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Zhong H, Jiang J, Hussain M, Zhang H, Chen L, Guan R. The Encapsulation Strategies for Targeted Delivery of Probiotics in Preventing and Treating Colorectal Cancer: A Review. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2500304. [PMID: 40192333 PMCID: PMC12079478 DOI: 10.1002/advs.202500304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 03/01/2025] [Indexed: 05/16/2025]
Abstract
Colorectal cancer (CRC) ranks as the third most prevalent cancer worldwide. It is associated with imbalanced gut microbiota. Probiotics can help restore this balance, potentially reducing the risk of CRC. However, the hostile environment and constant changes in the gastrointestinal tract pose significant challenges to the efficient delivery of probiotics to the colon. Traditional delivery methods are often insufficient due to their low viability and lack of targeting. To address these challenges, researchers are increasingly focusing on innovative encapsulation technologies. One such approach is single-cell encapsulation, which involves applying nanocoatings to individual probiotic cells. This technique can improve their resistance to the harsh gastrointestinal environment, enhance mucosal adhesion, and facilitate targeted release, thereby increasing the effectiveness of probiotic delivery. This article reviews the latest developments in probiotic encapsulation methods for targeted CRC treatment, emphasizing the potential benefits of emerging single-cell encapsulation techniques. It also analyzes and compares the advantages and disadvantages of current encapsulation technologies. Furthermore, it elucidates the underlying mechanisms through which probiotics can prevent and treat CRC, evaluates the efficacy and safety of probiotics in CRC treatment and adjuvant therapy, and discusses future directions and potential challenges in the targeted delivery of probiotics for CRC treatment and prevention.
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Affiliation(s)
- Hao Zhong
- College of Food Science and TechnologyZhejiang University of TechnologyHangzhou310014China
| | - Jin Jiang
- College of Food Science and TechnologyZhejiang University of TechnologyHangzhou310014China
| | - Muhammad Hussain
- College of Food Science and TechnologyZhejiang University of TechnologyHangzhou310014China
- Moganshan Institute ZJUTKangqianDeqing313200China
| | - Haoxuan Zhang
- College of Food Science and TechnologyZhejiang University of TechnologyHangzhou310014China
| | - Ling Chen
- Sanya Branch of Hainan Academy of Inspection and TestingSan Ya572011China
| | - Rongfa Guan
- College of Food Science and TechnologyZhejiang University of TechnologyHangzhou310014China
- Moganshan Institute ZJUTKangqianDeqing313200China
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Rampanelli E, Romp N, Troise AD, Ananthasabesan J, Wu H, Gül IS, De Pascale S, Scaloni A, Bäckhed F, Fogliano V, Nieuwdorp M, Bui TPN. Gut bacterium Intestinimonas butyriciproducens improves host metabolic health: evidence from cohort and animal intervention studies. MICROBIOME 2025; 13:15. [PMID: 39833973 PMCID: PMC11744835 DOI: 10.1186/s40168-024-02002-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 12/10/2024] [Indexed: 01/22/2025]
Abstract
BACKGROUND The human gut microbiome strongly influences host metabolism by fermenting dietary components into metabolites that signal to the host. Our previous work has shown that Intestinimonas butyriciproducens is a prevalent commensal bacterium with the unique ability to convert dietary fructoselysine to butyrate, a well-known signaling molecule with proven health benefits. Dietary fructoselysine is an abundant Amadori product formed in foods during thermal treatment and is part of foods rich in dietary advanced glycation end products which have been associated with cardiometabolic disease. It is therefore of interest to investigate the causal role of this bacterium and fructoselysine metabolism in metabolic disorders. RESULTS We assessed associations of I. butyriciproducens with metabolic risk biomarkers at both strain and functional levels using a human cohort characterized by fecal metagenomic analysis. We observed that the level of the bacterial strain as well as fructoselysine fermentation genes were negatively associated with BMI, triglycerides, HbA1c, and fasting insulin levels. We also investigated the fructoselysine degradation capacity within the Intestinimonas genus using a culture-dependent approach and found that I. butyriciproducens is a key player in the butyrogenic fructoselysine metabolism in the gut. To investigate the function of I. butyriciproducens in host metabolism, we used the diet-induced obesity mouse model to mimic the human metabolic syndrome. Oral supplementation with I. butyriciproducens counteracted body weight gain, hyperglycemia, and adiposity. In addition, within the inguinal white adipose tissue, bacterial administration reduced inflammation and promoted pathways involved in browning and insulin signaling. The observed effects may be partly attributable to the formation of the short-chain fatty acids butyrate from dietary fructoselysine, as butyrate plasma and cecal levels were significantly increased by the bacterial strain, thereby contributing to the systemic effects of the bacterial treatment. CONCLUSIONS I. butyriciproducens ameliorates host metabolism in the context of obesity and may therefore be a good candidate for new microbiota-therapeutic approaches to prevent or treat metabolic diseases. Video Abstract.
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Affiliation(s)
- Elena Rampanelli
- Department of Experimental Vascular Medicine, Amsterdam UMC, Amsterdam, the Netherlands
- Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam, the Netherlands
| | - Nadia Romp
- Department of Experimental Vascular Medicine, Amsterdam UMC, Amsterdam, the Netherlands
- Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam, the Netherlands
| | - Antonio Dario Troise
- Proteomics, Metabolomics & Mass Spectrometry Laboratory, Institute for the Animal Production System in the Mediterranean Environment, National Research Council, 80055, Portici (Naples), Italy
| | | | - Hao Wu
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan Microbiome Center, and Human Phenome Institute, Fudan University, Shanghai, 200438, China
| | | | - Sabrina De Pascale
- Proteomics, Metabolomics & Mass Spectrometry Laboratory, Institute for the Animal Production System in the Mediterranean Environment, National Research Council, 80055, Portici (Naples), Italy
| | - Andrea Scaloni
- Proteomics, Metabolomics & Mass Spectrometry Laboratory, Institute for the Animal Production System in the Mediterranean Environment, National Research Council, 80055, Portici (Naples), Italy
| | - Fredrik Bäckhed
- The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Bruna Stråket 16, 41345, Gothenburg, Sweden
| | - Vincenzo Fogliano
- Department of Food Quality and Design, Wageningen University, Wageningen, the Netherlands
| | - Max Nieuwdorp
- Department of Experimental Vascular Medicine, Amsterdam UMC, Amsterdam, the Netherlands
| | - Thi Phuong Nam Bui
- Department of Experimental Vascular Medicine, Amsterdam UMC, Amsterdam, the Netherlands.
- Laboratory of Microbiology, Wageningen University, Wageningen, the Netherlands.
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Ho J, Puoplo N, Pokharel N, Hirdaramani A, Hanyaloglu AC, Cheng CW. Nutrigenomic underpinnings of intestinal stem cells in inflammatory bowel disease and colorectal cancer development. Front Genet 2024; 15:1349717. [PMID: 39280096 PMCID: PMC11393785 DOI: 10.3389/fgene.2024.1349717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 08/12/2024] [Indexed: 09/18/2024] Open
Abstract
Food-gene interaction has been identified as a leading risk factor for inflammatory bowel disease (IBD) and colorectal cancer (CRC). Accordingly, nutrigenomics emerges as a new approach to identify biomarkers and therapeutic targets for these two strongly associated gastrointestinal diseases. Recent studies in stem cell biology have further shown that diet and nutrition signal to intestinal stem cells (ISC) by altering nutrient-sensing transcriptional activities, thereby influencing barrier integrity and susceptibility to inflammation and tumorigenesis. This review recognizes the dietary factors related to both CRC and IBD and investigates their impact on the overlapping transcription factors governing stem cell activities in homeostasis and post-injury responses. Our objective is to provide a framework to study the food-gene regulatory network of disease-contributing cells and inspire new nutrigenomic approaches for detecting and treating diet-related IBD and CRC.
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Affiliation(s)
- Jennifer Ho
- Institute of Human Nutrition, Columbia University Irving Medical Center, New York City, NY, United States
- Columbia Stem Cell Initiative, Columbia University Irving Medical Center, New York City, NY, United States
| | - Nicholas Puoplo
- Columbia Stem Cell Initiative, Columbia University Irving Medical Center, New York City, NY, United States
- Division of Neonatology-Perinatology, Department of Pediatrics, Columbia University Irving Medical Center, New York City, NY, United States
| | - Namrata Pokharel
- Columbia Stem Cell Initiative, Columbia University Irving Medical Center, New York City, NY, United States
| | - Aanya Hirdaramani
- Department of Metabolism, Digestion and Reproduction, Division of Digestive Diseases, Section of Nutrition, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Aylin C Hanyaloglu
- Department of Metabolism, Digestion and Reproduction, Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Chia-Wei Cheng
- Columbia Stem Cell Initiative, Columbia University Irving Medical Center, New York City, NY, United States
- Department of Genetics and Development, Columbia University Irving Medical Center, New York City, NY, United States
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Zheng P, Gao W, Cong S, Leng L, Wang T, Shi L. High-Energy Supplemental Feeding Shifts Gut Microbiota Composition and Function in Red Deer ( Cervus elaphus). Animals (Basel) 2024; 14:1428. [PMID: 38791646 PMCID: PMC11117297 DOI: 10.3390/ani14101428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 05/02/2024] [Accepted: 05/07/2024] [Indexed: 05/26/2024] Open
Abstract
Winter supplemental feeding (SF) is commonly used to improve the survival of captive wildlife. To investigate the impact of winter supplementation on the gut microbiota of wildlife, we assessed changes in the gut microbiota of red deer (Cervus elaphus) during the supplementary and non-supplementary feeding (NSF) groups using 16S rRNA sequencing technology. We found no significant differences in the diversity of the gut microbiota between SF and NSF except for the Simpson's index. However, the relative abundance of Bacteroidetes, Lentisphaerae, and Proteobacteria in the gut microbiota was significantly higher during SF. Further, genera such as Intestinimonas, Rikenella, Lawsonibacter, Muribaculum, and Papillibacter were more abundant during SF. Beta diversity analysis showed significant differences between SF and NSF. The microbes detected during SF were primarily associated with lipid metabolism, whereas those detected during NSF were linked to fiber catabolism. High-energy feed affects the gut microbial composition and function in red deer. During SF, the gut microbes in red deer were enriched in microorganisms associated with butyrate and lipid metabolism, such as R. microfusus, M. intestinale, and Papillibacter cinnamivorans. These gut microbes may be involved in ameliorating obesity associated with high-energy diets. In summary, SF is a reasonable and effective management strategy.
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Affiliation(s)
- Peng Zheng
- College of Animal Sciences, Xinjiang Agricultural University, Urumqi 830052, China; (P.Z.); (W.G.)
- Key Laboratory of Ecological Adaptation and Evolution of Extreme Environment Biology in Xinjiang, College of Life Sciences, Xinjiang Agricultural University, Urumqi 830052, China; (L.L.); (T.W.)
| | - Weizhen Gao
- College of Animal Sciences, Xinjiang Agricultural University, Urumqi 830052, China; (P.Z.); (W.G.)
- Key Laboratory of Ecological Adaptation and Evolution of Extreme Environment Biology in Xinjiang, College of Life Sciences, Xinjiang Agricultural University, Urumqi 830052, China; (L.L.); (T.W.)
| | - Shaobo Cong
- Xinjiang Tianshan Wildlife Park, Urumqi 830039, China;
| | - Lin Leng
- Key Laboratory of Ecological Adaptation and Evolution of Extreme Environment Biology in Xinjiang, College of Life Sciences, Xinjiang Agricultural University, Urumqi 830052, China; (L.L.); (T.W.)
| | - Tao Wang
- Key Laboratory of Ecological Adaptation and Evolution of Extreme Environment Biology in Xinjiang, College of Life Sciences, Xinjiang Agricultural University, Urumqi 830052, China; (L.L.); (T.W.)
| | - Lei Shi
- College of Animal Sciences, Xinjiang Agricultural University, Urumqi 830052, China; (P.Z.); (W.G.)
- Key Laboratory of Ecological Adaptation and Evolution of Extreme Environment Biology in Xinjiang, College of Life Sciences, Xinjiang Agricultural University, Urumqi 830052, China; (L.L.); (T.W.)
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Chen Z, Guan D, Wang Z, Li X, Dong S, Huang J, Zhou W. Microbiota in cancer: molecular mechanisms and therapeutic interventions. MedComm (Beijing) 2023; 4:e417. [PMID: 37937304 PMCID: PMC10626288 DOI: 10.1002/mco2.417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 10/04/2023] [Accepted: 10/12/2023] [Indexed: 11/09/2023] Open
Abstract
The diverse bacterial populations within the symbiotic microbiota play a pivotal role in both health and disease. Microbiota modulates critical aspects of tumor biology including cell proliferation, invasion, and metastasis. This regulation occurs through mechanisms like enhancing genomic damage, hindering gene repair, activating aberrant cell signaling pathways, influencing tumor cell metabolism, promoting revascularization, and remodeling the tumor immune microenvironment. These microbiota-mediated effects significantly impact overall survival and the recurrence of tumors after surgery by affecting the efficacy of chemoradiotherapy. Moreover, leveraging the microbiota for the development of biovectors, probiotics, prebiotics, and synbiotics, in addition to utilizing antibiotics, dietary adjustments, defensins, oncolytic virotherapy, and fecal microbiota transplantation, offers promising alternatives for cancer treatment. Nonetheless, due to the extensive and diverse nature of the microbiota, along with tumor heterogeneity, the molecular mechanisms underlying the role of microbiota in cancer remain a subject of intense debate. In this context, we refocus on various cancers, delving into the molecular signaling pathways associated with the microbiota and its derivatives, the reshaping of the tumor microenvironmental matrix, and the impact on tolerance to tumor treatments such as chemotherapy and radiotherapy. This exploration aims to shed light on novel perspectives and potential applications in the field.
