lee
- Center for Drug Platform Technology, Korea Research Institute of Chemical Technology, Daejeon, 305-343, Republic of Korea
| | - Woon Kyu Lee
- Department of Biomedical Sciences, School of Medicine, Inha University, Incheon, 22212, Republic of Korea
| | - Joo-Yong Lee
- Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, 305-764, Republic of Korea
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Pang Y, Lin W, Zhan L, Zhang J, Zhang S, Jin H, Zhang H, Wang X, Li X. Inhibiting Autophagy Pathway of PI3K/AKT/mTOR Promotes Apoptosis in SK-N-SH Cell Model of Alzheimer's Disease. JOURNAL OF HEALTHCARE ENGINEERING 2022; 2022:6069682. [PMID: 35178230 PMCID: PMC8846974 DOI: 10.1155/2022/6069682] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 12/22/2021] [Accepted: 12/31/2021] [Indexed: 01/31/2023]
Abstract
Alzheimer's disease is the most common dementia disease characterized by chronic progressive neurodegeneration. The incidence of Alzheimer's disease is on the rise as the population ages at an accelerating pace. According to epidemiological data, by 2050, the number of Alzheimer's patients in the United States will be three times higher than that in 2010, and a similar trend is occurring in China. To explore the effect and mechanism of let-7b by detecting the expression level of let-7b in Alzheimer's disease, fifty patients with Alzheimer's disease and thirty healthy controls were selected. The expression levels of let-7 families (let-7a, let-7b, let-7c, let-7d, let-7e, let-7f, let-7g, and let-7i) were detected by qPCR. Human neuroblastoma cell SK-N-SH were divided into control group (untreated), model group (treated with Aβ1-40), Aβ1-40+let-7b mimic group (treated with Aβ1-40 and transfected with let-7b mimic), and Aβ1-40+miR-NC group (treated with aβ1-40 and transfected with miR-NC). let-7b expression and cell survival rate were detected by qPCR and CCK-8, and the levels of caspase 3, LC3, beclin-1, PI3K, p-AKT, and p-mTOR were detected by Western blot. let-7b was significantly different between the case group and the control group (p < 0.001). CCK-8 showed a significant decrease in cell viability in Aβ1-40 treatment group compared with that in the control group (p < 0.01). Overexpression of let-7b significantly reduced the survival rate of the cells, and the expression of LC3II/LC3I and beclin-1 in the cells was significantly reduced by aβ1-40 treatment (p < 0.001). let-7b overexpression also inhibited autophagy via reducing the level of LC3II/LC3I and beclin-1 (p < 0.001). Aβ1-40 treatment and let-7b overexpression promoted apoptosis by increasing the expression of cleavage caspase 3. Western blot indicated that Aβ1-40 treatment and let-7b overexpression could increase the expression of PI3K, p-AKT, and p-mTOR. let-7b overexpression could inhibit autophagy and promote apoptosis in Alzheimer's cells by promoting PI3K/AKT/mTOR signaling pathway. PI3K/AKT/mTOR signaling pathway is involved in the imbalance between autophagy and apoptosis.
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Affiliation(s)
- Yu Pang
- Department of Neurology, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar 161000, China
| | - Wennan Lin
- General Department, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar 161000, China
| | - Lan Zhan
- Department of Neurology, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar 161000, China
| | - Jiawen Zhang
- Department of Neurology, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar 161000, China
| | - Shicun Zhang
- Department of Neurology, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar 161000, China
| | - Hongwei Jin
- Department of Neurology, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar 161000, China
| | - He Zhang
- Department of Neurology, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar 161000, China
| | - Xiaoli Wang
- School of Pharmacy, Qiqihar Medical University, Qiqihar 161000, China
| | - Xiaoming Li
- The Institute of Medicine, Qiqihar Medical University, Qiqihar 161000, China
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20
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Zhou B, Liu D, Tan Y. Role of HDAC6 and Its Selective Inhibitors in Gastrointestinal Cancer. Front Cell Dev Biol 2021; 9:719390. [PMID: 34938729 PMCID: PMC8687743 DOI: 10.3389/fcell.2021.719390] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 11/08/2021] [Indexed: 12/24/2022] Open
Abstract
Worldwide, cancer is the second leading cause of mortality after cardiovascular diseases. Among the numerous malignant tumors in human, digestive system cancers are the primary cause of morbidity and mortality. Acetylation and deacetylation are crucially involved in cancer occurrence and development; in addition, the deacetylation process is regulated by histone deacetylases (HDACs). Among the 18 human HDACs that have been reported, HDAC6 has been widely studied. There is upregulated HDAC6 expression in numerous types of tumor tissues and is closely associated with clinicopathological characteristics. Moreover, several HDAC6 inhibitors have been identified; furthermore, there has been extensive research on their ability to inhibit the growth of many tumors. This review summarizes the roles of HDAC6 in different primary digestive system malignancies.
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Affiliation(s)
- Bingyi Zhou
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, China.,Research Center of Digestive Disease, Central South University, Changsha, China
| | - Deliang Liu
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, China.,Research Center of Digestive Disease, Central South University, Changsha, China
| | - Yuyong Tan
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, China.,Research Center of Digestive Disease, Central South University, Changsha, China
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21
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Trisciuoglio D, Degrassi F. The Tubulin Code and Tubulin-Modifying Enzymes in Autophagy and Cancer. Cancers (Basel) 2021; 14:cancers14010006. [PMID: 35008169 PMCID: PMC8750717 DOI: 10.3390/cancers14010006] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 12/15/2021] [Accepted: 12/16/2021] [Indexed: 12/17/2022] Open
Abstract
Simple Summary Microtubules are tubulin polymers that constitute the structure of eukaryotic cells. They control different cell functions that are often deregulated in cancer, such as cell shape, cell motility and the intracellular movement of organelles. Here, we focus on the crucial role of tubulin modifications in determining different cancer characteristics, including metastatic cell migration and therapy resistance. We also discuss the influence of microtubule modifications on the autophagic process—the cellular degradation pathway that influences cancer growth. We discuss findings showing that inducing microtubule modifications can be used as a means to kill cancer cells by inhibiting autophagy. Abstract Microtubules are key components of the cytoskeleton of eukaryotic cells. Microtubule dynamic instability together with the “tubulin code” generated by the choice of different α- and β- tubulin isoforms and tubulin post-translational modifications have essential roles in the control of a variety of cellular processes, such as cell shape, cell motility, and intracellular trafficking, that are deregulated in cancer. In this review, we will discuss available evidence that highlights the crucial role of the tubulin code in determining different cancer phenotypes, including metastatic cell migration, drug resistance, and tumor vascularization, and the influence of modulating tubulin-modifying enzymes on cancer cell survival and aggressiveness. We will also discuss the role of post-translationally modified microtubules in autophagy—the lysosomal-mediated cellular degradation pathway—that exerts a dual role in many cancer types, either promoting or suppressing cancer growth. We will give particular emphasis to the role of tubulin post-translational modifications and their regulating enzymes in controlling the different stages of the autophagic process in cancer cells, and consider how the experimental modulation of tubulin-modifying enzymes influences the autophagic process in cancer cells and impacts on cancer cell survival and thereby represents a new and fruitful avenue in cancer therapy.
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22
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Enhancing Therapeutic Approaches for Melanoma Patients Targeting Epigenetic Modifiers. Cancers (Basel) 2021; 13:cancers13246180. [PMID: 34944799 PMCID: PMC8699560 DOI: 10.3390/cancers13246180] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/30/2021] [Accepted: 12/03/2021] [Indexed: 12/25/2022] Open
Abstract
Melanoma is the least common but deadliest type of skin cancer. Melanomagenesis is driven by a series of mutations and epigenetic alterations in oncogenes and tumor suppressor genes that allow melanomas to grow, evolve, and metastasize. Epigenetic alterations can also lead to immune evasion and development of resistance to therapies. Although the standard of care for melanoma patients includes surgery, targeted therapies, and immune checkpoint blockade, other therapeutic approaches like radiation therapy, chemotherapy, and immune cell-based therapies are used for patients with advanced disease or unresponsive to the conventional first-line therapies. Targeted therapies such as the use of BRAF and MEK inhibitors and immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA4 only improve the survival of a small subset of patients. Thus, there is an urgent need to identify alternative standalone or combinatorial therapies. Epigenetic modifiers have gained attention as therapeutic targets as they modulate multiple cellular and immune-related processes. Due to melanoma's susceptibility to extrinsic factors and reversible nature, epigenetic drugs are investigated as a therapeutic avenue and as adjuvants for targeted therapies and immune checkpoint inhibitors, as they can sensitize and/or reverse resistance to these therapies, thus enhancing their therapeutic efficacy. This review gives an overview of the role of epigenetic changes in melanoma progression and resistance. In addition, we evaluate the latest advances in preclinical and clinical research studying combinatorial therapies and discuss the use of epigenetic drugs such as HDAC and DNMT inhibitors as potential adjuvants for melanoma patients.
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23
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Chang P, Li H, Hu H, Li Y, Wang T. The Role of HDAC6 in Autophagy and NLRP3 Inflammasome. Front Immunol 2021; 12:763831. [PMID: 34777380 PMCID: PMC8578992 DOI: 10.3389/fimmu.2021.763831] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 09/28/2021] [Indexed: 12/12/2022] Open
Abstract
Autophagy fights against harmful stimuli and degrades cytosolic macromolecules, organelles, and intracellular pathogens. Autophagy dysfunction is associated with many diseases, including infectious and inflammatory diseases. Recent studies have identified the critical role of the NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasomes activation in the innate immune system, which mediates the secretion of proinflammatory cytokines IL-1β/IL-18 and cleaves Gasdermin D to induce pyroptosis in response to pathogenic and sterile stimuli. Accumulating evidence has highlighted the crosstalk between autophagy and NLRP3 inflammasome in multifaceted ways to influence host defense and inflammation. However, the underlying mechanisms require further clarification. Histone deacetylase 6 (HDAC6) is a class IIb deacetylase among the 18 mammalian HDACs, which mainly localizes in the cytoplasm. It is involved in two functional deacetylase domains and a ubiquitin-binding zinc finger domain (ZnF-BUZ). Due to its unique structure, HDAC6 regulates various physiological processes, including autophagy and NLRP3 inflammasome, and may play a role in the crosstalk between them. In this review, we provide insight into the mechanisms by which HDAC6 regulates autophagy and NLRP3 inflammasome and we explored the possibility and challenges of HDAC6 in the crosstalk between autophagy and NLRP3 inflammasome. Finally, we discuss HDAC6 inhibitors as a potential therapeutic approach targeting either autophagy or NLRP3 inflammasome as an anti-inflammatory strategy, although further clarification is required regarding their crosstalk.
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Affiliation(s)
- Panpan Chang
- Trauma Medicine Center, Peking University People's Hospital, Key Laboratory of Trauma and Neural Regeneration (Peking University), National Center for Trauma Medicine of China, Beijing, China
| | - Hao Li
- Department of Emergency, First Hospital of China Medical University, Shenyang, China
| | - Hui Hu
- Department of Traumatology, Central Hospital of Chongqing University, Chongqing Emergency Medical Center, Chongqing, China
| | - Yongqing Li
- Department of Surgery, University of Michigan, Ann Arbor, MI, United States
| | - Tianbing Wang
- Trauma Medicine Center, Peking University People's Hospital, Key Laboratory of Trauma and Neural Regeneration (Peking University), National Center for Trauma Medicine of China, Beijing, China
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24
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Kwon Y, Choi Y, Kim M, Jeong MS, Jung HS, Jeoung D. HDAC6 and CXCL13 Mediate Atopic Dermatitis by Regulating Cellular Interactions and Expression Levels of miR-9 and SIRT1. Front Pharmacol 2021; 12:691279. [PMID: 34588978 PMCID: PMC8473914 DOI: 10.3389/fphar.2021.691279] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 08/30/2021] [Indexed: 12/16/2022] Open
Abstract
Histone deacetylase 6 (HDAC6) has been known to regulate inflammatory diseases. The role of HDAC6 in allergic skin inflammation has not been studied. We studied the role of HDAC6 in atopic dermatitis (AD) and the mechanisms associated with it. The decreased expression or chemical inhibition of HDAC6 suppressed AD by decreasing autophagic flux and cellular features of AD. AD increased expression levels of the Th1 and Th2 cytokines, but decreased expression levels of forkhead box P3 (FoxP3) and interleukin-10 (IL-10) in an HDAC6-dependent manner. CXC chemokine ligand 13 (CXCL13), which was increased in an HDAC6-depenednt manner, mediated AD. MiR-9, negatively regulated by HDAC6, suppressed AD by directly regulating the expression of sirtuin 1 (SIRT1). The downregulation or inhibition of SIRT1 suppressed AD. Experiments employing culture medium and transwell suggested that cellular interactions involving mast cells, keratinocytes, and dermal fibroblast cells could promote AD; HDAC6 and CXCL13 were found to be necessary for these cellular interactions. Mouse recombinant CXCL13 protein increased HDAC6 expression in skin mast cells and dermal fibroblast cells. CXCL13 protein was found to be present in the exosomes of DNCB-treated skin mast cells. Exosomes of DNCB-treated skin mast cells enhanced invasion potentials of keratinocytes and dermal fibroblast cells and increased expression levels of HDAC6, SIRT1 and CXCL13 in keratinocytes and dermal fibroblast cells. These results indicate that HDAC6 and CXCL13 may serve as targets for the developing anti-atopic drugs.
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Affiliation(s)
- Yoojung Kwon
- Department of Biochemistry, Kangwon National University, Chuncheon, Korea
| | - Yunji Choi
- Department of Biochemistry, Kangwon National University, Chuncheon, Korea
| | - Misun Kim
- Department of Biochemistry, Kangwon National University, Chuncheon, Korea
| | - Myeong Seon Jeong
- Department of Biochemistry, Kangwon National University, Chuncheon, Korea.,Chuncheon Center, Korea Basic Science Institute, Chuncheon, Korea
| | - Hyun Suk Jung
- Department of Biochemistry, Kangwon National University, Chuncheon, Korea
| | - Dooil Jeoung
- Department of Biochemistry, Kangwon National University, Chuncheon, Korea
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25
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Yang Y, Sangwung P, Kondo R, Jung Y, McConnell MJ, Jeong J, Utsumi T, Sessa WC, Iwakiri Y. Alcohol-induced Hsp90 acetylation is a novel driver of liver sinusoidal endothelial dysfunction and alcohol-related liver disease. J Hepatol 2021; 75:377-386. [PMID: 33675874 PMCID: PMC8292196 DOI: 10.1016/j.jhep.2021.02.028] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 02/20/2021] [Accepted: 02/24/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Liver sinusoidal endothelial cell (LSEC) dysfunction has been reported in alcohol-related liver disease, yet it is not known whether LSECs metabolize alcohol. Thus, we investigated this, as well as the mechanisms of alcohol-induced LSEC dysfunction and a potential therapeutic approach for alcohol-induced liver injury. METHODS Primary human, rat and mouse LSECs were used. Histone deacetylase 6 (HDAC6) was overexpressed specifically in liver ECs via adeno-associated virus (AAV)-mediated gene delivery to decrease heat shock protein 90 (Hsp90) acetylation in ethanol-fed mice. RESULTS LSECs expressed CYP2E1 and alcohol dehydrogenase 1 (ADH1) and metabolized alcohol. Ethanol induced CYP2E1 in LSECs, but not ADH1. Alcohol metabolism by CYP2E1 increased Hsp90 acetylation and decreased its interaction with endothelial nitric oxide synthase (eNOS) leading to a decrease in nitric oxide (NO) production. A non-acetylation mutant of Hsp90 increased its interaction with eNOS and NO production, whereas a hyperacetylation mutant decreased NO production. These results indicate that Hsp90 acetylation is responsible for decreases in its interaction with eNOS and eNOS-derived NO production. AAV8-driven HDAC6 overexpression specifically in liver ECs deacetylated Hsp90, restored Hsp90's interaction with eNOS and ameliorated alcohol-induced liver injury in mice. CONCLUSION Restoring LSEC function is important for ameliorating alcohol-induced liver injury. To this end, blocking acetylation of Hsp90 specifically in LSECs via AAV-mediated gene delivery has the potential to be a new therapeutic strategy. LAY SUMMARY Alcohol metabolism in liver sinusoidal endothelial cells (LSECs) and the mechanism of alcohol-induced LSEC dysfunction are largely unknown. Herein, we demonstrate that LSECs can metabolize alcohol. We also uncover a mechanism by which alcohol induces LSEC dysfunction and liver injury, and we identify a potential therapeutic strategy to prevent this.
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Affiliation(s)
- Yilin Yang
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA
| | - Panjamaporn Sangwung
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA
| | - Reiichiro Kondo
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA,Department of Pathology, Kurume University School of Medicine, Kurume, Japan
| | - Yirang Jung
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA
| | - Matthew J. McConnell
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA
| | - Jain Jeong
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA
| | - Teruo Utsumi
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA
| | - William C. Sessa
- Department of Pharmacology, Yale School of Medicine, New Haven, CT, USA
| | - Yasuko Iwakiri
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA.
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26
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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: 16] [Impact Index Per Article: 4.0] [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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27
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Role of Nitric Oxide in Gene Expression Regulation during Cancer: Epigenetic Modifications and Non-Coding RNAs. Int J Mol Sci 2021; 22:ijms22126264. [PMID: 34200849 PMCID: PMC8230456 DOI: 10.3390/ijms22126264] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/06/2021] [Accepted: 06/08/2021] [Indexed: 12/12/2022] Open
Abstract
Nitric oxide (NO) has been identified and described as a dual mediator in cancer according to dose-, time- and compartment-dependent NO generation. The present review addresses the different epigenetic mechanisms, such as histone modifications and non-coding RNAs (ncRNAs), miRNA and lncRNA, which regulate directly or indirectly nitric oxide synthase (NOS) expression and NO production, impacting all hallmarks of the oncogenic process. Among lncRNA, HEIH and UCA1 develop their oncogenic functions by inhibiting their target miRNAs and consequently reversing the inhibition of NOS and promoting tumor proliferation. The connection between miRNAs and NO is also involved in two important features in cancer, such as the tumor microenvironment that includes key cellular components such as tumor-associated macrophages (TAMs), cancer associated fibroblasts (CAFs) and cancer stem cells (CSCs).