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Affiliation(s)
- Zhou Chen
- The First Clinical Medical CollegeLanzhou UniversityLanzhouGansuChina
- The First Hospital of Lanzhou UniversityLanzhouGansuChina
| | - Defeng Guan
- The First Clinical Medical CollegeLanzhou UniversityLanzhouGansuChina
- The First Hospital of Lanzhou UniversityLanzhouGansuChina
| | - Zhengfeng Wang
- The First Clinical Medical CollegeLanzhou UniversityLanzhouGansuChina
- The First Hospital of Lanzhou UniversityLanzhouGansuChina
| | - Xin Li
- The Second Clinical Medical CollegeLanzhou UniversityLanzhouGansuChina
- The Department of General SurgeryLanzhou University Second HospitalLanzhouGansuChina
| | - Shi Dong
- The Second Clinical Medical CollegeLanzhou UniversityLanzhouGansuChina
- The Department of General SurgeryLanzhou University Second HospitalLanzhouGansuChina
| | - Junjun Huang
- The First Hospital of Lanzhou UniversityLanzhouGansuChina
| | - Wence Zhou
- The First Clinical Medical CollegeLanzhou UniversityLanzhouGansuChina
- The Department of General SurgeryLanzhou University Second HospitalLanzhouGansuChina
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Zhang Y, Tao Y, Gu Y, Ma Q. Butyrate facilitates immune clearance of colorectal cancer cells by suppressing STAT1-mediated PD-L1 expression. Clinics (Sao Paulo) 2023; 78:100303. [PMID: 37931529 PMCID: PMC10654141 DOI: 10.1016/j.clinsp.2023.100303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 10/20/2023] [Indexed: 11/08/2023] Open
Abstract
OBJECTIVE Immunotherapy has been proven to improve the prognosis of patients with advanced malignancy but has shown limited efficacy in patients with Colorectal Cancer (CRC). Increasing evidence suggests that butyrate, a bacterial metabolite, enhances the efficacy of cancer therapies by modulating immune responses. Here, the effect and the mechanism of butyrate on anti-PD-L1 therapy were investigated in CRC. METHODS The expression of PD-L1 and STAT1, and the lysine acetylation of STAT1 in CRC cells were observed after treatment with butyrate (2, 5, and 10 mM) for 24h or butyrate (5 mM) for 8, 16, and 24h. Site-directed mutations of STAT1 (K410R or K413R) were introduced to determine the role of STAT1 acetylation in modulating PD-L1 expression. The effect of butyrate on the cytotoxicity of CD8+ T-cells against CRC cells with or without PD-L1 overexpression was explored in vitro and in vivo. RESULTS Butyrate could suppress IFN-γ-induced PD-L1 up-regulation in CRC cells in a dose- and time-dependent way. Butyrate promoted the lysine acetylation of STAT1 to reduce STAT1 expression. Non-acetylated mutant STAT1 not only ameliorated butyrate-induced suppression of lysine acetylation and nuclear translocation of STAT1 but also blocked the effect of butyrate on PD-L1. Butyrate attenuated the IFN-γ-induced impairment of CD8+ T-cell cytotoxicity against CRC cells. Meanwhile, butyrate suppressed CRC tumor growth by enhancing CD8+ T-cell infiltration. However, directly overexpressing PD-L1 in CRC cells could abolish the effect of butyrate. CONCLUSION Butyrate strengthens the immune response to CRC cells by suppressing PD-L1 expression via acetylation of STAT1.
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Affiliation(s)
- Yan Zhang
- Department of Pathology, Beijing Changping Traditional Chinese Medicine Hospital, Beijing, China
| | - Yuan Tao
- Department of Gastroenterology, Beijing Changping Traditional Chinese Medicine Hospital, Beijing, China
| | - Yuqing Gu
- Department of Pathology, Beijing Changping Traditional Chinese Medicine Hospital, Beijing, China
| | - Qiujie Ma
- Department of Pathology, Guang'anmen Hospital South Campus, China Academy of Chinese Medical Sciences, Beijing, China.
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Li Y, Huang Y, Liang H, Wang W, Li B, Liu T, Huang Y, Zhang Z, Qin Y, Zhou X, Wang R, Huang T. The roles and applications of short-chain fatty acids derived from microbial fermentation of dietary fibers in human cancer. Front Nutr 2023; 10:1243390. [PMID: 37614742 PMCID: PMC10442828 DOI: 10.3389/fnut.2023.1243390] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 07/21/2023] [Indexed: 08/25/2023] Open
Abstract
Dietary fibers (DFs) and their metabolites attract significant attention in research on health and disease, attributing to their effects on regulating metabolism, proliferation, inflammation, and immunity. When fermented by gut microbiota, DFs mainly produce short-chain fatty acids (SCFAs), such as acetic acid, propionic acid, and butyric acid. As the essential nutrients for intestinal epithelial cells, SCFAs maintain intestinal homeostasis and play essential roles in a wide range of biological functions. SCFAs have been found to inhibit histone deacetylase, activate G protein-coupled receptors, and modulate the immune response, which impacts cancer and anti-cancer treatment. Notably, while extensive studies have illuminated the roles of SCFAs in colorectal cancer development, progression, and treatment outcomes, limited evidence is available for other types of cancers. This restricts our understanding of the complex mechanisms and clinical applications of SCFAs in tumors outside the intestinal tract. In this study, we provide a comprehensive summary of the latest evidence on the roles and mechanisms of SCFAs, with a focus on butyric acid and propionic acid, derived from microbial fermentation of DFs in cancer. Additionally, we recapitulate the clinical applications of SCFAs in cancer treatments and offer our perspectives on the challenges, limitations, and prospects of utilizing SCFAs in cancer research and therapy.
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Affiliation(s)
- Yuanqing Li
- Department of Radiation Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, China
| | - Yaxuan Huang
- Department of Otolaryngology-Head and Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Haili Liang
- Guangxi Zhuang Autonomous Region Institute of Product Quality Inspection (GXQT), Nanning, China
| | - Wen Wang
- Guangxi Zhuang Autonomous Region Institute of Product Quality Inspection (GXQT), Nanning, China
| | - Bo Li
- Department of Radiation Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Ting Liu
- Department of Radiation Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yuqi Huang
- The First School of Clinical Medicine, Guangxi Medical University, Nanning, China
| | - Zhe Zhang
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, China
- Department of Otolaryngology-Head and Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yutao Qin
- Department of Radiation Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xiaoying Zhou
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, China
- Life Science Institute, Guangxi Medical University, Nanning, China
| | - Rensheng Wang
- Department of Radiation Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, China
| | - Tingting Huang
- Department of Radiation Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, China
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Wong CC, Yu J. Gut microbiota in colorectal cancer development and therapy. Nat Rev Clin Oncol 2023:10.1038/s41571-023-00766-x. [PMID: 37169888 DOI: 10.1038/s41571-023-00766-x] [Citation(s) in RCA: 225] [Impact Index Per Article: 112.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/13/2023] [Indexed: 05/13/2023]
Abstract
Colorectal cancer (CRC) is one of the commonest cancers globally. A unique aspect of CRC is its intimate association with the gut microbiota, which forms an essential part of the tumour microenvironment. Research over the past decade has established that dysbiosis of gut bacteria, fungi, viruses and Archaea accompanies colorectal tumorigenesis, and these changes might be causative. Data from mechanistic studies demonstrate the ability of the gut microbiota to interact with the colonic epithelia and immune cells of the host via the release of a diverse range of metabolites, proteins and macromolecules that regulate CRC development. Preclinical and some clinical evidence also underscores the role of the gut microbiota in modifying the therapeutic responses of patients with CRC to chemotherapy and immunotherapy. Herein, we summarize our current understanding of the role of gut microbiota in CRC and outline the potential translational and clinical implications for CRC diagnosis, prevention and treatment. Emphasis is placed on how the gut microbiota could now be better harnessed by developing targeted microbial therapeutics as chemopreventive agents against colorectal tumorigenesis, as adjuvants for chemotherapy and immunotherapy to boost drug efficacy and safety, and as non-invasive biomarkers for CRC screening and patient stratification. Finally, we highlight the hurdles and potential solutions to translating our knowledge of the gut microbiota into clinical practice.
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Affiliation(s)
- Chi Chun Wong
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Jun Yu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
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Cheng C, Yin Y, Bian G. Effects of whole maize high-grain diet feeding on colonic fermentation and bacterial community in weaned lambs. Front Microbiol 2022; 13:1018284. [PMID: 36569065 PMCID: PMC9772272 DOI: 10.3389/fmicb.2022.1018284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Accepted: 11/22/2022] [Indexed: 12/13/2022] Open
Abstract
High-grain diet is commonly used in intensive production to boost yield in short term, which may cause adverse effects such as rumen and colonic acidosis in ruminants. Maize is one of the key components of high-grain diet, and different processing methods of maize affect the digestive absorption and gastrointestinal development of ruminants. To investigate the effects of maize form in high-grain diets on colonic fermentation and bacterial community of weaned lambs, twenty-two 2.5-month-old healthy Hu lambs were fed separately a maize meal low-grain diet (19.2% grain; CON), a maize meal high-grain diet (50.4% grain; CM), and a whole maize high-grain diet (50.4% grain; CG). After 7 weeks of feeding, the total volatile fatty acid concentration (P = 0.035) were significantly higher in lambs from CM than that from CON. The sequencing results of colonic content microbial composition revealed that the relative abundance of genera Parasutterella (P = 0.028), Comamonas (P = 0.031), Butyricicoccus (P = 0.049), and Olsenella (P = 0.010) were higher in CM than those in CON; compared with CM, the CG diet had the higher relative abundance of genera Bacteroides (P = 0.024) and Angelakisella (P = 0.020), while the lower relative abundance of genera Olsenella (P = 0.031) and Paraprevotella (P = 0.006). For colonic mucosal microbiota, the relative abundance of genera Duncaniella (P = 0.024), Succiniclasticum (P = 0.044), and Comamonas (P = 0.012) were significantly higher in CM than those in CON. In comparison, the relative abundance of genera Alistipes (P = 0.020) and Campylobacter (P = 0.017) were significantly lower. And the relative abundance of genera Colidextribacter (P = 0.005), Duncaniella (P = 0.032), Christensenella (P = 0.042), and Lawsonibacter (P = 0.018) were increased in the CG than those in the CM. Furthermore, the CG downregulated the relative abundance of genes encoding infectious-disease-parasitic (P = 0.049), cancer-specific-types (P = 0.049), and neurodegenerative-disease (P = 0.037) in colonic microbiota than those in the CM. Overall, these results indicated that maize with different grain sizes might influence the colonic health of weaned lambs by altering the composition of the colonic bacterial community.
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Affiliation(s)
- Chao Cheng
- College of Animal Science and Food Engineering, Jinling Institute of Technology, Nanjing, China
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Yuyang Yin
- Huzhou Academy of Agricultural Sciences, Huzhou, China
| | - Gaorui Bian
- College of Animal Science and Food Engineering, Jinling Institute of Technology, Nanjing, China
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Relationship between gut microbiota and colorectal cancer: Probiotics as a potential strategy for prevention. Food Res Int 2022; 156:111327. [DOI: 10.1016/j.foodres.2022.111327] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 04/27/2022] [Accepted: 04/28/2022] [Indexed: 12/15/2022]
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Jourova L, Anzenbacherova E, Dostal Z, Anzenbacher P, Briolotti P, Rigal E, Daujat-Chavanieu M, Gerbal-Chaloin S. Butyrate, a typical product of gut microbiome, affects function of the AhR gene, being a possible agent of crosstalk between gut microbiome and hepatic drug metabolism. J Nutr Biochem 2022; 107:109042. [PMID: 35533897 DOI: 10.1016/j.jnutbio.2022.109042] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 01/11/2022] [Accepted: 03/21/2022] [Indexed: 02/06/2023]
Abstract
Modulation of gut microbiome composition seems to be a promising therapeutic strategy for a wide range of pathological states. However, these microbiota-targeted interventions may affect production of microbial metabolites, circulating factors in the gut-liver axis influencing hepatic drug metabolism with possible clinical relevance. Butyrate, a short-chain fatty acid produced through microbial fermentation of dietary fibers in the colon, has well established anti-inflammatory role in the intestine, while the effect of butyrate on the liver is unknown. In this study, we have evaluated the effect of butyrate on hepatic AhR activity and AhR-regulated gene expression. We have showed that AhR and its target genes were upregulated by butyrate in dose dependent manner in HepG2-C3 as well as in primary human hepatocytes. The involvement of AhR has been proved using specific AhR antagonist and siRNA-mediated AhR silencing. Experiments with AhR reporter cells have shown that butyrate regulates the expression of AhR target genes by modulating the AhR activity. Our results suggest also epigenetic action by butyrate on AhR and its repressor (AHRR) presumably through mechanisms based on HDAC inhibition in the liver. Our results demonstrate that butyrate may influence the drug metabolizing ability of liver enzymes e.g. through the interaction with AhR dependent pathways.