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28
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Festa Ortega JF, Heidor R, Auriemo AP, Marques Affonso J, Pereira D' Amico T, Herz C, de Conti A, Ract J, Gioieli LA, Purgatto E, Lamy E, P Pogribny I, Salvador Moreno F. Butyrate-containing structured lipids act on HDAC4, HDAC6, DNA damage and telomerase activity during promotion of experimental hepatocarcinogenesis. Carcinogenesis 2021; 42:1026-1036. [PMID: 33999989 DOI: 10.1093/carcin/bgab039] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 04/28/2021] [Accepted: 05/13/2021] [Indexed: 12/20/2022] Open
Abstract
Hepatocellular carcinoma (HCC) presents with a high treatment resistance and poor prognosis. Early diagnosis and preventive approaches such as chemoprevention are essential for the HCC control. Therefore, we evaluated the chemopreventive effects of butyrate-containing structured lipids (STLs) administered during the promotion stage of hepatocarcinogenesis in rats submitted to the 'resistant hepatocyte' (RH) model. Administration of butyrate-containing STLs inhibited the incidence and mean number of visible hepatic nodules per rat and reduced the number and area of glutathione S-transferase placental form-positive (GST-P+) preneoplastic focal lesions in the livers. This was accompanied by the induction of apoptosis and an increased level of hepatic butyric acid. Treatment with butyrate-containing STLs resulted in increased histone H3 lysine 9 (H3K9) acetylation, reduction of total histone deacetylase (HDAC) activity, and lower levels of HDAC4 and HDAC6 proteins. The chemopreventive effect of butyrate-containing STLs was also associated with the increased nuclear compartmentalization of p53 protein and reduced expression of the Bcl-2 protein. In addition, rats treated with butyrate-containing STLs showed decreased DNA damage and telomerase activity in the livers. These results demonstrate that the suppressive activity of butyrate-containing STLs is associated with inhibition of elevated during hepatocarcinogenesis chromatin-modifying proteins HDAC4 and HDAC6, subcellular redistribution of the p53 protein, and decreased DNA damage and telomerase activity.
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Affiliation(s)
- Juliana Festa Festa Ortega
- Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Renato Heidor
- Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.,Food Research Center (FORC), Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Ana Paula Auriemo
- Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Juliana Marques Affonso
- Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Thais Pereira D' Amico
- Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Corinna Herz
- Molecular Preventive Medicine, University of Freiburg, Breisacherstraße 115b, 79106 Freiburg im Breisgau, Germany
| | - Aline de Conti
- Division of Biochemical Toxicology, FDA National Center for Toxicological Research, Jefferson, AR, USA
| | - Juliana Ract
- Department of Biochemical and Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Luiz Antônio Gioieli
- Department of Biochemical and Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Eduardo Purgatto
- Food Research Center (FORC), Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.,Laboratory of Food Chemistry and Biochemistry, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Evelyn Lamy
- Molecular Preventive Medicine, University of Freiburg, Breisacherstraße 115b, 79106 Freiburg im Breisgau, Germany
| | - Igor P Pogribny
- Division of Biochemical Toxicology, FDA National Center for Toxicological Research, Jefferson, AR, USA
| | - Fernando Salvador Moreno
- Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.,Food Research Center (FORC), Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
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29
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Liver Cancer: Therapeutic Challenges and the Importance of Experimental Models. Can J Gastroenterol Hepatol 2021; 2021:8837811. [PMID: 33728291 PMCID: PMC7937489 DOI: 10.1155/2021/8837811] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 01/16/2021] [Accepted: 02/16/2021] [Indexed: 02/06/2023] Open
Abstract
Liver cancer is one of the main causes of death related to cancer worldwide; its etiology is related with infections by C or B hepatitis virus, alcohol consumption, smoking, obesity, nonalcoholic fatty liver disease, diabetes, and iron overload, among other causes. Several kinds of primary liver cancer occur, but we will focus on hepatocellular carcinoma (HCC). Numerous cellular signaling pathways are implicated in hepatocarcinogenesis, including YAP-HIPPO, Wnt-β-catenin, and nuclear factor-κB (NF-κB); these in turn are considered novel therapeutic targets. In this review, the role of lipid metabolism regulated by peroxisome proliferator-activated receptor gamma (PPARγ) in the development of HCC will also be discussed. Moreover, recent evidence has been obtained regarding the participation of epigenetic changes such as acetylation and methylation of histones and DNA methylation in the development of HCC. In this review, we provide detailed and current information about these topics. Experimental models represent useful tools for studying the different stages of liver cancer and help to develop new pharmacologic treatments. Each model in vivo and in vitro has several characteristics and advantages to offer for the study of this disease. Finally, the main therapies approved for the treatment of HCC patients, first- and second-line therapies, are described in this review. We also describe a novel option, pirfenidone, which due to its pharmacological properties could be considered in the future as a therapeutic option for HCC treatment.
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30
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Overcome the tumor immunotherapy resistance by combination of the HDAC6 inhibitors with antitumor immunomodulatory agents. Bioorg Chem 2021; 109:104754. [PMID: 33677416 DOI: 10.1016/j.bioorg.2021.104754] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 02/10/2021] [Accepted: 02/16/2021] [Indexed: 11/21/2022]
Abstract
Tumor immunotherapy is currently subject of intense scientific and clinical developments. In previous decade, therapists used natural immune system from the human body to treat several diseases. Although tumor immune disease is a big challenge, combinatorial therapeutic strategy has been succeeded to show the clinical significance. In this context, we discuss the HDAC6 and tumor immune diseases relationship. Also, we summarized the current state of knowledge that based on the combination treatments of the HDAC6 inhibitors (HDAC6is) with antitumor immunomodulatory agents. We observed that, the combination therapies slow down the tumor immune diseases by blocking the aggresome and proteasome pathway. The combination therapy was able to reduce M2 macrophage and increasing PD-L1 blockade sensitivity. Most importantly, multiple combinations of HDAC6is with other agents may consider as potential strategies to treat tumor immune diseases, by reducing the side effects and improve efficacy for the future clinical development.
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Bi L, Ren Y, Feng M, Meng P, Wang Q, Chen W, Jiao Q, Wang Y, Du L, Zhou F, Jiang Y, Chen F, Wang C, Tang B, Wang Y. HDAC11 Regulates Glycolysis through the LKB1/AMPK Signaling Pathway to Maintain Hepatocellular Carcinoma Stemness. Cancer Res 2021; 81:2015-2028. [PMID: 33602787 DOI: 10.1158/0008-5472.can-20-3044] [Citation(s) in RCA: 98] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Revised: 12/30/2020] [Accepted: 02/15/2021] [Indexed: 11/16/2022]
Abstract
Hepatocellular carcinoma (HCC) contains a subset of cancer stem cells (CSC) that cause tumor recurrence, metastasis, and chemical resistance. Histone deacetylase 11 (HDAC11) mediates diverse immune functions and metabolism, yet little is known about its role in HCC CSCs. In this study, we report that HDAC11 is highly expressed in HCC and is closely related to disease prognosis. Depletion of HDAC11 in a conditional knockout mouse model reduced hepatocellular tumorigenesis and prolonged survival. Loss of HDAC11 increased transcription of LKB1 by promoting histone acetylation in its promoter region, thereby activating the AMPK signaling pathway and inhibiting the glycolysis pathway, which in turn leads to the suppression of cancer stemness and HCC progression. Furthermore, HDAC11 overexpression reduced HCC sensitivity to sorafenib. Collectively, these data propose HDAC11 as a new target for combination therapy in patients with kinase-resistant HCC. SIGNIFICANCE: This study finds that HDAC11 suppresses LKB1 expression in HCC to promote cancer stemness, progression, and sorafenib resistance, suggesting the potential of targeting HDAC11 to treat HCC and overcome kinase inhibitor resistance.
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Affiliation(s)
- Lei Bi
- School of Preclinical Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yidan Ren
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Maoxiao Feng
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Peng Meng
- Burning Rock Biotech, International Biotech Island, Guangzhou, China
| | - Qin Wang
- Department of Anesthesiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Weiping Chen
- School of Preclinical Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Qinlian Jiao
- Shandong Quality Inspection Center for Medical Devices, Jinan, Shandong, China
| | - Yuli Wang
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Lutao Du
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Fuqiong Zhou
- School of Preclinical Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yucui Jiang
- School of Preclinical Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Feiyan Chen
- School of Preclinical Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Chuanxin Wang
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Bo Tang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, P.R. China. .,Department of Health Sciences, Hiroshima Shudo University, Hiroshima, Japan
| | - Yunshan Wang
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
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Histone deacetylase 6 inhibition improves survival in a swine model of lethal hemorrhage, polytrauma, and bacteremia. J Trauma Acute Care Surg 2021; 89:932-939. [PMID: 32195993 DOI: 10.1097/ta.0000000000002677] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Trauma is the leading cause of death for young Americans. Nonspecific histone deacetylase inhibitors, such as valproic acid, have been shown to improve survival in preclinical models of lethal trauma, hemorrhage, and sepsis. The doses needed to achieve a survival benefit are higher than Food and Drug Administration-approved doses, and the nonspecificity raises concerns about unintended adverse effects. The isoform-specific histone deacetylase 6 inhibitor, ACY-1083, has been found to be as efficacious as valproic acid in a rodent model of hemorrhagic shock. We hypothesized that ACY-1083 treatment would improve survival in a swine model of lethal hemorrhage, polytrauma, and bacteremia. METHODS Swine were subjected to 45% blood volume hemorrhage, brain injury, femur fracture, rectus crush, splenic and liver lacerations, and colon injury. After 1 hour of shock (mean arterial pressure, 30-35 mm Hg), animals were randomized to normal saline resuscitation (control) or normal saline plus ACY-1083 30 mg/kg treatment (n = 5/group). After 3 hours (simulating delayed evacuation), packed red blood cells and antibiotics were administered, the colon injury was repaired, and the abdomen was closed. Animals were then monitored for another 4 hours. Survival was assessed using Kaplan-Meier and log-rank test. RESULTS This combination of injuries was lethal. All animals became bacteremic, in addition to the severe hemorrhagic shock. Survival in the control group was 0%, and ACY-1083 treatment increased survival to 80% (p = 0.019). There was no difference in the brain lesion size between the groups. CONCLUSION A single dose of ACY-1083 markedly improves survival in an otherwise lethal model of polytrauma, hemorrhagic shock, and bacteremia.
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Kouroumalis E, Voumvouraki A, Augoustaki A, Samonakis DN. Autophagy in liver diseases. World J Hepatol 2021; 13:6-65. [PMID: 33584986 PMCID: PMC7856864 DOI: 10.4254/wjh.v13.i1.6] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 12/10/2020] [Accepted: 12/26/2020] [Indexed: 02/06/2023] Open
Abstract
Autophagy is the liver cell energy recycling system regulating a variety of homeostatic mechanisms. Damaged organelles, lipids and proteins are degraded in the lysosomes and their elements are re-used by the cell. Investigations on autophagy have led to the award of two Nobel Prizes and a health of important reports. In this review we describe the fundamental functions of autophagy in the liver including new data on the regulation of autophagy. Moreover we emphasize the fact that autophagy acts like a two edge sword in many occasions with the most prominent paradigm being its involvement in the initiation and progress of hepatocellular carcinoma. We also focused to the implication of autophagy and its specialized forms of lipophagy and mitophagy in the pathogenesis of various liver diseases. We analyzed autophagy not only in well studied diseases, like alcoholic and nonalcoholic fatty liver and liver fibrosis but also in viral hepatitis, biliary diseases, autoimmune hepatitis and rare diseases including inherited metabolic diseases and also acetaminophene hepatotoxicity. We also stressed the different consequences that activation or impairment of autophagy may have in hepatocytes as opposed to Kupffer cells, sinusoidal endothelial cells or hepatic stellate cells. Finally, we analyzed the limited clinical data compared to the extensive experimental evidence and the possible future therapeutic interventions based on autophagy manipulation.
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Affiliation(s)
- Elias Kouroumalis
- Liver Research Laboratory, University of Crete Medical School, Heraklion 71110, Greece
| | - Argryro Voumvouraki
- 1 Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54636, Greece
| | - Aikaterini Augoustaki
- Department of Gastroenterology and Hepatology, University Hospital of Crete, Heraklion 71110, Greece
| | - Dimitrios N Samonakis
- Department of Gastroenterology and Hepatology, University Hospital of Crete, Heraklion 71110, Greece.
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Son SM, Park SJ, Fernandez-Estevez M, Rubinsztein DC. Autophagy regulation by acetylation-implications for neurodegenerative diseases. Exp Mol Med 2021; 53:30-41. [PMID: 33483607 PMCID: PMC8080689 DOI: 10.1038/s12276-021-00556-4] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 11/27/2020] [Indexed: 01/30/2023] Open
Abstract
Posttranslational modifications of proteins, such as acetylation, are essential for the regulation of diverse physiological processes, including metabolism, development and aging. Autophagy is an evolutionarily conserved catabolic process that involves the highly regulated sequestration of intracytoplasmic contents in double-membrane vesicles called autophagosomes, which are subsequently degraded after fusing with lysosomes. The roles and mechanisms of acetylation in autophagy control have emerged only in the last few years. In this review, we describe key molecular mechanisms by which previously identified acetyltransferases and deacetylases regulate autophagy. We highlight how p300 acetyltransferase controls mTORC1 activity to regulate autophagy under starvation and refeeding conditions in many cell types. Finally, we discuss how altered acetylation may impact various neurodegenerative diseases in which many of the causative proteins are autophagy substrates. These studies highlight some of the complexities that may need to be considered by anyone aiming to perturb acetylation under these conditions.
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Affiliation(s)
- Sung Min Son
- grid.5335.00000000121885934Department of Medical Genetics, University of Cambridge, Cambridge, UK ,grid.5335.00000000121885934UK Dementia Research Institute, Cambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge, UK
| | - So Jung Park
- grid.5335.00000000121885934Department of Medical Genetics, University of Cambridge, Cambridge, UK ,grid.5335.00000000121885934UK Dementia Research Institute, Cambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge, UK
| | - Marian Fernandez-Estevez
- grid.5335.00000000121885934Department of Medical Genetics, University of Cambridge, Cambridge, UK ,grid.5335.00000000121885934UK Dementia Research Institute, Cambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge, UK
| | - David C. Rubinsztein
- grid.5335.00000000121885934Department of Medical Genetics, University of Cambridge, Cambridge, UK ,grid.5335.00000000121885934UK Dementia Research Institute, Cambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge, UK
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Sheng JQ, Wang MR, Fang D, Liu L, Huang WJ, Tian DA, He XX, Li PY. LncRNA NBR2 inhibits tumorigenesis by regulating autophagy in hepatocellular carcinoma. Biomed Pharmacother 2021; 133:111023. [PMID: 33378941 DOI: 10.1016/j.biopha.2020.111023] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 11/09/2020] [Accepted: 11/15/2020] [Indexed: 02/06/2023] Open
Abstract
Long noncoding RNAs (lncRNAs) have been identified to play increasingly important roles in tumorigenesis, and they may serve as novel biomarkers for cancer therapy. LncRNA NBR2 (neighbor of BRCA1 gene 2), a novel identified lncRNA, is demonstrated to decrease in several cancers. However, it is still unknown whether lncRNA NBR2 is involved in hepatocellular carcinoma and autophagy. We found that HCC cases with lower NBR2 expression had significantly worse overall survival than those with higher NBR2 expression in advanced patients. And the expression of NBR2 was negatively correlated with the degree of malignancy of HCC cell lines and differentiation of hepatocellular carcinoma. Besides, NBR2 inhibited the proliferation, invasion, and migration of liver cancer cells. We further found that NBR2 repressed cytoprotective autophagy to restrain HCC cell proliferation. Moreover, NBR2 inhibited Beclin 1-dependent autophagy through ERK and JNK pathways. Taken together, NBR2 suppressed autophagy-induced cell proliferation at least partly through ERK and JNK pathways. These data indicated that NBR2 served as a tumor suppressor gene in hepatocellular carcinoma. The current study provides a novel insight and treatment strategy for hepatocellular carcinoma.
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Affiliation(s)
- Jia-Qi Sheng
- Division of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Mu-Ru Wang
- Division of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Dan Fang
- Division of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Lian Liu
- Division of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Wen-Jie Huang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China.
| | - De-An Tian
- Division of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Xing-Xing He
- Division of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Pei-Yuan Li
- Division of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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36
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Bhol CS, Panigrahi DP, Praharaj PP, Mahapatra KK, Patra S, Mishra SR, Behera BP, Bhutia SK. Epigenetic modifications of autophagy in cancer and cancer therapeutics. Semin Cancer Biol 2020; 66:22-33. [DOI: 10.1016/j.semcancer.2019.05.020] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Revised: 05/09/2019] [Accepted: 05/30/2019] [Indexed: 12/30/2022]
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Liu YX, Li QZ, Cao YN, Zhang LQ. Identification of key genes and important histone modifications in hepatocellular carcinoma. Comput Struct Biotechnol J 2020; 18:2657-2669. [PMID: 33033585 PMCID: PMC7533298 DOI: 10.1016/j.csbj.2020.09.013] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 08/26/2020] [Accepted: 09/10/2020] [Indexed: 01/14/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death in the world. It has been reported that HCC is closely related to the changes of histone modifications. However, finding histone modification patterns in key genes which related to HCC is still an important task. In our study, the patterns of 11 kinds of histone modifications in the promoter regions for the different types of genes were analyzed by hierarchical screening for hepatocyte (normal) cell line and HepG2 (tumor) cell line. The important histone modifications and their key modification regions in different types of genes were found. The results indicate that these important genes may play a pivotal role in the occurrence of HCC. By analyzing the differences of histone modifications and gene expression levels for these important genes between the two cell lines, we found that the signals of H3K4me3, H3K27ac, H3K9ac, and H3K4me2 in HCC are significantly stronger. The changed regions of important histone modifications in 17 key genes were also identified. For example, the H3K4me3 signals increased 150 times in regions (−1500, −500) bp and (0, 1000) bp of ARHGAP5 in tumor cell line than in normal cell line. Finally, a prognostic risk scoring model was constructed, and the effects of key genes on the prognosis of HCC were verified by the survival analysis. Our results may provide a more precise potential therapeutic targets for identifying key genes and histone modifications in HCC as new biomarkers.