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Affiliation(s)
- Lenka Jourova
- Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hněvotínská 3, Olomouc 775 15, Czech Republic.
| | - Eva Anzenbacherova
- Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hněvotínská 3, Olomouc 775 15, Czech Republic
| | - Zdenek Dostal
- Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hněvotínská 3, Olomouc 775 15, Czech Republic
| | - Pavel Anzenbacher
- Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hněvotínská 3, Olomouc 775 15, Czech Republic
| | - Philippe Briolotti
- IRMB, University Montpellier, INSERM, CHU Montpellier, Montpellier, France
| | - Emilie Rigal
- IRMB, University Montpellier, INSERM, CHU Montpellier, Montpellier, France
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12
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Kim N. Sex Difference of Colorectal Cancer. SEX/GENDER-SPECIFIC MEDICINE IN THE GASTROINTESTINAL DISEASES 2022:301-339. [DOI: 10.1007/978-981-19-0120-1_20] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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13
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Chiang CJ, Hong YH. In situ delivery of biobutyrate by probiotic Escherichia coli for cancer therapy. Sci Rep 2021; 11:18172. [PMID: 34518590 PMCID: PMC8438071 DOI: 10.1038/s41598-021-97457-3] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 08/18/2021] [Indexed: 02/08/2023] Open
Abstract
Butyrate has a bioactive function to reduce carcinogenesis. To achieve targeted cancer therapy, this study developed bacterial cancer therapy (BCT) with butyrate as a payload. By metabolic engineering, Escherichia coli Nissle 1917 (EcN) was reprogrammed to synthesize butyrate (referred to as biobutyrate) and designated EcN-BUT. The adopted strategy includes construction of a synthetic pathway for biobutyrate and the rational design of central metabolism to increase the production of biobutyrate at the expense of acetate. With glucose, EcN-BUT produced primarily biobutyrate under the hypoxic condition. Furthermore, human colorectal cancer cell was administrated with the produced biobutyrate. It caused the cell cycle arrest at the G1 phase and induced the mitochondrial apoptosis pathway independent of p53. In the tumor-bearing mice, the injected EcN-BUT exhibited tumor-specific colonization and significantly reduced the tumor volume by 70%. Overall, this study opens a new avenue for BCT based on biobutyrate.
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Affiliation(s)
- Chung-Jen Chiang
- Department of Medical Laboratory Science and Biotechnology, China Medical University, No. 91, Hsueh-Shih Road, Taichung, Taiwan, 40402.
| | - Yan-Hong Hong
- Department of Chemical Engineering, Feng Chia University, Taichung, Taiwan, 40724
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14
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Tomari H, Kawamura T, Asanoma K, Egashira K, Kawamura K, Honjo K, Nagata Y, Kato K. Contribution of senescence in human endometrial stromal cells during proliferative phase to embryo receptivity†. Biol Reprod 2021; 103:104-113. [PMID: 32285109 PMCID: PMC7313258 DOI: 10.1093/biolre/ioaa044] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Revised: 02/25/2020] [Accepted: 04/10/2020] [Indexed: 12/15/2022] Open
Abstract
Successful assisted reproductive technology pregnancy depends on the viability of embryos and endometrial receptivity. However, the literature has neglected effects of the endometrial environment during the proliferative phase on implantation success or failure. Human endometrial stromal cells (hESCs) were isolated from endometrial tissues sampled at oocyte retrieval during the proliferative phase from women undergoing infertility treatment. Primary hESC cultures were used to investigate the relationship between stemness and senescence induction in this population and embryo receptivity. Patients were classified as receptive or non-receptive based on their pregnancy diagnosis after embryo transfer. Biomarkers of cellular senescence and somatic stem cells were compared between each sample. hESCs from non-receptive patients exhibited significantly higher (P < 0.01) proportions of senescent cells, mRNA expressions of CDKN2A and CDKN1A transcripts (P < 0.01), and expressions of genes encoding the senescence-associated secretory phenotype (P < 0.05). hESCs from receptive patients had significantly higher (P < 0.01) mRNA expressions of ABCG2 and ALDH1A1 transcripts. Our findings suggest that stemness is inversely associated with senescence induction in hESCs and, by extension, that implantation failure in infertility treatment may be attributable to a combination of senescence promotion and disruption of this maintenance function in this population during the proliferative phase of the menstrual cycle. This is a promising step towards potentially improving the embryo receptivity of endometrium. The specific mechanism by which implantation failure is prefigured by a loss of stemness among endometrial stem cells, and cellular senescence induction among hESCs, should be elucidated in detail in the future.
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Affiliation(s)
- Hiroyuki Tomari
- Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.,Center for Reproductive Medicine, IVF Nagata Clinic, Fukuoka, Japan
| | - Teruhiko Kawamura
- Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kazuo Asanoma
- Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Katsuko Egashira
- Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Keiko Kawamura
- Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Ko Honjo
- Center for Reproductive Medicine, IVF Nagata Clinic, Fukuoka, Japan
| | - Yumi Nagata
- Center for Reproductive Medicine, IVF Nagata Clinic, Fukuoka, Japan
| | - Kiyoko Kato
- Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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15
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Mahananda B, Vinay J, Palo A, Singh A, Sahu SK, Singh SP, Dixit M. SERPINB5 Genetic Variants rs2289519 and rs2289521 are Significantly Associated with Gallbladder Cancer Risk. DNA Cell Biol 2021; 40:706-712. [PMID: 33691472 DOI: 10.1089/dna.2021.0056] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Serine protease inhibitor b5 (SERPINB5) is a tumor suppressor gene that plays a critical role in various cellular processes. In gallbladder cancer (GBC), SERPINB5's aberrant expression is reported but its role in genetic predisposition is not known. We enrolled 270 cases and 296 controls and genotyped them for single nucleotide polymorphisms (SNPs) using direct DNA sequencing, followed by genotype-phenotype analysis in GBC and other cancer cell lines. Luciferase assay was done to determine the role of rs2289521 SNP on expression regulation. We found that two SERPINB5 variants rs2289519 and rs2289521 are significantly associated with GBC and contribute to genetic predisposition. The TT genotype of variant rs2289519 was found to be significantly associated (p = 0.008) with GBC in a recessive model. C allele of rs2289521 increased the risk for GBC significantly at genotypic (CT, p = 0.026) and allelic (p = 0.04) levels. In silico analysis and luciferase assay uncovered the probable regulatory role of the rs2289521 variant on expression. Genotype-phenotype correlation in GBC and breast cancer cell lines showed reduced expression of SERPINB5 in the presence of C allele that was consistent with the result of luciferase assay. Overall, our study reveals the genetic association of two SERPINB5 variants with GBC and rs2289521's possible role in the regulation of expression.
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Affiliation(s)
- Biswaheree Mahananda
- School of Biological Sciences, National Institute of Science Education and Research, Bhubaneswar, India.,Homi Bhabha National Institute, Mumbai, India
| | - J Vinay
- School of Biological Sciences, National Institute of Science Education and Research, Bhubaneswar, India.,Homi Bhabha National Institute, Mumbai, India
| | - Ananya Palo
- School of Biological Sciences, National Institute of Science Education and Research, Bhubaneswar, India.,Homi Bhabha National Institute, Mumbai, India
| | - Ayaskanta Singh
- Department of Gastroenterology and Hepato-Biliary Sciences, IMS & SUM Hospital, Sikshya O Anusandhan University, Bhubaneswar, India
| | - Saroj Kanta Sahu
- Department of Gastroenterology and Hepato-Biliary Sciences, IMS & SUM Hospital, Sikshya O Anusandhan University, Bhubaneswar, India
| | - Shivaram Prasad Singh
- Department of Gastroenterology, Sriram Chandra Bhanja Medical College and Hospital, Cuttack, India
| | - Manjusha Dixit
- School of Biological Sciences, National Institute of Science Education and Research, Bhubaneswar, India.,Homi Bhabha National Institute, Mumbai, India
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16
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Wu D, Yan Y, Wei T, Ye Z, Xiao Y, Pan Y, Orme JJ, Wang D, Wang L, Ren S, Huang H. An acetyl-histone vulnerability in PI3K/AKT inhibition-resistant cancers is targetable by both BET and HDAC inhibitors. Cell Rep 2021; 34:108744. [PMID: 33596421 DOI: 10.1016/j.celrep.2021.108744] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 10/06/2020] [Accepted: 01/20/2021] [Indexed: 02/08/2023] Open
Abstract
Acquisition of resistance to phosphatidylinositol 3-kinase (PI3K)/AKT-targeted monotherapy implies the existence of common resistance mechanisms independent of cancer type. Here, we demonstrate that PI3K/AKT inhibitors cause glycolytic crisis, acetyl-coenzyme A (CoA) shortage, and a global decrease in histone acetylation. In addition, PI3K/AKT inhibitors induce drug resistance by selectively augmenting histone H3 lysine 27 acetylation (H3K27ac) and binding of CBP/p300 and BRD4 proteins at a subset of growth factor and receptor (GF/R) gene loci. BRD4 occupation at these loci and drug-resistant cell growth are vulnerable to both bromodomain and histone deacetylase (HDAC) inhibitors. Little or no occupation of HDAC proteins at the GF/R gene loci underscores the paradox that cells respond equivalently to the two classes of inhibitors with opposite modes of action. Targeting this unique acetyl-histone-related vulnerability offers two clinically viable strategies to overcome PI3K/AKT inhibitor resistance in different cancers.
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Affiliation(s)
- Di Wu
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, MN 55905, USA; Wuxi Institute of Health Sciences of Beijing Institute of Genomics, Wuxi 214174, China
| | - Yuqian Yan
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, MN 55905, USA
| | - Ting Wei
- Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA
| | - Zhenqing Ye
- Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA
| | - Yutian Xiao
- Department of Urology, Shanghai Changhai Hospital, Shanghai 200433, China
| | - Yunqian Pan
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, MN 55905, USA
| | - Jacob J Orme
- Division of Medical Oncology, Department of Internal Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Dejie Wang
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, MN 55905, USA
| | - Liguo Wang
- Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA.
| | - Shancheng Ren
- Wuxi Institute of Health Sciences of Beijing Institute of Genomics, Wuxi 214174, China; Department of Urology, Shanghai Changhai Hospital, Shanghai 200433, China.
| | - Haojie Huang
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, MN 55905, USA; Department of Urology, Mayo Clinic College of Medicine and Science, MN 55905, USA; Mayo Clinic Cancer Center, Mayo Clinic College of Medicine and Science, MN 55905, USA.
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17
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Shi F, Li Y, Han R, Fu A, Wang R, Nusbaum O, Qin Q, Chen X, Hou L, Zhu Y. Valerian and valeric acid inhibit growth of breast cancer cells possibly by mediating epigenetic modifications. Sci Rep 2021; 11:2519. [PMID: 33510252 PMCID: PMC7844014 DOI: 10.1038/s41598-021-81620-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 01/06/2021] [Indexed: 12/27/2022] Open
Abstract
Valerian root (Valeriana officinalis) is a popular and widely available herbal supplement used to treat sleeping disorders and insomnia. The herb's ability to ameliorate sleep dysfunction may signify an unexplored anti-tumorigenic effect due to the connection between circadian factors and tumorigenesis. Of particular interest are the structural similarities shared between valeric acid, valerian's active chemical ingredient, and certain histone deacteylase (HDAC) inhibitors, which imply that valerian may play a role in epigenetic gene regulation. In this study, we tested the hypothesis that the circadian-related herb valerian can inhibit breast cancer cell growth and explored epigenetic changes associated with valeric acid treatment. Our results showed that aqueous valerian extract reduced growth of breast cancer cells. In addition, treatment of valeric acid was associated with decreased breast cancer cell proliferation, migration, colony formation and 3D formation in vitro in a dose- and time-dependent manner, as well as reduced HDAC activity and a global DNA hypomethylation. Overall, these findings demonstrate that valeric acid can decrease the breast cancer cell proliferation possibly by mediating epigenetic modifications such as the inhibition of histone deacetylases and alterations of DNA methylation. This study highlights a potential utility of valeric acid as a novel HDAC inhibitor and a therapeutic agent in the treatment of breast cancer.
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Affiliation(s)
- Fengqin Shi
- Department of Environmental Health Sciences, Yale University School of Public Health, New Haven, CT, 06520, USA
- Department of Oncology and Hematology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Ya Li
- Department of Environmental Health Sciences, Yale University School of Public Health, New Haven, CT, 06520, USA
- Department of Oncology and Hematology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Rui Han
- Department of Environmental Health Sciences, Yale University School of Public Health, New Haven, CT, 06520, USA
- Department of Oncology and Hematology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Alan Fu
- Department of Environmental Health Sciences, Yale University School of Public Health, New Haven, CT, 06520, USA
| | - Ronghua Wang
- Department of Environmental Health Sciences, Yale University School of Public Health, New Haven, CT, 06520, USA
- Department of Oncology and Hematology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Olivia Nusbaum
- Department of Environmental Health Sciences, Yale University School of Public Health, New Haven, CT, 06520, USA
| | - Qin Qin
- Department of Environmental Health Sciences, Yale University School of Public Health, New Haven, CT, 06520, USA
| | - Xinyi Chen
- Department of Oncology and Hematology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Li Hou
- Department of Environmental Health Sciences, Yale University School of Public Health, New Haven, CT, 06520, USA
- Department of Oncology and Hematology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Yong Zhu
- Department of Environmental Health Sciences, Yale University School of Public Health, New Haven, CT, 06520, USA.
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18
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Niina A, Kibe R, Suzuki R, Yuchi Y, Teshima T, Matsumoto H, Kataoka Y, Koyama H. Fecal microbiota transplantation as a new treatment for canine inflammatory bowel disease. BIOSCIENCE OF MICROBIOTA FOOD AND HEALTH 2020; 40:98-104. [PMID: 33996366 PMCID: PMC8099633 DOI: 10.12938/bmfh.2020-049] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 11/10/2020] [Indexed: 12/14/2022]
Abstract
In human medicine, fecal microbiota transplantation (FMT) is an effective treatment for recurrent Clostridioides difficile infection. It has also been tested as a treatment for multiple gastrointestinal diseases, including inflammatory bowel disease (IBD). However, only a few studies have focused on the changes in the microbiome following FMT for canine IBD. Here, we performed FMT in nine dogs with IBD using the fecal matter of healthy dogs and investigated the subsequent changes in the fecal microbiome and clinical signs. In three dogs, the fecal microbiome was examined by 16S rRNA sequencing. Fusobacteria were observed at a low proportion in dogs with IBD. However, the post-FMT microbiome became diverse and showed a significant increase in Fusobacteria proportion. Fusobacterium was detected in the nine dogs by quantitative polymerase chain reaction. The proportion of Fusobacterium in the post-FMT fecal microbiome was significantly increased (p<0.05). The changes in clinical signs (e.g., vomiting, diarrhea, and weight loss) were evaluated according to the canine inflammatory bowel disease activity index. The score of this index significantly decreased in all dogs (p<0.05) with improvements in clinical signs. These improvements were related to the changes in the proportion of microbes, particularly the increase in Fusobacterium. The dogs with IBD showed a lower proportion of Fusobacterium than healthy dogs. This suggests that a low proportion of Fusobacterium is a characteristic feature of canine IBD and that Fusobacterium is involved in this disease. The results of this study may help elucidate the pathogenesis of this disease and its association with Fusobacterium.
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Affiliation(s)
- Ayaka Niina
- Laboratory of Veterinary Internal Medicine, School of Veterinary Medicine, Faculty of Veterinary Medicine, Nippon Veterinary and Life Science University, 1-7-1 Kyonan-cho, Musashino-shi, Tokyo 180-8602, Japan
| | - Ryoko Kibe
- Laboratory of Veterinary Microbiology, School of Veterinary Medicine, Faculty of Veterinary Medicine, Nippon Veterinary and Life Science University, 1-7-1 Kyonan-cho, Musashino-shi, Tokyo 180-8602, Japan
| | - Ryohei Suzuki
- Laboratory of Veterinary Internal Medicine, School of Veterinary Medicine, Faculty of Veterinary Medicine, Nippon Veterinary and Life Science University, 1-7-1 Kyonan-cho, Musashino-shi, Tokyo 180-8602, Japan
| | - Yunosuke Yuchi
- Laboratory of Veterinary Internal Medicine, School of Veterinary Medicine, Faculty of Veterinary Medicine, Nippon Veterinary and Life Science University, 1-7-1 Kyonan-cho, Musashino-shi, Tokyo 180-8602, Japan
| | - Takahiro Teshima
- Laboratory of Veterinary Internal Medicine, School of Veterinary Medicine, Faculty of Veterinary Medicine, Nippon Veterinary and Life Science University, 1-7-1 Kyonan-cho, Musashino-shi, Tokyo 180-8602, Japan
| | - Hirotaka Matsumoto
- Laboratory of Veterinary Internal Medicine, School of Veterinary Medicine, Faculty of Veterinary Medicine, Nippon Veterinary and Life Science University, 1-7-1 Kyonan-cho, Musashino-shi, Tokyo 180-8602, Japan
| | - Yasushi Kataoka
- Laboratory of Veterinary Microbiology, School of Veterinary Medicine, Faculty of Veterinary Medicine, Nippon Veterinary and Life Science University, 1-7-1 Kyonan-cho, Musashino-shi, Tokyo 180-8602, Japan
| | - Hidekazu Koyama
- Laboratory of Veterinary Internal Medicine, School of Veterinary Medicine, Faculty of Veterinary Medicine, Nippon Veterinary and Life Science University, 1-7-1 Kyonan-cho, Musashino-shi, Tokyo 180-8602, Japan
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19
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ATM inhibition overcomes resistance to histone deacetylase inhibitor due to p21 induction and cell cycle arrest. Oncotarget 2020; 11:3432-3442. [PMID: 32973968 PMCID: PMC7500109 DOI: 10.18632/oncotarget.27723] [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: 03/14/2020] [Accepted: 06/20/2020] [Indexed: 12/05/2022] Open
Abstract
The antiproliferative effect induced by histone deactylase inhibitors (HDACi) is associated with the up-regulated expression of the cyclin-dependent kinase inhibitor p21. Paradoxically, the increased expression of p21 correlates with a reduced cell killing to the drug. The direct targeting of p21 is not feasible. An alternate approach could selectively target factors upstream or downstream of p21 that affect one or more specific aspects of p21 function. HDAC inhibitors appear to activate p21 expression via ataxia telangiectasia mutated (ATM) activity. KU60019, a specific ATM inhibitor, has shown to decrease the p21 protein levels in a concentration dependent manner. We explored the potential synergistic interaction of the ATM inhibitor with romidepsin, given the potential complementary impact around p21. A synergistic cytotoxic effect was observed in all lymphoma cell lines examined when the HDACi was combined with KU60019. The increase in apoptosis correlates with decreased expression of p21 due to the ATM inhibitor. KU60019 decreased expression of the cyclin-dependent kinase inhibitor at the transcriptional level, compromising the ability of HDACi to induce p21 and cell cycle arrest and ultimately facilitating a shift toward the apoptotic phase. Central to the increased apoptosis observed when romidepsin is combined with KU60019 is the reduced expression of p21 and the absence of a G2/M cell cycle arrest that would be exploited by the tumor cells to evade the cytotoxic effect of the HDAC inhibitor. We believe this strategy may offer a promising way to identify rational combinations for HDACi directed therapy, improving their activity in malignant disease.
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20
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Gomes SD, Oliveira CS, Azevedo-Silva J, Casanova MR, Barreto J, Pereira H, Chaves SR, Rodrigues LR, Casal M, Côrte-Real M, Baltazar F, Preto A. The Role of Diet Related Short-Chain Fatty Acids in Colorectal Cancer Metabolism and Survival: Prevention and Therapeutic Implications. Curr Med Chem 2020; 27:4087-4108. [PMID: 29848266 DOI: 10.2174/0929867325666180530102050] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Revised: 12/22/2017] [Accepted: 05/15/2018] [Indexed: 12/16/2022]
Abstract
Colorectal Cancer (CRC) is a major cause of cancer-related death worldwide. CRC increased risk has been associated with alterations in the intestinal microbiota, with decreased production of Short Chain Fatty Acids (SCFAs). SCFAs produced in the human colon are the major products of bacterial fermentation of undigested dietary fiber and starch. While colonocytes use the three major SCFAs, namely acetate, propionate and butyrate, as energy sources, transformed CRC cells primarily undergo aerobic glycolysis. Compared to normal colonocytes, CRC cells exhibit increased sensitivity to SCFAs, thus indicating they play an important role in cell homeostasis. Manipulation of SCFA levels in the intestine, through changes in microbiota, has therefore emerged as a potential preventive/therapeutic strategy for CRC. Interest in understanding SCFAs mechanism of action in CRC cells has increased in the last years. Several SCFA transporters like SMCT-1, MCT-1 and aquaporins have been identified as the main transmembrane transporters in intestinal cells. Recently, it was shown that acetate promotes plasma membrane re-localization of MCT-1 and triggers changes in the glucose metabolism. SCFAs induce apoptotic cell death in CRC cells, and further mechanisms have been discovered, including the involvement of lysosomal membrane permeabilization, associated with mitochondria dysfunction and degradation. In this review, we will discuss the current knowledge on the transport of SCFAs by CRC cells and their effects on CRC metabolism and survival. The impact of increasing SCFA production by manipulation of colon microbiota on the prevention/therapy of CRC will also be addressed.
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Affiliation(s)
- Sara Daniela Gomes
- CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho,
Campus de Gualtar, 4710-057 Braga, Portugal,ICVS - Life and Health Sciences Research Institute, School of Medicine, University of Minho, Braga, Portugal
| | - Cláudia Suellen Oliveira
- CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho,
Campus de Gualtar, 4710-057 Braga, Portugal,ICBAS - Institute of Biomedical Sciences Abel Salazar, University of Porto, 4050-313 Porto, Portugal
| | - João Azevedo-Silva
- CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho,
Campus de Gualtar, 4710-057 Braga, Portugal
| | - Marta R Casanova
- CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho,
Campus de Gualtar, 4710-057 Braga, Portugal,CEB - Centre of Biological Engineering, University of Minho, Braga, Portugal
| | - Judite Barreto
- CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho,
Campus de Gualtar, 4710-057 Braga, Portugal
| | - Helena Pereira
- CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho,
Campus de Gualtar, 4710-057 Braga, Portugal
| | - Susana R Chaves
- CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho,
Campus de Gualtar, 4710-057 Braga, Portugal
| | - Lígia R Rodrigues
- CEB - Centre of Biological Engineering, University of Minho, Braga, Portugal
| | - Margarida Casal
- CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho,
Campus de Gualtar, 4710-057 Braga, Portugal
| | - Manuela Côrte-Real
- CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho,
Campus de Gualtar, 4710-057 Braga, Portugal
| | - Fátima Baltazar
- ICVS - Life and Health Sciences Research Institute, School of Medicine, University of Minho, Braga, Portugal,ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Ana Preto
- CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho,
Campus de Gualtar, 4710-057 Braga, Portugal
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21
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Chen R, Zhang M, Zhou Y, Guo W, Yi M, Zhang Z, Ding Y, Wang Y. The application of histone deacetylases inhibitors in glioblastoma. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:138. [PMID: 32682428 PMCID: PMC7368699 DOI: 10.1186/s13046-020-01643-6] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 07/13/2020] [Indexed: 12/14/2022]
Abstract
The epigenetic abnormality is generally accepted as the key to cancer initiation. Epigenetics that ensure the somatic inheritance of differentiated state is defined as a crucial factor influencing malignant phenotype without altering genotype. Histone modification is one such alteration playing an essential role in tumor formation, progression, and resistance to treatment. Notably, changes in histone acetylation have been strongly linked to gene expression, cell cycle, and carcinogenesis. The balance of two types of enzyme, histone acetyltransferases (HATs) and histone deacetylases (HDACs), determines the stage of histone acetylation and then the architecture of chromatin. Changes in chromatin structure result in transcriptional dysregulation of genes that are involved in cell-cycle progression, differentiation, apoptosis, and so on. Recently, HDAC inhibitors (HDACis) are identified as novel agents to keep this balance, leading to numerous researches on it for more effective strategies against cancers, including glioblastoma (GBM). This review elaborated influences on gene expression and tumorigenesis by acetylation and the antitumor mechanism of HDACis. Besdes, we outlined the preclinical and clinical advancement of HDACis in GBM as monotherapies and combination therapies.
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Affiliation(s)
- Rui Chen
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Mengxian Zhang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Yangmei Zhou
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Wenjing Guo
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Ming Yi
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Ziyan Zhang
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510000, Guangdong, China
| | - Yanpeng Ding
- Department of Oncology, Zhongnan Hospital, Wuhan University, Wuhan, 430030, China
| | - Yali Wang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
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22
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Toumazi D, Constantinou C. A Fragile Balance: The Important Role of the Intestinal Microbiota in the Prevention and Management of Colorectal Cancer. Oncology 2020; 98:593-602. [PMID: 32604093 DOI: 10.1159/000507959] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 04/16/2020] [Indexed: 11/19/2022]
Abstract
BACKGROUND Colorectal cancer is the second leading cause of cancer-related death worldwide. In recent years, researchers have focussed on the role of the intestinal microbiota in both the prevention and the treatment of colorectal cancer. SUMMARY The evidence in the literature supports that there is a fragile balance between different species of bacteria in the human gut. A disturbance of this balance towards increased levels of the bacteria Fusobacterium nucleatum and Bacteroides fragilis is associated with an increased risk of colorectal cancer. The mechanisms involved include the release of toxins which activate inflammation and the regulation of specific miRNAs (with an increase in the expression of oncogenic miRNAs and a decrease in the expression of tumour suppressor miRNAs), thereby increasing cell proliferation and leading to tumorigenesis. On the other hand, Lactobacillus and Bifidobacterium have a protective effect against the development of colorectal cancer through mechanisms that involve an increase in the levels of anticarcinogenic metabolites such as butyrate and a decrease in the activity of proinflammatory pathways. Even though preliminary studies support that the use of probiotics in the prevention and management of colorectal cancer is promising, more research is needed in this field. Key Message: The association between the intestinal microbiota, diet and colorectal cancer remains an active area of research with expected future applications in the use of probiotics for the prevention and management of this significant disease.