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Key Words
- Biomarkers
- DHLEG, Different highly and lowly expressed genes
- Gene expression
- H2AFZ, H2A histone family member Z
- H3K27ac, Histone H3 acetylated at lysine 27
- H3K27me3, Histone H3 trimethylated at lysine 27
- H3K36me3, Histone H3 trimethylated at lysine 36
- H3K4me1, Histone H3 monomethylated at lysine 4
- H3K4me2, Histone H3 dimethylated at lysine 4
- H3K4me3, Histone H3 trimethylated at lysine 4
- H3K79me2, Histone H3 dimethylated at lysine 79
- H3K9ac, Histone H3 acetylated at lysine 9
- H3K9me3, Histone H3 trimethylated at lysine 9
- H4K20me1, Histone H4 monomethylated at lysine 20
- HCC, Hepatocellular carcinoma
- Histone modification signals
- NH, The genes are highly expressed in normal cell line but not in tumor cell line
- NH-TL, The genes are highly expressed in normal cell line and lowly expressed in tumor cell line
- NL, The genes are lowly expressed in normal cell line but not in tumor cell line
- NL-TH, The genes are lowly expressed in normal cell line and highly expressed in tumor cell line
- ONCO, Oncogenes
- Oncogenes
- TH, The genes are highly expressed in tumor cell line but not in normal cell line
- TL, The genes are lowly expressed in tumor cell line but not in normal cell line
- TSG, Tumor suppressor genes
- Tumor suppressor genes
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Affiliation(s)
- Yu-Xian Liu
- Laboratory of Theoretical Biophysics, School of Physical Science and Technology, Inner Mongolia University, Hohhot 010021, China
| | - Qian-Zhong Li
- Laboratory of Theoretical Biophysics, School of Physical Science and Technology, Inner Mongolia University, Hohhot 010021, China.,The State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Inner Mongolia University, Hohhot 010070, China
| | - Yan-Ni Cao
- Laboratory of Theoretical Biophysics, School of Physical Science and Technology, Inner Mongolia University, Hohhot 010021, China
| | - Lu-Qiang Zhang
- Laboratory of Theoretical Biophysics, School of Physical Science and Technology, Inner Mongolia University, Hohhot 010021, China
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Liu Z, Lv X, Xu L, Liu X, Zhu X, Song E, Song Y. Zinc oxide nanoparticles effectively regulate autophagic cell death by activating autophagosome formation and interfering with their maturation. Part Fibre Toxicol 2020; 17:46. [PMID: 32948194 PMCID: PMC7501661 DOI: 10.1186/s12989-020-00379-7] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Accepted: 09/10/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND With the development of zinc oxide nanoparticles (ZnO NPs) in the field of nanotechnology, their toxicological effects are attracting increasing attention, and the mechanisms for ZnO NPs neurotoxicity remain obscure. In an attempt to address concerns regarding neurotoxicity of ZnO NPs, we explored the relationship between free zinc ions, reactive oxygen species (ROS) and neurotoxic mechanisms in ZnO NPs-exposed PC12 cells. RESULT This study demonstrated the requirement of free zinc ions shed by ZnO NPs to over generation of intracellular ROS. Next, we identified autophagic cell death was the major mode of cell death induced by ZnO NPs, and autophagosome accumulation resulted from not only induction of autophagy, but also blockade of autophagy flux. We concluded that autophagic cell death, resulting from zinc ions-ROS-c-Jun N-terminal kinase (JNK)-autophagy positive feedback loop and blockade of autophagosomal-lysosomal fusion, played a major role in the neurotoxicity of ZnO NPs. CONCLUSION Our study contributes to a better understanding of the neurotoxicity of ZnO NPs and might be useful for designing and developing new biosafety nanoparticles in the future.
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Affiliation(s)
- Zixuan Liu
- Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Beibei, Chongqing, 400715, People's Republic of China
| | - Xuying Lv
- Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Beibei, Chongqing, 400715, People's Republic of China
| | - Lei Xu
- Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Beibei, Chongqing, 400715, People's Republic of China
| | - Xuting Liu
- Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Beibei, Chongqing, 400715, People's Republic of China
| | - Xiangyu Zhu
- Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Beibei, Chongqing, 400715, People's Republic of China
| | - Erqun Song
- Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Beibei, Chongqing, 400715, People's Republic of China
| | - Yang Song
- Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Beibei, Chongqing, 400715, People's Republic of China.
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Chang S, Wang LHC, Chen BS. Investigating Core Signaling Pathways of Hepatitis B Virus Pathogenesis for Biomarkers Identification and Drug Discovery via Systems Biology and Deep Learning Method. Biomedicines 2020; 8:biomedicines8090320. [PMID: 32878239 PMCID: PMC7555687 DOI: 10.3390/biomedicines8090320] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 08/19/2020] [Accepted: 08/21/2020] [Indexed: 12/17/2022] Open
Abstract
Hepatitis B Virus (HBV) infection is a major cause of morbidity and mortality worldwide. However, poor understanding of its pathogenesis often gives rise to intractable immune escape and prognosis recurrence. Thus, a valid systematic approach based on big data mining and genome-wide RNA-seq data is imperative to further investigate the pathogenetic mechanism and identify biomarkers for drug design. In this study, systems biology method was applied to trim false positives from the host/pathogen genetic and epigenetic interaction network (HPI-GEN) under HBV infection by two-side RNA-seq data. Then, via the principal network projection (PNP) approach and the annotation of KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways, significant biomarkers related to cellular dysfunctions were identified from the core cross-talk signaling pathways as drug targets. Further, based on the pre-trained deep learning-based drug-target interaction (DTI) model and the validated pharmacological properties from databases, i.e., drug regulation ability, toxicity, and sensitivity, a combination of promising multi-target drugs was designed as a multiple-molecule drug to create more possibility for the treatment of HBV infection. Therefore, with the proposed systems medicine discovery and repositioning procedure, we not only shed light on the etiologic mechanism during HBV infection but also efficiently provided a potential drug combination for therapeutic treatment of Hepatitis B.
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Affiliation(s)
- Shen Chang
- Laboratory of Automatic Control, Signal Processing and Systems Biology, Department of Electrical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan;
| | - Lily Hui-Ching Wang
- Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu 30013, Taiwan;
| | - Bor-Sen Chen
- Laboratory of Automatic Control, Signal Processing and Systems Biology, Department of Electrical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan;
- Correspondence:
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40
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Yang Y, Lin Z, Cheng J, Ding S, Mao WW, Shi S, Liang B, Jiang L. The roles of autophagy in osteogenic differentiation in rat ligamentum fibroblasts: Evidence and possible implications. FASEB J 2020; 34:8876-8886. [PMID: 32510740 DOI: 10.1096/fj.201903216rr] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 05/12/2020] [Accepted: 05/15/2020] [Indexed: 12/27/2022]
Abstract
Autophagy, a macromolecular degradation process, plays a pivotal role in cell differentiation and survival. This study was designed to investigate the role of autophagy in the osteogenic differentiation in ligamentum fibroblasts. Rat ligamentum fibroblasts were isolated from the posterior longitudinal ligament and cultured in osteogenic induction medium. Ultrastructural analysis, immunofluorescence assay, western blot, flow cytometry, and lysosomal activity assessment were performed to determine the presence and activity of autophagy in the cells. The mineralization deposit and osteogenic gene expressions were evaluated to classify the association between autophagy activity and the bone formation ability of the spinal ligament cells. The influence of leptin and endothelin-1 on the autophagy activity was also evaluated. Our study demonstrated that autophagy was present and increased in the ligament cells under osteogenic induction. Inhibition of autophagy with either pharmacologic inhibitors (Bafilomycin A and 3-methyladenine) or Belcin1 (BECN1) knocking down weakened the mineralization capacity, decreased the gene expressions of COL1A1, osteocalcin (Ocn), and runt-related transcription factor 2 (Runx2) in the ligamentum fibroblasts and increased cell apoptosis. The Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)-BECN1 autophagic pathway was activated in the osteogenic differentiating ligamentum fibroblasts. Leptin significantly increased the autophagy activity in the ligament cells under osteogenic induction. These discoveries might improve our understanding for the mechanism of ossification of the posterior longitudinal ligament (OPLL) and provide new approaches on the prevention and treatment of this not uncommon disease.