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Affiliation(s)
- Daniela Toumazi
- Department of Basic and Clinical Sciences, University of Nicosia Medical School, Nicosia, Cyprus
| | - Constantina Constantinou
- Department of Basic and Clinical Sciences, University of Nicosia Medical School, Nicosia, Cyprus,
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23
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Liao P, Bhattarai N, Cao B, Zhou X, Jung JH, Damera K, Fuselier TT, Thareja S, Wimley WC, Wang B, Zeng SX, Lu H. Crotonylation at serine 46 impairs p53 activity. Biochem Biophys Res Commun 2020; 524:730-735. [PMID: 32035620 PMCID: PMC7703795 DOI: 10.1016/j.bbrc.2020.01.152] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 01/27/2020] [Indexed: 02/03/2023]
Abstract
Post-translational modifications (PTMs) play pivotal roles in controlling the stability and activity of the tumor suppressor p53 in response to distinct stressors. Here we report an unexpected finding of a short chain fatty acid modification of p53 in human cells. Crotonic acid (CA) treatment induces p53 crotonylation, but surprisingly reduces its protein, but not mRNA level, leading to inhibition of p53 activity in a dose dependent fashion. Surprisingly this crotonylation targets serine 46, instead of any predicted lysine residues, of p53, as detected in TCEP-probe labeled crotonylation and anti-crotonylated peptide antibody reaction assays. This is further confirmed by substitution of serine 46 with alanine, which abolishes p53 crotonylation in vitro and in cells. CA increases p53-dependent glycolytic activity, and augments cancer cell proliferation in response to metabolic or DNA damage stress. Since serine 46 is only found in human p53, our studies unveil an unconventional PTM unique for human p53, impairing its activity in response to CA. Because CA is likely produced by the gut microbiome, our results also predict that this type of PTM might play a role in early human colorectal neoplasia development by negating p53 activity without mutation of this tumor suppressor gene.
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Affiliation(s)
- Peng Liao
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA, 70112, USA; Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, 70112, USA; Department of Surgery, University of Michigan of Medicine, Ann Arbor, MI, USA
| | - Nimisha Bhattarai
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA, 70112, USA; Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Bo Cao
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA, 70112, USA; Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Xiang Zhou
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA, 70112, USA; Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, 70112, USA; Cancer Institute of Fudan University-Shanghai Cancer Hospital, Shanghai, China
| | - Ji Hoon Jung
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA, 70112, USA; Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, 70112, USA; Department of Korean Pathology, College of Korean Medicine, Kyung Hee Seoul, 02447, South Korea
| | - Krishna Damera
- Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, 30303, USA
| | - Taylor T Fuselier
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Suresh Thareja
- Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, 30303, USA
| | - William C Wimley
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Binghe Wang
- Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, 30303, USA
| | - Shelya X Zeng
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA, 70112, USA; Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Hua Lu
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA, 70112, USA; Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, 70112, USA.
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24
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Lambert IH, Nielsen D, Stürup S. Impact of the histone deacetylase inhibitor trichostatin A on active uptake, volume-sensitive release of taurine, and cell fate in human ovarian cancer cells. Am J Physiol Cell Physiol 2020; 318:C581-C597. [PMID: 31913698 DOI: 10.1152/ajpcell.00460.2019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The histone deacetylase inhibitor trichostatin A (TSA) reduces cell viability in cisplatin-sensitive (A2780WT) and cisplatin-resistant (A2780RES) human ovarian cancer cells due to progression of apoptosis (increased caspase-9 activity), autophagy (increased LC3-II expression), and cell cycle arrest (increased p21 expression). The TSA-mediated effect on p21 and caspase-9 is mainly p53 independent. Cisplatin increases DNA-damage (histone H2AX phosphorylation) in A2780WT cells, whereas cisplatin, due to reduced uptake [inductively coupled-plasma-mass spectrometry (Pt) analysis], has no DNA-damaging effect in A2780RES cells. TSA has no effect on cisplatin accumulation or cisplatin-induced DNA-damage in A2780WT/A2780RES cells. Tracer technique indicates that TSA inhibits the volume-sensitive organic anion channel (VSOAC) in A2780WT/A2780RES cells and that the activity is restored by exogenous H2O2. As TSA reduces NOX4 mRNA accumulation and concomitantly increases catalase mRNA/protein accumulation, we suggest that TSA increases the antioxidative defense in A2780 cells. Inhibition of the kinase mTOR (rapamycin, palomid, siRNA), which is normally associated with cell growth, reduces VSOAC activity synergistically to TSA. However, as TSA increases mTOR activity (phosphorylation of 4EBP1, S6 kinase, S6, ULK1, SGK1), the effect of TSA on VSOAC activity does not reflect the shift in mTOR signaling. Upregulation of the protein expression and activity of the taurine transporter (TauT) is a phenotypic characteristic of A2780RES cells. However, TSA reduces TauT protein expression in A2780RES cells and activity to values seen in A2780WT cells. It is suggested that therapeutic benefits of TSA in A2780 do not imply facilitation of cisplatin uptake but more likely a synergistic activation of apoptosis/autophagy and reduced TauT activity.
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Affiliation(s)
- Ian Henry Lambert
- Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Dorthe Nielsen
- Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Stefan Stürup
- Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark
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25
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Dong J, Tai JW, Lu LF. miRNA-Microbiota Interaction in Gut Homeostasis and Colorectal Cancer. Trends Cancer 2019; 5:666-669. [PMID: 31735285 DOI: 10.1016/j.trecan.2019.08.003] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 08/23/2019] [Accepted: 08/27/2019] [Indexed: 12/15/2022]
Abstract
Gut homeostasis is maintained by dynamic host-microbiota interactions. Recently, miRNAs have emerged as key molecular regulators in the mediation of such interactions. Here, we discuss the role of a host miRNA-microbiome axis in gut homeostasis and colorectal cancer (CRC) and the involvement of diet and microbial metabolites in miRNA-mediated intestinal health.
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Affiliation(s)
- Jiayi Dong
- Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA
| | - Jesse W Tai
- Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA
| | - Li-Fan Lu
- Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA 92093, USA.
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26
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Autin P, Blanquart C, Fradin D. Epigenetic Drugs for Cancer and microRNAs: A Focus on Histone Deacetylase Inhibitors. Cancers (Basel) 2019; 11:E1530. [PMID: 31658720 PMCID: PMC6827107 DOI: 10.3390/cancers11101530] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 09/09/2019] [Accepted: 10/03/2019] [Indexed: 02/06/2023] Open
Abstract
Over recent decades, it has become clear that epigenetic abnormalities are involved in the hallmarks of cancer. Histone modifications, such as acetylation, play a crucial role in cancer development and progression, by regulating gene expression, such as for oncogenes or tumor suppressor genes. Therefore, histone deacetylase inhibitors (HDACi) have recently shown efficacy against both hematological and solid cancers. Designed to target histone deacetylases (HDAC), these drugs can modify the expression pattern of numerous genes including those coding for micro-RNAs (miRNA). miRNAs are small non-coding RNAs that regulate gene expression by targeting messenger RNA. Current research has found that miRNAs from a tumor can be investigated in the tumor itself, as well as in patient body fluids. In this review, we summarized current knowledge about HDAC and HDACi in several cancers, and described their impact on miRNA expression. We discuss briefly how circulating miRNAs may be used as biomarkers of HDACi response and used to investigate response to treatment.
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Affiliation(s)
- Pierre Autin
- CRCINA, INSERM, Université d'Angers, Université de Nantes, 44007 Nantes, France.
| | - Christophe Blanquart
- CRCINA, INSERM, Université d'Angers, Université de Nantes, 44007 Nantes, France.
| | - Delphine Fradin
- CRCINA, INSERM, Université d'Angers, Université de Nantes, 44007 Nantes, France.
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27
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Disruption of the Molecular Circadian Clock and Cancer: An Epigenetic Link. Biochem Genet 2019; 58:189-209. [DOI: 10.1007/s10528-019-09938-w] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Accepted: 09/03/2019] [Indexed: 01/08/2023]
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28
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Blanquart C, Linot C, Cartron PF, Tomaselli D, Mai A, Bertrand P. Epigenetic Metalloenzymes. Curr Med Chem 2019; 26:2748-2785. [PMID: 29984644 DOI: 10.2174/0929867325666180706105903] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Revised: 06/04/2018] [Accepted: 06/04/2018] [Indexed: 12/12/2022]
Abstract
Epigenetics controls the expression of genes and is responsible for cellular phenotypes. The fundamental basis of these mechanisms involves in part the post-translational modifications (PTMs) of DNA and proteins, in particular, the nuclear histones. DNA can be methylated or demethylated on cytosine. Histones are marked by several modifications including acetylation and/or methylation, and of particular importance are the covalent modifications of lysine. There exists a balance between addition and removal of these PTMs, leading to three groups of enzymes involved in these processes: the writers adding marks, the erasers removing them, and the readers able to detect these marks and participating in the recruitment of transcription factors. The stimulation or the repression in the expression of genes is thus the result of a subtle equilibrium between all the possibilities coming from the combinations of these PTMs. Indeed, these mechanisms can be deregulated and then participate in the appearance, development and maintenance of various human diseases, including cancers, neurological and metabolic disorders. Some of the key players in epigenetics are metalloenzymes, belonging mostly to the group of erasers: the zinc-dependent histone deacetylases (HDACs), the iron-dependent lysine demethylases of the Jumonji family (JMJ or KDM) and for DNA the iron-dependent ten-eleven-translocation enzymes (TET) responsible for the oxidation of methylcytosine prior to the demethylation of DNA. This review presents these metalloenzymes, their importance in human disease and their inhibitors.
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Affiliation(s)
- Christophe Blanquart
- CRCINA, INSERM, Universite d'Angers, Universite de Nantes, Nantes, France.,Réseau Epigénétique du Cancéropôle Grand Ouest, France
| | - Camille Linot
- CRCINA, INSERM, Universite d'Angers, Universite de Nantes, Nantes, France
| | - Pierre-François Cartron
- CRCINA, INSERM, Universite d'Angers, Universite de Nantes, Nantes, France.,Réseau Epigénétique du Cancéropôle Grand Ouest, France
| | - Daniela Tomaselli
- Department of Chemistry and Technologies of Drugs, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy
| | - Antonello Mai
- Department of Chemistry and Technologies of Drugs, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy.,Pasteur Institute - Cenci Bolognetti Foundation, Sapienza University of Rome, Rome, Italy
| | - Philippe Bertrand
- Réseau Epigénétique du Cancéropôle Grand Ouest, France.,Institut de Chimie des Milieux et Matériaux de Poitiers, UMR CNRS 7285, 4 rue Michel Brunet, TSA 51106, B27, 86073, Poitiers cedex 09, France
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29
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Chen Q, Swist E, Kafenzakis M, Raju J, Brooks SPJ, Scoggan KA. Fructooligosaccharides and wheat bran fed at similar fermentation levels differentially affect the expression of genes involved in transport, signaling, apoptosis, cell proliferation, and oncogenesis in the colon epithelia of healthy Fischer 344 rats. Nutr Res 2019; 69:101-113. [PMID: 31675536 DOI: 10.1016/j.nutres.2019.07.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 05/17/2019] [Accepted: 07/30/2019] [Indexed: 10/26/2022]
Abstract
The influence of the source of fermentable material (FM) on the luminal concentrations of their end products and its effects on colon cell metabolism and disease susceptibility is not well characterized. We hypothesized that total fermentation but not the source (type) of FM would be the main factor in determining cellular /molecular outcomes in the healthy colon epithelia. The main aim of this study was to elucidate the role of two different sources of FM, fructooligosaccharides (FOS) and wheat bran (WB), on the expression of genes involved in short chain fatty acid (SCFA) transport, G-protein signaling, apoptosis, cell proliferation and oncogenesis in colon epithelia of healthy rats. Male Fischer 344 rats (n = 10/group) were fed AIN-93G control (0% FM) or experimental diets containing WB (~1%, 2%, or 5% FM) or FOS (~2%, 5%, or 8% FM). Rats were killed after 6 weeks and the colon mucosa was assessed for the expression of target genes using real-time quantitative polymerase chain reaction. By comparison to the control, dose-related changes of mRNA levels were found in rats fed FOS-based diets, including: (a) upregulation of three SCFA transporters (Smct2, Mct1 and Mct4) but downregulation of Mct2, (b) upregulation of Gpr109a and downregulation of Gpr120, Gpr43, Gprc5a, Rgs2 and Rgs16, (c) upregulation of apoptosis-related genes including Bcl2, Bcl2-like 1, Bak1, Caspase 3, Caspase 8 and Caspase 9, (d) downregulation of the oncogenes and metastasis genes Ros1, Fos, Cd44, Fn1 and Plau, and (e) downregulation of several genes involved in cellular proliferation including Hbegf, Hoxb13, Cgref1, Wfdc1, Tgm3, Fgf7, Nov and Lumican. In contrast, rats fed WB-based diets resulted in dose-related upregulation of mRNA levels of Smct2, Rgs16, Gprc5a, Gpr109a, Bcl2-like 1, Caspase 8, and Fos. Additionally, different gene expression responses were observed in rats fed FOS and WB at 2% and 5% FM. Over all, these gene changes elicited by FOS and WB were independent of the expression of the tumor suppressor Tp53. These results suggest that fermentation alone is not the sole determinant of gene responses in the healthy rat colon.
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Affiliation(s)
- Qixuan Chen
- Canadian Food Inspection Agency, Ottawa, Ontario, Canada
| | - Eleonora Swist
- Nutrition Research Division, Food Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada
| | - Morgan Kafenzakis
- Nutrition Research Division, Food Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada
| | - Jayadev Raju
- Regulatory Toxicology Research Division, Food Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada.
| | - Stephen P J Brooks
- Nutrition Research Division, Food Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada.
| | - Kylie A Scoggan
- Nutrition Research Division, Food Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada; Sector Strategies Division, Safe Environments Directorate, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario, Canada
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30
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Wang G, Yu Y, Wang YZ, Wang JJ, Guan R, Sun Y, Shi F, Gao J, Fu XL. Role of SCFAs in gut microbiome and glycolysis for colorectal cancer therapy. J Cell Physiol 2019; 234:17023-17049. [PMID: 30888065 DOI: 10.1002/jcp.28436] [Citation(s) in RCA: 123] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2018] [Revised: 02/02/2019] [Accepted: 02/14/2019] [Indexed: 12/19/2022]
Abstract
Increased risk of colorectal cancer (CRC) is associated with altered intestinal microbiota as well as short-chain fatty acids (SCFAs) reduction of output The energy source of colon cells relies mainly on three SCFAs, namely butyrate (BT), propionate, and acetate, while CRC transformed cells rely mainly on aerobic glycolysis to provide energy. This review summarizes recent research results for dysregulated glucose metabolism of SCFAs, which could be initiated by gut microbiome of CRC. Moreover, the relationship between SCFA transporters and glycolysis, which may correlate with the initiation and progression of CRC, are also discussed. Additionally, this review explores the linkage of BT to transport of SCFAs expressions between normal and cancerous colonocyte cell growth for tumorigenesis inhibition in CRC. Furthermore, the link between gut microbiota and SCFAs in the metabolism of CRC, in addition, the proteins and genes related to SCFAs-mediated signaling pathways, coupled with their correlation with the initiation and progression of CRC are also discussed. Therefore, targeting the SCFA transporters to regulate lactate generation and export of BT, as well as applying SCFAs or gut microbiota and natural compounds for chemoprevention may be clinically useful for CRCs treatment. Future research should focus on the combination these therapeutic agents with metabolic inhibitors to effectively target the tumor SCFAs and regulate the bacterial ecology for activation of potent anticancer effect, which may provide more effective application prospect for CRC therapy.
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Affiliation(s)
- Gang Wang
- Department of Pharmaceutics, Shanghai Eighth People's Hospital, Jiangsu University, Shanghai, China
| | - Yang Yu
- Department of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Yu-Zhu Wang
- Department of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Jun-Jie Wang
- Department of Pharmaceutics, Shanghai Eighth People's Hospital, Jiangsu University, Shanghai, China
| | - Rui Guan
- Information Resources Department, Hubei University of Medicine, Shiyan, Hubei, China
| | - Yan Sun
- Information Resources Department, Hubei University of Medicine, Shiyan, Hubei, China
| | - Feng Shi
- Department of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Jing Gao
- Department of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Xing-Li Fu
- Department of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
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31
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Marié IJ, Chang HM, Levy DE. HDAC stimulates gene expression through BRD4 availability in response to IFN and in interferonopathies. J Exp Med 2018; 215:3194-3212. [PMID: 30463877 PMCID: PMC6279398 DOI: 10.1084/jem.20180520] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Revised: 08/15/2018] [Accepted: 10/19/2018] [Indexed: 01/12/2023] Open
Abstract
In contrast to the common role of histone deacetylases (HDACs) for gene repression, HDAC activity provides a required positive function for IFN-stimulated gene (ISG) expression. Here, we show that HDAC1/2 as components of the Sin3A complex are required for ISG transcriptional elongation but not for recruitment of RNA polymerase or transcriptional initiation. Transcriptional arrest by HDAC inhibition coincides with failure to recruit the epigenetic reader Brd4 and elongation factor P-TEFb due to sequestration of Brd4 on hyperacetylated chromatin. Brd4 availability is regulated by an equilibrium cycle between opposed acetyltransferase and deacetylase activities that maintains a steady-state pool of free Brd4 available for recruitment to inducible promoters. An ISG expression signature is a hallmark of interferonopathies and other autoimmune diseases. Combined inhibition of HDAC1/2 and Brd4 resolved the aberrant ISG expression detected in cells derived from patients with two inherited interferonopathies, ISG15 and USP18 deficiencies, defining a novel therapeutic approach to ISG-associated autoimmune diseases.
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Affiliation(s)
- Isabelle J Marié
- Departments of Pathology and Microbiology and Perlmutter Cancer Center, New York University School of Medicine, New York, NY
| | - Hao-Ming Chang
- Departments of Pathology and Microbiology and Perlmutter Cancer Center, New York University School of Medicine, New York, NY
| | - David E Levy
- Departments of Pathology and Microbiology and Perlmutter Cancer Center, New York University School of Medicine, New York, NY
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32
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Abstract
Purpose of Review Metabolic reprogramming is essential for the rapid proliferation of cancer cells and is thus recognized as a hallmark of cancer. In this review, we will discuss the etiologies and effects of metabolic reprogramming in colorectal cancer. Recent Findings Changes in cellular metabolism may precede the acquisition of driver mutations ultimately leading to colonocyte transformation. Oncogenic mutations and loss of tumor suppressor genes further reprogram CRC cells to upregulate glycolysis, glutaminolysis, one-carbon metabolism, and fatty acid synthesis. These metabolic changes are not uniform throughout tumors, as subpopulations of tumor cells may rely on different pathways to adapt to nutrient availability in the local tumor microenvironment. Finally, metabolic cross-communication between stromal cells, immune cells, and the gut microbiota enable CRC growth, invasion, and metastasis. Summary Altered cellular metabolism occurs in CRC at multiple levels, including in the cells that make up the bulk of CRC tumors, cancer stem cells, the tumor microenvironment, and host-microbiome interactions. This knowledge may inform the development of improved screening and therapeutics for CRC.
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Affiliation(s)
- Rachel E Brown
- Program in Cancer Biology, Vanderbilt University, Nashville, TN, USA.,Vanderbilt University School of Medicine, Vanderbilt University, Nashville, TN, USA
| | - Sarah P Short
- Program in Cancer Biology, Vanderbilt University, Nashville, TN, USA.,Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, B2215 Garland Ave., 1065D MRB-IV, Nashville, TN 37232-0252, USA
| | - Christopher S Williams
- Program in Cancer Biology, Vanderbilt University, Nashville, TN, USA.,Vanderbilt University School of Medicine, Vanderbilt University, Nashville, TN, USA.,Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, B2215 Garland Ave., 1065D MRB-IV, Nashville, TN 37232-0252, USA.,Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.,Veterans Affairs Tennessee Valley HealthCare System, Nashville, TN, USA
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33
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Lombardi VC, De Meirleir KL, Subramanian K, Nourani SM, Dagda RK, Delaney SL, Palotás A. Nutritional modulation of the intestinal microbiota; future opportunities for the prevention and treatment of neuroimmune and neuroinflammatory disease. J Nutr Biochem 2018; 61:1-16. [PMID: 29886183 PMCID: PMC6195483 DOI: 10.1016/j.jnutbio.2018.04.004] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2018] [Revised: 04/11/2018] [Accepted: 04/13/2018] [Indexed: 01/09/2023]
Abstract
The gut-brain axis refers to the bidirectional communication between the enteric nervous system and the central nervous system. Mounting evidence supports the premise that the intestinal microbiota plays a pivotal role in its function and has led to the more common and perhaps more accurate term gut-microbiota-brain axis. Numerous studies have identified associations between an altered microbiome and neuroimmune and neuroinflammatory diseases. In most cases, it is unknown if these associations are cause or effect; notwithstanding, maintaining or restoring homeostasis of the microbiota may represent future opportunities when treating or preventing these diseases. In recent years, several studies have identified the diet as a primary contributing factor in shaping the composition of the gut microbiota and, in turn, the mucosal and systemic immune systems. In this review, we will discuss the potential opportunities and challenges with respect to modifying and shaping the microbiota through diet and nutrition in order to treat or prevent neuroimmune and neuroinflammatory disease.
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Affiliation(s)
- Vincent C Lombardi
- Nevada Center for Biomedical Research, University of Nevada, Reno, 1664 N. Virginia St. MS 0552, Reno, NV, 89557, USA; University of Nevada, Reno, School of Medicine, Department of Pathology, 1664 N. Virginia St. MS 0357, Reno, NV, 89557, USA.
| | - Kenny L De Meirleir
- Nevada Center for Biomedical Research, University of Nevada, Reno, 1664 N. Virginia St. MS 0552, Reno, NV, 89557, USA.
| | - Krishnamurthy Subramanian
- Nevada Center for Biomedical Research, University of Nevada, Reno, 1664 N. Virginia St. MS 0552, Reno, NV, 89557, USA.
| | - Sam M Nourani
- University of Nevada, Reno, School of Medicine, Department of Internal Medicine, 1664 N. Virginia St. MS 0357, Reno, NV, 89557, USA; Advanced Therapeutic, General Gastroenterology & Hepatology Digestive Health Associates, Reno, NV, USA.
| | - Ruben K Dagda
- University of Nevada, Reno, School of Medicine, Department of Pharmacology, 1664 N. Virginia St. MS 0318, Reno, NV, 89557, USA.
| | | | - András Palotás
- Kazan Federal University, Institute of Fundamental Medicine and Biology, (Volga Region) 18 Kremlyovskaya St., Kazan, 420008, Republic of Tatarstan, Russian Federation; Asklepios-Med (private medical practice and research center), Kossuth Lajos sgt. 23, Szeged, H-6722, Hungary.
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34
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Yoon K, Kim N. The Effect of Microbiota on Colon Carcinogenesis. J Cancer Prev 2018; 23:117-125. [PMID: 30370256 PMCID: PMC6197845 DOI: 10.15430/jcp.2018.23.3.117] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Revised: 09/20/2018] [Accepted: 09/21/2018] [Indexed: 12/11/2022] Open
Abstract
Although genetic background is known to contribute to colon carcinogenesis, the exact etiology of the disease remains elusive. The organ’s extensive interaction with microbes necessitated research on the role of microbiota on development of colon cancer. In this review, we summarized the defense mechanism of colon from foreign organism, and germ-free animal models that have been employed to elucidate microbial effect. We also comprehensively discussed the metabolic property of microbiota such as butyrate production, facilitation of heme toxicity, bile acid transformation, and nitrate reduction that has been shown to contribute to the development of the tumor. Finally, up-to-date subjects such as the effect of age and gender on microbiota are briefly discussed.
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Affiliation(s)
- Kichul Yoon
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.,Department of Internal Medicine and Digestive Disease Research Institute, Wonkwang University Sanbon Hospital, Gunpo, Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.,Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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35
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Han A, Bennett N, Ahmed B, Whelan J, Donohoe DR. Butyrate decreases its own oxidation in colorectal cancer cells through inhibition of histone deacetylases. Oncotarget 2018; 9:27280-27292. [PMID: 29930765 PMCID: PMC6007476 DOI: 10.18632/oncotarget.25546] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Accepted: 05/14/2018] [Indexed: 01/12/2023] Open
Abstract
Colorectal cancer is characterized by an increase in the utilization of glucose and a diminishment in the oxidation of butyrate, which is a short chain fatty acid. In colorectal cancer cells, butyrate inhibits histone deacetylases to increase the expression of genes that slow the cell cycle and induce apoptosis. Understanding the mechanisms that contribute to the metabolic shift away from butyrate oxidation in cancer cells is important in in understanding the beneficial effects of the molecule toward colorectal cancer. Here, we demonstrate that butyrate decreased its own oxidation in cancerous colonocytes. Butyrate lowered the expression of short chain acyl-CoA dehydrogenase, an enzyme that mediates the oxidation of short-chain fatty acids. Butyrate does not alter short chain acyl-CoA dehydrogenase levels in non-cancerous colonocytes. Trichostatin A, a structurally unrelated inhibitor of histone deacetylases, and propionate also decreased the level of short chain acyl-CoA dehydrogenase, which alluded to inhibition of histone deacetylases as a part of the mechanism. Knockdown of histone deacetylase isoform 1, but not isoform 2 or 3, inhibited the ability of butyrate to decrease short chain acyl-CoA dehydrogenase expression. This work identifies a mechanism by which butyrate selective targets colorectal cancer cells to reduce its own metabolism.
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Affiliation(s)
- Anna Han
- Department of Nutrition, University of Tennessee, Knoxville, TN 37996, USA
| | - Natalie Bennett
- Department of Nutrition, University of Tennessee, Knoxville, TN 37996, USA
| | - Bettaieb Ahmed
- Department of Nutrition, University of Tennessee, Knoxville, TN 37996, USA
| | - Jay Whelan
- Department of Nutrition, University of Tennessee, Knoxville, TN 37996, USA
| | - Dallas R Donohoe
- Department of Nutrition, University of Tennessee, Knoxville, TN 37996, USA
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36
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Pan Z, Wang M, Ye Z, Zhang S, Xu X. Global analysis of histone lysine acetylation and proteomic changes in EC109 cells treated with the histone deacetylase inhibitor FK228. Oncol Lett 2018; 15:7973-7980. [PMID: 29725483 DOI: 10.3892/ol.2018.8312] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Accepted: 05/23/2017] [Indexed: 12/30/2022] Open
Abstract
FK228 is a selective inhibitor of histone deacetylases that exhibits marked antitumor activity in cancer cells and xenograft models. However, the effect of FK228 on the global profile of histone lysine acetylation and the proteome of EC109 cells remains poorly understood. The present study aimed at analyzing histone lysine acetylation and identifying the proteomic changes in EC109 cells following treatment with FK228, using the stable isotope labelling by amino acids in cell culture technique and a high-sensitivity mass spectrometer. In total, 87 acetylation sites and 3,515 proteins revealed changes in response to FK228 treatment. Of the 87 acetylation sites, 25 were quantifiable and 19 were quantified with ratio of >1.3. Notably, no downregulated lysine acetylation (Kac) sites were quantified in the present study and the 62 unquantified Kac sites were only identified in the FK228-treated cells. Bioinformatic analysis revealed that these quantifiable proteins were primarily involved in multiple biological functions and metabolic pathways as well as in protein complexes. The results of the present study revealed the extensive lysine acetylome and proteome in EC109 cells and expanded upon the current understanding of the anticancer mechanism of FK228 in EC109 cells.