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Affiliation(s)
- Yuehua Yang
- Spine Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.,Department of Orthopaedics, Fifth Affiliated Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Zunwen Lin
- Department of Orthopedic Surgery, First Affiliated Hospital, Nanchang University, Jiangxi, P.R. China
| | - Jiangwei Cheng
- Department of Orthopedic Surgery, First Affiliated Hospital, Nanchang University, Jiangxi, P.R. China
| | - Sheng Ding
- Department of Stomatology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
| | - Wei-Wei Mao
- Department of Pediatric Neurosurgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
| | - Sheng Shi
- Department of Orthopedics, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, P.R. China
| | - Biru Liang
- Department of Orthopaedics, Fifth Affiliated Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Leisheng Jiang
- Spine Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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Qiu W, Wang B, Gao Y, Tian Y, Tian M, Chen Y, Xu L, Yao TP, Li P, Yang P. Targeting Histone Deacetylase 6 Reprograms Interleukin-17-Producing Helper T Cell Pathogenicity and Facilitates Immunotherapies for Hepatocellular Carcinoma. Hepatology 2020; 71:1967-1987. [PMID: 31539182 DOI: 10.1002/hep.30960] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2019] [Accepted: 09/16/2019] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND AIMS Hepatocellular carcinoma (HCC) is often accompanied by resistance to immunotherapies despite the presence of tumor-infiltrating lymphocytes. We report that histone deacetylase 6 (HDAC6) represses interleukin-17 (IL-17)-producing helper T (TH 17) cell pathogenicity and the antitumor immune response, dependent on its deacetylase activity. APPROACH AND RESULTS Adoptive transfer of HDAC6-deficient TH 17 cells impedes HCC growth, dependent on elevated IL-17A, by enhancing the production of antitumor cytokine and cluster of differentiation 8-positive (CD8+) T cell-mediated antitumor responses. Intriguingly, HDAC6-depleted T cells trigger programmed cell death protein 1 (PD-1)-PD-1 ligand 1 expression to achieve a strong synergistic effect to sensitize advanced HCC to an immune checkpoint blocker, while blockade of IL-17A partially suppresses it. Mechanistically, HDAC6 limits TH 17 pathogenicity and the antitumor effect through regulating forkhead box protein O1 (FoxO1). HDAC6 binds and deacetylates cytosolic FoxO1 at K242, which is required for its nuclear translocation and stabilization to repress retinoic acid-related orphan receptor gamma (RoRγt), the transcription factor of TH 17 cell. This regulation of HDAC6 for murine and human TH 17 cell is highly conserved. CONCLUSIONS These results demonstrate that targeting the cytosolic HDAC6-FoxO1 axis reprograms the pathogenicity and antitumor response of TH 17 cells in HCC, with a pathogenicity-driven responsiveness to facilitate immunotherapies.
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Affiliation(s)
- Weinan Qiu
- Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China
| | - Bin Wang
- Center for Clinic Stem Cell, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Yanan Gao
- Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China
| | - Yuan Tian
- Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China
| | - Meijie Tian
- Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China
| | - Yuanying Chen
- State Key Laboratory of Membrane and Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China
| | - Li Xu
- State Key Laboratory of Membrane and Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China
| | - Tso-Pang Yao
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Duke University, Durham, NC
| | - Peng Li
- State Key Laboratory of Membrane and Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China
| | - Pengyuan Yang
- Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China
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42
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Role of miR-221/222 in Tumor Development and the Underlying Mechanism. JOURNAL OF ONCOLOGY 2019; 2019:7252013. [PMID: 31929798 PMCID: PMC6942871 DOI: 10.1155/2019/7252013] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 10/22/2019] [Accepted: 11/01/2019] [Indexed: 12/24/2022]
Abstract
MicroRNA-221/222 (miRNA-221/222, miR-221/222) is a noncoding microRNA which is widely distributed in eukaryotic organisms and deeply involved in the posttranscriptional regulation of gene expressions. According to recent studies, abnormal expressions of miR-221/222 are closely related to the occurrence and development of various kinds of malignant tumors. The role of miR-221/222 in tumor development and their potential molecular mechanism in various cancers, including liver cancer, colorectal cancer, cervical cancer, ovarian cancer, and endometrial carcinoma, are summarized and reviewed in this paper. Moreover, the potential translational biomarker role of abnormal miR-221/222 level in tumor or blood circulation for tumor diagnosis is also discussed.
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Sharifi-Rad J, Ozleyen A, Boyunegmez Tumer T, Oluwaseun Adetunji C, El Omari N, Balahbib A, Taheri Y, Bouyahya A, Martorell M, Martins N, Cho WC. Natural Products and Synthetic Analogs as a Source of Antitumor Drugs. Biomolecules 2019; 9:E679. [PMID: 31683894 PMCID: PMC6920853 DOI: 10.3390/biom9110679] [Citation(s) in RCA: 106] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 10/26/2019] [Accepted: 10/27/2019] [Indexed: 02/06/2023] Open
Abstract
Cancer is a heterogeneous disease and one of the major issues of health concern, especially for the public health system globally. Nature is a source of anticancer drugs with abundant pool of diverse chemicals and pharmacologically active compounds. In recent decade, some natural products and synthetic analogs have been investigated for the cancer treatment. This article presents the utilization of natural products as a source of antitumor drugs.
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Affiliation(s)
- Javad Sharifi-Rad
- Zabol Medicinal Plants Research Center, Zabol University of Medical Sciences, Zabol 61615-585, Iran.
| | - Adem Ozleyen
- Graduate Program of Biomolecular Sciences, Institute of Natural and Applied Sciences, Canakkale Onsekiz Mart University, Canakkale 17020, Turkey.
| | - Tugba Boyunegmez Tumer
- Department of Molecular Biology and Genetics, Faculty of Arts and Science, Canakkale Onsekiz Mart University, Canakkale 17020, Turkey.
| | - Charles Oluwaseun Adetunji
- Applied Microbiology, Biotechnology and Nanotechnology Laboratory, Department of Microbiology, Edo University, Iyamho, Edo State 300271, Nigeria.
| | - Nasreddine El Omari
- Laboratory of Histology, Embryology and Cytogenetic, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat 10100, Morocco.
| | - Abdelaali Balahbib
- Laboratory of Zoology and General Biology, Faculty of Sciences, Mohammed V University, Rabat 10106, Morocco.
| | - Yasaman Taheri
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran 1991953381, Iran.
- Department of Pharmacology and Toxicology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran 11369, Iran.
| | - Abdelhakim Bouyahya
- Laboratory of Human Pathologies Biology, Department of Biology, Faculty of Sciences, and Genomic Center of Human Pathologies, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat 10106, Morocco.
| | - Miquel Martorell
- Department of Nutrition and Dietetics, Faculty of Pharmacy, University of Concepcion, Concepcion 4070386, Chile.
- Universidad de Concepción, Unidad de Desarrollo Tecnológico, UDT, Concepcion 4070386, Chile.
| | - Natália Martins
- Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal.
- Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135 Porto, Portugal.
| | - William C Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, China.
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Liu J, Cui X, Guo F, Li X, Li L, Pan J, Tao S, Huang R, Feng Y, Ma L, Fu P. 2-methylquinazoline derivative F7 as a potent and selective HDAC6 inhibitor protected against rhabdomyolysis-induced acute kidney injury. PLoS One 2019; 14:e0224158. [PMID: 31639165 PMCID: PMC6804997 DOI: 10.1371/journal.pone.0224158] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Accepted: 10/07/2019] [Indexed: 02/05/2023] Open
Abstract
Histone deacetylases 6 (HDAC6) has been reported to be involved in the pathogenesis of rhabdomyolysis-induced acute kidney injury (AKI). Selective inhibition of HDAC6 activity might be a potential treatment for AKI. In our lab, N-hydroxy-6-(4-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)nicotinamide (F7) has been synthesized and inhibited HDAC6 activity with the IC50 of 5.8 nM. However, whether F7 possessed favorable renoprotection against rhabdomyolysis-induced AKI and the involved mechanisms remained unclear. In the study, glycerol-injected mice developed severe AKI symptoms as indicated by acute renal dysfunction and pathological changes, accompanied by the overexpression of HDAC6 in tubular epithelial cells. Pretreatment with F7 at a dose of 40 mg/kg/d for 3 days significantly attenuated serum creatinine, serum urea, renal tubular damage and suppressed renal inflammatory responses. Mechanistically, F7 enhanced the acetylation of histone H3 and α-tubulin to reduce HDAC6 activity. Glycerol-induced AKI triggered multiple signal mediators of NF-κB pathway as well as the elevation of ERK1/2 protein and p38 phosphorylation. Glycerol also induced the high expression of proinflammatory cytokine IL-1β and IL-6 in kidney and human renal proximal tubule HK-2 cells. Treatment of F7 notably improved above-mentioned inflammatory responses in the injured kidney tissue and HK-2 cell. Overall, these data highlighted that 2-methylquinazoline derivative F7 inhibited renal HDAC6 activity and inflammatory responses to protect against rhabdomyolysis-induced AKI.