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Affiliation(s)
- Zhiwen Pan
- Clinical Laboratory Department, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Mingli Wang
- Clinical Laboratory Department, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Zhen Ye
- Clinical Laboratory Department, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Shengjie Zhang
- Key Laboratory Diagnosis and Treatment Technology on Thoracic Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Xiaohong Xu
- Clinical Laboratory Department, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China.,Key Laboratory Diagnosis and Treatment Technology on Thoracic Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
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37
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Wang LL, Guo HH, Zhan Y, Feng CL, Huang S, Han YX, Zheng WS, Jiang JD. Specific up-regulation of p21 by a small active RNA sequence suppresses human colorectal cancer growth. Oncotarget 2018; 8:25055-25065. [PMID: 28445988 PMCID: PMC5421909 DOI: 10.18632/oncotarget.15918] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Accepted: 11/22/2016] [Indexed: 12/25/2022] Open
Abstract
The double stranded small active RNA (saRNA)- p21-saRNA-322 inhibits tumor growth by stimulating the p21 gene expression. We focused our research of p21-saRNA-322 on colorectal cancer because 1) p21 down-regulation is a signature abnormality of the cancer, and 2) colorectal cancer might be a suitable target for in situ p21-saRNA-322 delivery. The goal of the present study is to learn the activity of p21-saRNA-322 in colorectal cancer. Three human colorectal cancer cell lines, HCT-116, HCT-116 (p53–/−) and HT-29 were transfected with the p21-saRNA-322. The expression of P21 protein and p21 mRNA were measured using the Western blot and reverse transcriptase polymerase chain reaction (RT-PCR). The effect of p21-saRNA-322 on cancer cells was evaluated in vitro; and furthermore, a xenograft colorectal tumor mode in mice was established to estimate the tumor suppressing ability of p21-saRNA-322 in vivo. The results showed that in all three colorectal cancer cell lines, the expression of p21 mRNA and P21 protein were dramatically elevated after p21-saRNA-322 transfection. Transfection of p21-saRNA-322 caused apoptosis and cell cycle arrest at the G0/G1. Furthermore, anti-proliferation effect, reduction of colonies formation and cell senescence were observed in p21-saRNA-322 treated cells. Animal studies showed that p21-saRNA-322 treatment significantly inhibited the HT-29 tumor growth and facilitated p21 activation in vivo. These results indicated that, p21-saRNA-322-induceded up-regulation of p21 might be a promising therapeutic option for the treatment of colorectal cancer.
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Affiliation(s)
- Lu-Lu Wang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China
| | - Hui-Hui Guo
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China
| | - Yun Zhan
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China
| | - Chen-Lin Feng
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China
| | - Shuai Huang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China
| | - Yan-Xing Han
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China
| | - Wen-Sheng Zheng
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China
| | - Jian-Dong Jiang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China
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Targeting Histone Deacetylase Activity to Arrest Cell Growth and Promote Neural Differentiation in Ewing Sarcoma. Mol Neurobiol 2018; 55:7242-7258. [PMID: 29397557 DOI: 10.1007/s12035-018-0874-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Accepted: 01/07/2018] [Indexed: 12/20/2022]
Abstract
There is an urgent need for advances in the treatment of Ewing sarcoma (EWS), an aggressive childhood tumor with possible neuroectodermal origin. Inhibition of histone deacetylases (HDAC) can revert aberrant epigenetic states and reduce growth in different experimental cancer types. Here, we investigated whether the potent HDAC inhibitor, sodium butyrate (NaB), has the ability to reprogram EWS cells towards a more differentiated state and affect their growth and survival. Exposure of two EWS cell lines to NaB resulted in rapid and potent inhibition of HDAC activity (1 h, IC50 1.5 mM) and a significant arrest of cell cycle progression (72 h, IC50 0.68-0.76 mM), marked by G0/G1 accumulation. Delayed cell proliferation and reduced colony formation ability were observed in EWS cells after long-term culture. NaB-induced effects included suppression of cell proliferation accompanied by reduced transcriptional expression of the EWS-FLI1 fusion oncogene, decreased expression of key survival and pluripotency-associated genes, and re-expression of the differentiation neuronal marker βIII-tubulin. Finally, NaB reduced c-MYC levels and impaired survival in putative EWS cancer stem cells. Our findings support the use of HDAC inhibition as a strategy to impair cell growth and survival and to reprogram EWS tumors towards differentiation. These results are consistent with our previous studies indicating that HDis can inhibit the growth and modulate differentiation of cells from other types of childhood pediatric tumors possibly originating from neural stem cells.
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39
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Yuan H, Shi F, Meng L, Wang W. Effect of sea buckthorn protein on the intestinal microbial community in streptozotocin-induced diabetic mice. Int J Biol Macromol 2018; 107:1168-1174. [DOI: 10.1016/j.ijbiomac.2017.09.090] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Revised: 06/18/2017] [Accepted: 09/22/2017] [Indexed: 12/13/2022]
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40
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Nakatsuji T, Chen TH, Butcher AM, Trzoss LL, Nam SJ, Shirakawa KT, Zhou W, Oh J, Otto M, Fenical W, Gallo RL. A commensal strain of Staphylococcus epidermidis protects against skin neoplasia. SCIENCE ADVANCES 2018; 4:eaao4502. [PMID: 29507878 PMCID: PMC5834004 DOI: 10.1126/sciadv.aao4502] [Citation(s) in RCA: 180] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Accepted: 01/24/2018] [Indexed: 05/04/2023]
Abstract
We report the discovery that strains of Staphylococcus epidermidis produce 6-N-hydroxyaminopurine (6-HAP), a molecule that inhibits DNA polymerase activity. In culture, 6-HAP selectively inhibited proliferation of tumor lines but did not inhibit primary keratinocytes. Resistance to 6-HAP was associated with the expression of mitochondrial amidoxime reducing components, enzymes that were not observed in cells sensitive to this compound. Intravenous injection of 6-HAP in mice suppressed the growth of B16F10 melanoma without evidence of systemic toxicity. Colonization of mice with an S. epidermidis strain producing 6-HAP reduced the incidence of ultraviolet-induced tumors compared to mice colonized by a control strain that did not produce 6-HAP. S. epidermidis strains producing 6-HAP were found in the metagenome from multiple healthy human subjects, suggesting that the microbiome of some individuals may confer protection against skin cancer. These findings show a new role for skin commensal bacteria in host defense.
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Affiliation(s)
- Teruaki Nakatsuji
- Department of Dermatology, University of California, San Diego, La Jolla, CA 92093, USA
| | - Tiffany H. Chen
- Department of Dermatology, University of California, San Diego, La Jolla, CA 92093, USA
| | - Anna M. Butcher
- Department of Dermatology, University of California, San Diego, La Jolla, CA 92093, USA
| | - Lynnie L. Trzoss
- Scripps Institute of Oceanography, University of California, San Diego, La Jolla, CA 92093, USA
| | - Sang-Jip Nam
- Scripps Institute of Oceanography, University of California, San Diego, La Jolla, CA 92093, USA
| | - Karina T. Shirakawa
- Department of Dermatology, University of California, San Diego, La Jolla, CA 92093, USA
| | - Wei Zhou
- The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA
| | - Julia Oh
- The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA
| | - Michael Otto
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - William Fenical
- Scripps Institute of Oceanography, University of California, San Diego, La Jolla, CA 92093, USA
| | - Richard L. Gallo
- Department of Dermatology, University of California, San Diego, La Jolla, CA 92093, USA
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41
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Yan M, Qian YM, Yue CF, Wang ZF, Wang BC, Zhang W, Zheng FM, Liu Q. Inhibition of histone deacetylases induces formation of multipolar spindles and subsequent p53-dependent apoptosis in nasopharyngeal carcinoma cells. Oncotarget 2018; 7:44171-44184. [PMID: 27283770 PMCID: PMC5190087 DOI: 10.18632/oncotarget.9922] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Accepted: 05/16/2016] [Indexed: 11/25/2022] Open
Abstract
Histone deacetylases (HDACs) play crucial roles in the initiation and progression of cancer, offering a promising target for cancer therapy. HDACs inhibitor MGCD0103 (MGCD) exhibits effective anti-tumor activity by blocking proliferation and inducing cell death in malignant cells. However, the molecular mechanisms of HDACs inhibition induces cell death have not been well elucidated. In this study, we showed that MGCD effectively restored histone acetylation, suppressed cell growth and induced apoptosis in two-dimensional (2D) and three-dimensional (3D) cultured CNE1 and CNE2 nasopharyngeal carcinoma (NPC) cells. Importantly, MGCD arrested cell cycle at mitosis (M) phase with formation of multipolar spindles, which was associated with activated p53-mediated postmitotic checkpoint pathway to induce apoptotic cell death. Moreover, MGCD-induced apoptosis was decreased by inhibition of p53 using short interfering RNA (siRNA), suggesting that p53 was required for MGCD-induced cell apoptosis. Consistently, MGCD in combination with Nutlin-3, a MDM2 inhibitor showed synergistic effect on inducing apoptosis in 2D and 3D cultured CNE2 cells. Collectively, our data revealed that MGCD induced p53-dependent cell apoptosis following formation of multipolar spindles in NPC cells, suggesting the therapeutic potential of combinations of HDACs and MDM2 inhibitors for NPC treatment.
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Affiliation(s)
- Min Yan
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Institute of Cancer Stem Cell, Dalian, China.,Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Yuan-Min Qian
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Institute of Cancer Stem Cell, Dalian, China
| | - Cai-Feng Yue
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Institute of Cancer Stem Cell, Dalian, China.,Department of Laboratory Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zi-Feng Wang
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Institute of Cancer Stem Cell, Dalian, China
| | - Bi-Cheng Wang
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Institute of Cancer Stem Cell, Dalian, China
| | - Wei Zhang
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Institute of Cancer Stem Cell, Dalian, China
| | - Fei-Meng Zheng
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Institute of Cancer Stem Cell, Dalian, China.,Department of Medical Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Quentin Liu
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Institute of Cancer Stem Cell, Dalian, China
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Singh A, Vishwakarma V, Singhal B. Metabiotics: The Functional Metabolic Signatures of Probiotics: Current State-of-Art and Future Research Priorities—Metabiotics: Probiotics Effector Molecules. ACTA ACUST UNITED AC 2018. [DOI: 10.4236/abb.2018.94012] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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43
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Bian X, Liang Z, Feng A, Salgado E, Shim H. HDAC inhibitor suppresses proliferation and invasion of breast cancer cells through regulation of miR-200c targeting CRKL. Biochem Pharmacol 2018; 147:30-37. [PMID: 29155146 PMCID: PMC5733635 DOI: 10.1016/j.bcp.2017.11.008] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Accepted: 11/13/2017] [Indexed: 11/26/2022]
Abstract
Although histone deacetylase (HDAC) inhibitors have been shown to effectively induce the inhibition of proliferation and migration in breast cancer, the anticancer mechanism remains poorly understood. Our studies show that miR-200c was significantly downregulated in breast cancer cell lines compared to normal cell lines and inversely correlated with the levels of class IIa HDACs and CRKL. HDAC inhibitors and the ectopic expression of miR-200c as tumor suppressors inhibited the proliferation, invasion, and migration of breast cancer cells by downregulating CRKL. These results indicate that the anticancer mechanism of HDAC inhibitor was realized partially by regulating miR-200c via CRKL targeting. Our findings suggest that the HDAC-miR200c-CRKL signaling axis could be a novel diagnostic marker and potential therapeutic target in breast cancer.
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Affiliation(s)
- Xuehai Bian
- Department of Radiation Oncology, Emory University, Atlanta GA30322, USA; Department of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Jilin Provincial Key Laboratory of Surgical Translational Medicine, Changchun, China
| | - Zhongxing Liang
- Department of Radiation Oncology, Emory University, Atlanta GA30322, USA; Winship Cancer Institute, Emory University, Atlanta GA30322, USA.
| | - Amber Feng
- Department of Radiation Oncology, Emory University, Atlanta GA30322, USA
| | - Eric Salgado
- Department of Radiation Oncology, Emory University, Atlanta GA30322, USA
| | - Hyunsuk Shim
- Department of Radiation Oncology, Emory University, Atlanta GA30322, USA; Winship Cancer Institute, Emory University, Atlanta GA30322, USA.
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44
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Dai LN, Yan JK, Xiao YT, Wen J, Zhang T, Zhou KJ, Wang Y, Cai W. Butyrate stimulates the growth of human intestinal smooth muscle cells by activation of yes-associated protein. J Cell Physiol 2017; 233:3119-3128. [PMID: 28834539 DOI: 10.1002/jcp.26149] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Accepted: 08/11/2017] [Indexed: 01/15/2023]
Abstract
Intestinal smooth muscle cells play a critical role in the remodeling of intestinal structure and functional adaptation after bowel resection. Recent studies have shown that supplementation of butyrate (Bu) contributes to the compensatory expansion of a muscular layer of the residual intestine in a rodent model of short-bowel syndrome (SBS). However, the underlying mechanism remains elusive. In this study, we found that the growth of human intestinal smooth muscle cells (HISMCs) was significantly stimulated by Bu via activation of Yes-Associated Protein (YAP). Incubation with 0.5 mM Bu induced a distinct proliferative effect on HISMCs, as indicated by the promotion of cell cycle progression and increased DNA replication. Notably, YAP silencing by RNA interference or its specific inhibitor significantly abolished the proliferative effect of Bu on HISMCs. Furthermore, Bu induced YAP expression and enhanced the translocation of YAP from the cytoplasm to the nucleus, which led to changes in the expression of mitogenesis genes, including TEAD1, TEAD4, CTGF, and Cyr61. These results provide evidence that Bu stimulates the growth of human intestinal muscle cells by activation of YAP, which may be a potential treatment for improving intestinal adaptation.
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Affiliation(s)
- Li-Na Dai
- Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Kongjiang Road, Shanghai, P.R. China
| | - Jun-Kai Yan
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research, Shanghai, P.R. China
| | - Yong-Tao Xiao
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research, Shanghai, P.R. China
| | - Jie Wen
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research, Shanghai, P.R. China
| | - Tian Zhang
- Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Kongjiang Road, Shanghai, P.R. China
| | - Ke-Jun Zhou
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research, Shanghai, P.R. China
| | - Yang Wang
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research, Shanghai, P.R. China
| | - Wei Cai
- Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Kongjiang Road, Shanghai, P.R. China.,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research, Shanghai, P.R. China
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45
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Functional Changes in the Gut Microbiome Contribute to Transforming Growth Factor β-Deficient Colon Cancer. mSystems 2017; 2:mSystems00065-17. [PMID: 28951889 DOI: 10.1128/msystems.00065-17] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2017] [Accepted: 08/17/2017] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most treatable cancers, with a 5-year survival rate of ~64%, yet over 50,000 deaths occur yearly in the United States. In 15% of cases, deficiency in mismatch repair leads to null mutations in transforming growth factor β (TGF-β) type II receptor, yet genotype alone is not responsible for tumorigenesis. Previous work in mice shows that disruptions in TGF-β signaling combined with Helicobacter hepaticus cause tumorigenesis, indicating a synergistic effect between genotype and microbial environment. Here, we examine functional shifts in the gut microbiome in CRC using integrated -omics approaches to untangle the role of host genotype, inflammation, and microbial ecology. We profile the gut microbiome of 40 mice with/without deficiency in TGF-β signaling from a Smad3 (mothers against decapentaplegic homolog-3) knockout and with/without inoculation with H. hepaticus. Clear functional differences in the microbiome tied to specific bacterial species emerge from four pathways related to human colon cancer: lipopolysaccharide (LPS) production, polyamine synthesis, butyrate metabolism, and oxidative phosphorylation (OXPHOS). Specifically, an increase in Mucispirillum schaedleri drives LPS production, which is associated with an inflammatory response. We observe a commensurate decrease in butyrate production from Lachnospiraceae bacterium A4, which could promote tumor formation. H. hepaticus causes an increase in OXPHOS that may increase DNA-damaging free radicals. Finally, multiple bacterial species increase polyamines that are associated with colon cancer, implicating not just diet but also the microbiome in polyamine levels. These insights into cross talk between the microbiome, host genotype, and inflammation could promote the development of diagnostics and therapies for CRC. IMPORTANCE Most research on the gut microbiome in colon cancer focuses on taxonomic changes at the genus level using 16S rRNA gene sequencing. Here, we develop a new methodology to integrate DNA and RNA data sets to examine functional shifts at the species level that are important to tumor development. We uncover several metabolic pathways in the microbiome that, when perturbed by host genetics and H. hepaticus inoculation, contribute to colon cancer. The work presented here lays a foundation for improved bioinformatics methodologies to closely examine the cross talk between specific organisms and the host, important for the development of diagnostics and pre/probiotic treatment.
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46
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Bishop KS, Xu H, Marlow G. Epigenetic Regulation of Gene Expression Induced by Butyrate in Colorectal Cancer: Involvement of MicroRNA. GENETICS & EPIGENETICS 2017; 9:1179237X17729900. [PMID: 28979170 PMCID: PMC5617089 DOI: 10.1177/1179237x17729900] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Accepted: 06/02/2017] [Indexed: 12/15/2022]
Abstract
Colorectal cancer (CRC) is the third most common cause of cancer mortality globally. Development of CRC is closely associated with lifestyle, and diet may modulate risk. A Western-style diet is characterised by a high intake of red meat but low consumption of fruit, vegetables, and whole cereals. Such a diet is associated with CRC risks. It has been demonstrated that butyrate, produced by the fermentation of dietary plant fibre, can alter both genetic and epigenetic expressions. MicroRNAs (miRNAs) are small non-coding RNAs that are commonly present in both normal and tumour cells. Aberrant miRNA expression is associated with CRC initiation, progression, and metastasis. In addition, butyrate can modulate cell proliferation, differentiation, apoptosis, and miRNA expression in CRC. In this review, the effects of butyrate on modulating miRNA expression in CRC will be discussed. Furthermore, evidence on the effect of butyrate on CRC risk through reducing oncogenic miRNA expression will be presented.
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Affiliation(s)
- Karen S Bishop
- Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Huawen Xu
- Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Gareth Marlow
- Experimental Cancer Medicine Centre, Cardiff University, Cardiff, UK
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47
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Janaki Ramaiah M, Naushad SM, Lavanya A, Srinivas C, Anjana Devi T, Sampathkumar S, Dharan DB, Bhadra MP. Scriptaid cause histone deacetylase inhibition and cell cycle arrest in HeLa cancer cells: A study on structural and functional aspects. Gene 2017; 627:379-386. [PMID: 28668345 DOI: 10.1016/j.gene.2017.06.031] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Revised: 05/31/2017] [Accepted: 06/15/2017] [Indexed: 12/11/2022]
Abstract
Scriptaid (SCR), a well-known histone deacetylase inhibitor, cause various cellular effects such as cell growth inhibition and apoptosis. In this study, we have evaluated the anti-cancer effects of Scriptaid in HeLa cells, IMR-32 and HepG2 cells. Scriptaid inhibited the growth of HeLa cells with IC50 of 2μM at 48h in a dose-dependent manner. Flow-cytometric analysis indicated that SCR induced apoptosis. Scriptaid was found to inhibit HDAC-8 effectively than other HDAC inhibitor such as TSA as observed by HDAC-8 assay, Western blotting and modelling study. This observation was further strengthened by an artificial neuronal network (ANN) model.
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Affiliation(s)
- M Janaki Ramaiah
- School of Chemical and Biotechnology, SASTRA University, Thanjavur 613401, India.
| | - Shaik Mohammad Naushad
- School of Chemical and Biotechnology, SASTRA University, Thanjavur 613401, India; Sandor Life Sciences Pvt. Ltd, Banjara Hills, Road No: 3, Hyderabad-500034, India
| | - A Lavanya
- Chemical Biology Department, Indian Institute of Chemical Technology (IICT), Hyderabad 500007, India
| | - Chatla Srinivas
- Chemical Biology Department, Indian Institute of Chemical Technology (IICT), Hyderabad 500007, India
| | - Tangutur Anjana Devi
- Chemical Biology Department, Indian Institute of Chemical Technology (IICT), Hyderabad 500007, India
| | | | | | - Manika Pal Bhadra
- Chemical Biology Department, Indian Institute of Chemical Technology (IICT), Hyderabad 500007, India.
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Smolewski P, Robak T. The discovery and development of romidepsin for the treatment of T-cell lymphoma. Expert Opin Drug Discov 2017. [PMID: 28641053 DOI: 10.1080/17460441.2017.1341487] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
INTRODUCTION Romidepsin is a potent and selective inhibitor of histone deacetylases (HDCAi). It is also the only bicyclic inhibitor to undergo clinical assessment and is considered a promising drug for the treatment of T-cell lymphomas. The cellular action of romidepsin results in enhanced histone acetylation, as well as the acetylation of other nuclear or cytoplasmic proteins, influencing cell cycle, apoptosis, and angiogenesis. In phase II studies involving patients with relapsed or refractory of cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL), romidepsin produced overall response rates (ORR) of 34-35% and 25-38%, with complete response (CR) rates of 6% and 15-18%, respectively. Areas covered: This review summarizes the development of romidepsin, the mechanisms behind its antineoplastic action and its pharmacology. It also covers its pharmacokinetic and pharmacodynamic properties, as well as the preclinical and clinical data on its activity in T-cell lymphoma. Expert opinion: Since there are only few effective therapies available for T-cell lymphomas, romidepsin is a valuable option for relapsed/refractory patients with both CTCL and PTCL. It's also generally well tolerated, and gives potentially durable responses for patients with advanced and symptomatic disease. Combinations of romidepsin with other antineoplastic agents may also further improve drug response and outcomes in T-cell lymphoma.
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Affiliation(s)
- Piotr Smolewski
- a Department of Experimental Hematology , Medical University of Lodz , Lodz , Poland.,c Department of Hematology , Copernicus Memorial Hospital at Lodz , Lodz , Poland
| | - Tadeusz Robak
- b Department of Hematology , Medical University of Lodz , Lodz , Poland.,c Department of Hematology , Copernicus Memorial Hospital at Lodz , Lodz , Poland
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Engineered Resistant-Starch (ERS) Diet Shapes Colon Microbiota Profile in Parallel with the Retardation of Tumor Growth in In Vitro and In Vivo Pancreatic Cancer Models. Nutrients 2017; 9:nu9040331. [PMID: 28346394 PMCID: PMC5409670 DOI: 10.3390/nu9040331] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Revised: 03/21/2017] [Accepted: 03/23/2017] [Indexed: 12/15/2022] Open
Abstract
Background/aims: Pancreatic cancer (PC) is ranked as the fourth leading cause of cancer-related deaths worldwide. Despite recent advances in treatment options, a modest impact on the outcome of the disease is observed so far. We have previously demonstrated that short-term fasting cycles have the potential to improve the efficacy of chemotherapy against PC. The aim of this study was to assess the effect of an engineered resistant-starch (ERS) mimicking diet on the growth of cancer cell lines in vitro, on the composition of fecal microbiota, and on tumor growth in an in vivo pancreatic cancer mouse xenograft model. Materials and Methods: BxPC-3, MIA PaCa-2 and PANC-1 cells were cultured in the control, and in the ERS-mimicking diet culturing condition, to evaluate tumor growth and proliferation pathways. Pancreatic cancer xenograft mice were subjected to an ERS diet to assess tumor volume and weight as compared to mice fed with a control diet. The composition and activity of fecal microbiota were further analyzed in growth experiments by isothermal microcalorimetry. Results: Pancreatic cancer cells cultured in an ERS diet-mimicking medium showed decreased levels of phospho-ERK1/2 (extracellular signal-regulated kinase proteins) and phospho-mTOR (mammalian target of rapamycin) levels, as compared to those cultured in standard medium. Consistently, xenograft pancreatic cancer mice subjected to an ERS diet displayed significant retardation in tumor growth. In in vitro growth experiments, the fecal microbial cultures from mice fed with an ERS diet showed enhanced growth on residual substrates, higher production of formate and lactate, and decreased amounts of propionate, compared to fecal microbiota from mice fed with the control diet. Conclusion: A positive effect of the ERS diet on composition and metabolism of mouse fecal microbiota shown in vitro is associated with the decrease of tumor progression in the in vivo PC xenograft mouse model. These results suggest that engineered dietary interventions could be supportive as a synergistic approach to enhance the efficacy of existing cancer treatments in pancreatic cancer patients.
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Inhibiting histone deacetylases suppresses glucose metabolism and hepatocellular carcinoma growth by restoring FBP1 expression. Sci Rep 2017; 7:43864. [PMID: 28262837 PMCID: PMC5338333 DOI: 10.1038/srep43864] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Accepted: 02/01/2017] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers in the world. Elevated glucose metabolism in the availability of oxygen, a phenomenon called the Warburg effect, is important for cancer cell growth. Fructose-1,6-bisphosphatase (FBP1) is a rate-limiting enzyme in gluconeogenesis and is frequently lost in various types of cancer. Here, we demonstrated that expression of FBP1 was downregulated in HCC patient specimens and decreased expression of FBP1 associated with poor prognosis. Low expression of FBP1 correlated with high levels of histone deacetylase 1 (HDAC1) and HDAC2 proteins in HCC patient tissues. Treatment of HCC cells with HDAC inhibitors or knockdown of HDAC1 and/or HDAC2 restored FBP1 expression and inhibited HCC cell growth. HDAC-mediated suppression of FBP1 expression correlated with decreased histone H3 lysine 27 acetylation (H3K27Ac) in the FBP1 enhancer. Restored expression of FBP1 decreased glucose reduction and lactate secretion and inhibited HCC cell growth in vitro and tumor growth in mice. Our data reveal that loss of FBP1 due to histone deacetylation associates with poor prognosis of HCC and restored FBP1 expression by HDAC inhibitors suppresses HCC growth. Our findings suggest that repression of FBP1 by HDACs has important implications for HCC prognosis and treatment.
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