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Affiliation(s)
- Jing Liu
- Division of Nephrology and National Clinical Research Center for Geriatrics, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, China
| | - Xue Cui
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Fan Guo
- Division of Nephrology and National Clinical Research Center for Geriatrics, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, China
| | - Xinrui Li
- Division of Nephrology and National Clinical Research Center for Geriatrics, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, China
| | - Lingzhi Li
- Division of Nephrology and National Clinical Research Center for Geriatrics, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, China
| | - Jing Pan
- Division of Nephrology and National Clinical Research Center for Geriatrics, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, China
| | - Sibei Tao
- Division of Nephrology and National Clinical Research Center for Geriatrics, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, China
| | - Rongshuang Huang
- Division of Nephrology and National Clinical Research Center for Geriatrics, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, China
| | - Yanhuan Feng
- Division of Nephrology and National Clinical Research Center for Geriatrics, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, China
| | - Liang Ma
- Division of Nephrology and National Clinical Research Center for Geriatrics, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, China
- * E-mail:
| | - Ping Fu
- Division of Nephrology and National Clinical Research Center for Geriatrics, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, China
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Yang HD, Kim HS, Kim SY, Na MJ, Yang G, Eun JW, Wang HJ, Cheong JY, Park WS, Nam SW. HDAC6 Suppresses Let-7i-5p to Elicit TSP1/CD47-Mediated Anti-Tumorigenesis and Phagocytosis of Hepatocellular Carcinoma. Hepatology 2019; 70:1262-1279. [PMID: 30991448 DOI: 10.1002/hep.30657] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Accepted: 03/30/2019] [Indexed: 12/24/2022]
Abstract
Histone deacetylase 6 (HDAC6) uniquely serves as a tumor suppressor in hepatocellular carcinogenesis, but the underlying mechanisms leading to tumor suppression are not fully understood. To identify comprehensive microRNAs (miRNAs) regulated by HDAC6 in hepatocellular carcinogenesis, differential miRNA expression analysis of HDAC6-transfected Hep3B cells was performed. Using integrative analyses of publicly available transcriptome data and miRNA target prediction, we selected five candidate miRNAs and, through in vitro functional validation, showed that let-7i-5p specifically suppressed thrombospondin-1 (TSP1) in hepatocellular carcinoma (HCC). Ectopic expression of antisense let-7i-5p (AS-let-7i-5p) inhibited in vitro tumorigenesis of HCC cells. In addition, treatments of partially purified TSP1 from culture cell media (ppTSP1) and recombinant TSP1 (rTSP1) exhibited similar effects with AS-let-7i-5p treatment on the same HCC cells, whereas TSP1 neutralizing antibody treatment significantly attenuated these effects. Notably, treatments of HDAC6 plasmid, AS-let-7i-5p, ppTSP1, and rTSP1 significantly suppressed in vitro angiogenesis and metastatic potential of HCC cells, but the co-treatment of TSP1 antibody specific to cluster of differentiation 47 (CD47) binding domain successfully blocked these effects in the same cells. Furthermore, we demonstrated that recovery of HDAC6 elicited let-7i-5p suppression to de-repress TSP1 expression; therefore, it occupied the CD47 receptor to block CD47-SIRPα-mediated anti-phagocytosis of macrophage in HCC. We also observed that HCC-derived exosomal let-7i-5p suppressed TSP1 of recipient hepatocyte cells. Treatments of HDAC6 plasmid, AS-let-7i-5p, and rTSP1 suppressed tumor incidence as well as tumor growth rates in a spontaneous mouse HCC model. Conclusion: Our findings suggest that the HDAC6-let-7i-5p-TSP1 regulatory pathway suppresses neoplastic and antiphagocytic behaviors of HCC by interacting with cell surface receptor CD47 in HCC and neighboring cells of tumor microenvironment, providing a therapeutic target for the treatment of liver malignancy and metastasis.
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Affiliation(s)
- Hee Doo Yang
- Department of Pathology, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea.,Functional RNomics Research Center, the Catholic University of Korea, Seoul, Republic of Korea.,Department of Biomedicine & Health Sciences, Graduate School of Medicine, the Catholic University of Korea, Seoul, Republic of Korea
| | - Hyung Seok Kim
- Department of Pathology, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea.,Functional RNomics Research Center, the Catholic University of Korea, Seoul, Republic of Korea.,Department of Biomedicine & Health Sciences, Graduate School of Medicine, the Catholic University of Korea, Seoul, Republic of Korea
| | - Sang Yean Kim
- Department of Pathology, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea.,Functional RNomics Research Center, the Catholic University of Korea, Seoul, Republic of Korea.,Department of Biomedicine & Health Sciences, Graduate School of Medicine, the Catholic University of Korea, Seoul, Republic of Korea
| | - Min Jeong Na
- Department of Pathology, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea.,Functional RNomics Research Center, the Catholic University of Korea, Seoul, Republic of Korea.,Department of Biomedicine & Health Sciences, Graduate School of Medicine, the Catholic University of Korea, Seoul, Republic of Korea
| | - Gyeongdeok Yang
- Department of Pathology, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea.,Functional RNomics Research Center, the Catholic University of Korea, Seoul, Republic of Korea
| | - Jung Woo Eun
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Hee Jung Wang
- Department of Surgery, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Jae Youn Cheong
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Won Sang Park
- Department of Pathology, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea.,Functional RNomics Research Center, the Catholic University of Korea, Seoul, Republic of Korea
| | - Suk Woo Nam
- Department of Pathology, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea.,Functional RNomics Research Center, the Catholic University of Korea, Seoul, Republic of Korea.,Department of Biomedicine & Health Sciences, Graduate School of Medicine, the Catholic University of Korea, Seoul, Republic of Korea
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46
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Kim SH, Kim H. Astaxanthin Modulation of Signaling Pathways That Regulate Autophagy. Mar Drugs 2019; 17:md17100546. [PMID: 31547619 PMCID: PMC6836186 DOI: 10.3390/md17100546] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 09/18/2019] [Accepted: 09/20/2019] [Indexed: 01/07/2023] Open
Abstract
Autophagy is a lysosomal pathway that degrades and recycles unused or dysfunctional cell components as well as toxic cytosolic materials. Basal autophagy favors cell survival. However, the aberrant regulation of autophagy can promote pathological conditions. The autophagy pathway is regulated by several cell-stress and cell-survival signaling pathways that can be targeted for the purpose of disease control. In experimental models of disease, the carotenoid astaxanthin has been shown to modulate autophagy by regulating signaling pathways, including the AMP-activated protein kinase (AMPK), cellular homolog of murine thymoma virus akt8 oncogene (Akt), and mitogen-activated protein kinase (MAPK), such as c-Jun N-terminal kinase (JNK) and p38. Astaxanthin is a promising therapeutic agent for the treatment of a wide variety of diseases by regulating autophagy.
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Affiliation(s)
- Suhn Hyung Kim
- Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul 03722, Korea.
| | - Hyeyoung Kim
- Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul 03722, Korea.
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47
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Pan TJ, Li LX, Zhang JW, Yang ZS, Shi DM, Yang YK, Wu WZ. Antimetastatic Effect of Fucoidan-Sargassum against Liver Cancer Cell Invadopodia Formation via Targeting Integrin αVβ3 and Mediating αVβ3/Src/E2F1 Signaling. J Cancer 2019; 10:4777-4792. [PMID: 31598149 PMCID: PMC6775528 DOI: 10.7150/jca.26740] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 06/06/2019] [Indexed: 12/25/2022] Open
Abstract
Background: Fucoidan is a fucose-enriched, sulfated polysaccharide found in brown algae; in recent years, this polysaccharide has been found to exert several biological effects, including antitumor effects, such as antiproliferation, activating apoptosis, and anti-angiogenesis of cancer cells. However, the antimetastatic effect of fucoidan and the related targeting receptors remain unknown. In the present study, we examined the inhibition of invadopodia formation and underlying mechanism of fucoidan on human liver cancer cells. Methods: We used 98% purified fucoidan from Sargassum species to treat the hepatocellular carcinoma (HCC) cells SMMC-7721, Huh7 and HCCLM3 in vitro and the HCCLM3 cell line in vivo. The HCC cells were cultured with various concentrations of Fucoidan-Sargassum (0-30 mg/mL). Migration, invasion and wound healing assays were performed to determine the antimetastatic effect of fucoidan on the HCC cells. Western blot analysis and immunofluorescence staining were conducted to determine the expression levels of invadopodia formation-regulating proteins and the targeting membrane receptor proteins. Results: Fucoidan-Sargassum inhibited the migration and invasion of HCC SMMC-7721, Huh7 and HCCLM3 cells in a dose-dependent manner. In the HCCLM3 cells, Fucoidan-Sargassum also decreased the expression levels of invadopodia-related proteins including Src, Cortactin, N-WASP, ARP3, CDC42, MMP2, MT1-MMP, and the targeting receptors integrin αV and β3 in a dose-dependent manner. Fucoidan-Sargassum also increased the levels of endoplasmic reticulum-related proteins, including GRP78, IRE1, SPARC, and the type IV collagen receptor proteins integrin α1 and β1. In vivo, Fucoidan-Sargassum reduced the size of liver tumors and decreased the number of lung metastatic foci in nude mice with hepatocellular carcinoma xenografts. Conclusion: These findings indicate that Fucoidan-Sargassum has an antimetastatic effect on SMMC-7721, Huh7 and HCCLM3 liver cancer cells, and the underlying mechanism involves targeting ITGαVβ3 and mediating the ITGαVβ3/SRC/E2F1 signaling pathway. These results suggest that Fucoidan-Sargassum may be a promising therapeutic antimetastatic compound in the development of a metastasis-preventive drug for treating liver cancer.
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Affiliation(s)
- Ting-Jia Pan
- Department of Traditional Chinese Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Rd, Shanghai 200032, China
| | - Li-Xin Li
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Jia-Wei Zhang
- Department of Traditional Chinese Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Rd, Shanghai 200032, China
| | - Zhao-Shuo Yang
- Department of Traditional Chinese Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Rd, Shanghai 200032, China
| | - Dong-Min Shi
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Yun-Ke Yang
- Department of Traditional Chinese Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Rd, Shanghai 200032, China
| | - Wei-Zhong Wu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
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48
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Sharif T, Martell E, Dai C, Ghassemi-Rad MS, Hanes MR, Murphy PJ, Margam NN, Parmar HB, Giacomantonio CA, Duncan R, Lee PW, Gujar S. HDAC6 differentially regulates autophagy in stem-like versus differentiated cancer cells. Autophagy 2019; 15:686-706. [PMID: 30444165 PMCID: PMC6526821 DOI: 10.1080/15548627.2018.1548547] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Revised: 10/05/2018] [Accepted: 10/31/2018] [Indexed: 12/19/2022] Open
Abstract
Cancer stem-like cells (CSCs), a small population of pluripotent cells residing within heterogeneous tumor mass, remain highly resistant to various chemotherapies as compared to the differentiated cancer cells. It is being postulated that CSCs possess unique molecular mechanisms, such as autophagic homeostasis, that allow CSCs to withstand the therapeutic assaults. Here we demonstrate that HDAC6 inhibition differentially modulates macroautophagy/autophagy in CSCs as compared to that of differentiated cancer cells. Using human and murine CSC models and differentiated cells, we show that the inhibition or knockdown (KD) of HDAC6 decreases CSC pluripotency by downregulating major pluripotency factors POU5F1, NANOG and SOX2. This decreased HDAC6 expression increases ACTB, TUBB3 and CSN2 expression and promotes differentiation in CSCs in an apoptosis-independent manner. Mechanistically, HDAC6 KD in CSCs decreases pluripotency by promoting autophagy, whereas the inhibition of pluripotency via retinoic acid treatment, POU5F1 or autophagy-related gene (ATG7 and ATG12) KD in CSCs decreases HDAC6 expression and promotes differentiation. Interestingly, HDAC6 KD-mediated CSC growth inhibition is further enhanced in the presence of autophagy inducers Tat-Beclin 1 peptide and rapamycin. In contrast to the results observed in CSCs, HDAC6 KD in differentiated breast cancer cells downregulates autophagy and increases apoptosis. Furthermore, the autophagy regulator p-MTOR, upstream negative regulators of p-MTOR (TSC1 and TSC2) and downstream effectors of p-MTOR (p-RPS6KB and p-EIF4EBP1) are differentially regulated in CSCs versus differentiated cancer cells following HDAC6 KD. Overall these data identify the differential regulation of autophagy as a molecular link behind the differing chemo-susceptibility of CSCs and differentiated cancer cells.
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Affiliation(s)
- Tanveer Sharif
- Deaprtment of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Emma Martell
- Deaprtment of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Cathleen Dai
- Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
| | | | - Mark Robert Hanes
- Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Patrick J. Murphy
- Deaprtment of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Nandini N. Margam
- Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
| | | | - Carman A. Giacomantonio
- Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
- Surgery, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Roy Duncan
- Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
- Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada
- Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Patrick W.K. Lee
- Deaprtment of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada
- Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Shashi Gujar
- Deaprtment of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada
- Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
- Biology, Dalhousie University, Halifax, Nova Scotia, Canada
- Centre for Innovative and Collaborative Health Systems Research, IWK Health Centre, Halifax, Nova Scotia, Canada
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49
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Zhao J, Gray SG, Greene CM, Lawless MW. Unmasking the pathological and therapeutic potential of histone deacetylases for liver cancer. Expert Rev Gastroenterol Hepatol 2019; 13:247-256. [PMID: 30791763 DOI: 10.1080/17474124.2019.1568870] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, currently ranking as one of the highest neoplastic-related mortalities in the world. Due to the difficulty in early diagnosis and lack of effective treatment options, the 5-year survival rate of HCC remains extremely low. Histone deacetylation is one of the most important epigenetic mechanisms, regulating cellular events such as differentiation, proliferation and cell cycle. Histone deacetylases (HDACs), the chief mediators of this epigenetic mechanism, are often aberrantly expressed in various tumours including HCC. Areas covered: This review focuses on the most up-to-date findings of HDACs and their associated molecular mechanisms in HCC onset and progression. In addition, a potential network between HDACs and non-coding RNAs including microRNAs and long noncoding RNAs underlying hepatocarcinogenesis is considered. Expert opinion: Unmasking the role of HDACs and their association with HCC pathogenesis could have implications for future personalized therapeutic and diagnostic targeting.
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Affiliation(s)
- Jun Zhao
- a Experimental Medicine, UCD School of Medicine and Medical Science , Mater Misericordiae University Hospital , Dublin , Ireland
| | - Steven G Gray
- b Department of Clinical Medicine , Trinity Centre for Health Sciences, Trinity Translational Medicine Institute, St. James's Hospital & Trinity College , Dublin , Ireland
| | - Catherine M Greene
- c Clinical Microbiology , Royal College of Surgeons in Ireland, Beaumont Hospital , Dublin , Ireland
| | - Matthew W Lawless
- a Experimental Medicine, UCD School of Medicine and Medical Science , Mater Misericordiae University Hospital , Dublin , Ireland
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50
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Cai J, Yang J, Liu Q, Gong Y, Zhang Y, Zheng Y, Yu D, Zhang Z. Mir-215-5p induces autophagy by targeting PI3K and activating ROS-mediated MAPK pathways in cardiomyocytes of chicken. J Inorg Biochem 2019; 193:60-69. [PMID: 30684759 DOI: 10.1016/j.jinorgbio.2019.01.010] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2018] [Revised: 01/07/2019] [Accepted: 01/13/2019] [Indexed: 02/01/2023]
Abstract
Our previous study revealed that selenium (Se) deficiency can cause myocardial injury through triggering autophagy. MicroRNAs (miRNAs) play crucial roles in autophagic cell death. However, the relationship between miRNAs and myocardial autophagy injury caused by Se deficiency remains unclear. We selected differential microRNA-215-5p (miR-215-5p) in Se-deficient myocardial tissue using high-throughput miRNA-sequencing. To further explore the role of miR-215-5p in myocardial injury, overexpression/knockdown of miR-215-5p in primary cardiomyocyte model was established by miRNAs interference technology. In this study, we report that miR-215-5p can promote myocardial autophagy by directly binding to the 3'untranslated region (3'UTR) of phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3K). Its target gene PI3K was confirmed by dual luciferase reporter assay, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot in cardiomyocytes. Our results showed that overexpression of miR-215-5p could trigger myocardial autophagy through PI3K-threonine-protein kinase (AKT)-target of rapamycin (TOR) pathway. Further studies revealed that autophagic cell death was dependent on the activation of extracellular signal-regulated kinase1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), p38 kinase (p38) and generation of reactive oxygen species (ROS) in overexpression of miR-215-5p in cardiomyocytes. On the contrary, miR-215-5p inhibitor can enhance cell survival capacity against autophagy by inhibiting ROS-mitogen-activated protein kinase (MAPK) pathways and activating the PI3K/AKT/TOR pathway in cardiomyocytes. Together, our findings support that miR-215-5p may modulate cell survival programs by regulating autophagy, and miR-215-5p acts as an autophagic regulator in the regulatory feedback loop that regulates cardiomyocyte survival by modulating the PI3K/AKT/TOR pathway and ROS-dependent MAPK pathways.
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Affiliation(s)
- Jingzeng Cai
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Jie Yang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Qi Liu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Yafan Gong
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Yuan Zhang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Yingying Zheng
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Dahai Yu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Ziwei Zhang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China; Key Laboratory of the Provincial Education, Department of Heilongjiang for Common Animal Disease Prevention and Treatment, PR China.
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