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Lee MJ, Yim H, Park JE, Park I, Kim H, Shin GT. Urinary GADD45G Protein Excretion Is Associated with IgA Nephropathy Progression. Biomedicines 2024; 12:2846. [PMID: 39767752 PMCID: PMC11673765 DOI: 10.3390/biomedicines12122846] [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: 10/29/2024] [Revised: 12/09/2024] [Accepted: 12/11/2024] [Indexed: 01/11/2025] Open
Abstract
Background: Growth arrest and DNA damage 45G (GADD45G) is a family of proteins involved in DNA damage response and cell growth arrest. In this study, we show evidence that urinary GADD45G protein is associated with the progression of IgA nephropathy. Methods: Patients diagnosed with IgA nephropathy without reversible acute kidney injury at study initiation and with at least one subsequent serum creatinine (SCr) measurement were included. A 50% or greater increase in SCr level was used as an endpoint for the deterioration of renal function. Enzyme-linked immunosorbent assay (ELISA) was performed using a Human GADD45G ELISA kit. Renal biopsy tissues were stained with a monoclonal mouse anti-GADD45G antibody. Results: Forty-five patients whose renal biopsy revealed IgA nephropathy were enrolled. Urinary GADD45G and urinary protein concentrations were 1.26 [0.69-2.20] μg/g creatinine and 0.65 [0.24-1.60] g/g creatinine, respectively. Urinary GADD45G showed significant positive correlations with SCr-slopes and urinary protein. The SCr-slope of the highest tertile group of urinary GADD45G (above 1.95 μg/g creatinine) was significantly higher than that of the lowest tertile group (below 0.90 μg/g). Univariate Cox regression analysis showed that urinary GADD45G was significantly associated with deterioration of renal function. A Kaplan-Meier test showed a significant difference in event-free survival for deterioration of renal function between the highest urinary GADD45G tertile group and other tertile groups. The area under the receiver operating characteristics (ROC) curve indicated urinary GADD45G had a good performance in predicting renal outcome (cut-off point 1.67 μg/g, positive predictive value 36.8%, negative predictive value 100%). Immunohistochemistry showed that GADD45G was expressed across all pathologic grades of IgA nephropathy and mainly detected in the cytoplasm of renal tubules, whereas no staining was noted in normal tissues. Conclusions: Urinary GADD45G excretion was significantly associated with kidney disease progression in patients with IgA nephropathy.
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Affiliation(s)
- Min-Jeong Lee
- Department of Nephrology, Ajou University School of Medicine, Suwon 16499, Republic of Korea; (M.-J.L.); (J.E.P.); (I.P.); (H.K.)
| | - Hyunee Yim
- Department of Pathology, Ajou University School of Medicine, Suwon 16499, Republic of Korea;
| | - Ji Eun Park
- Department of Nephrology, Ajou University School of Medicine, Suwon 16499, Republic of Korea; (M.-J.L.); (J.E.P.); (I.P.); (H.K.)
- Department of Endocrinology & Metabolism, Ajou University School of Medicine, Suwon 16499, Republic of Korea
| | - Inwhee Park
- Department of Nephrology, Ajou University School of Medicine, Suwon 16499, Republic of Korea; (M.-J.L.); (J.E.P.); (I.P.); (H.K.)
| | - Heungsoo Kim
- Department of Nephrology, Ajou University School of Medicine, Suwon 16499, Republic of Korea; (M.-J.L.); (J.E.P.); (I.P.); (H.K.)
| | - Gyu-Tae Shin
- Department of Nephrology, Ajou University School of Medicine, Suwon 16499, Republic of Korea; (M.-J.L.); (J.E.P.); (I.P.); (H.K.)
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Palomer X, Salvador JM, Griñán-Ferré C, Barroso E, Pallàs M, Vázquez-Carrera M. GADD45A: With or without you. Med Res Rev 2024; 44:1375-1403. [PMID: 38264852 DOI: 10.1002/med.22015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 12/11/2023] [Accepted: 01/09/2024] [Indexed: 01/25/2024]
Abstract
The growth arrest and DNA damage inducible (GADD)45 family includes three small and ubiquitously distributed proteins (GADD45A, GADD45B, and GADD45G) that regulate numerous cellular processes associated with stress signaling and injury response. Here, we provide a comprehensive review of the current literature investigating GADD45A, the first discovered member of the family. We first depict how its levels are regulated by a myriad of genotoxic and non-genotoxic stressors, and through the combined action of intricate transcriptional, posttranscriptional, and even, posttranslational mechanisms. GADD45A is a recognized tumor suppressor and, for this reason, we next summarize its role in cancer, as well as the different mechanisms by which it regulates cell cycle, DNA repair, and apoptosis. Beyond these most well-known actions, GADD45A may also influence catabolic and anabolic pathways in the liver, adipose tissue and skeletal muscle, among others. Not surprisingly, GADD45A may trigger AMP-activated protein kinase activity, a master regulator of metabolism, and is known to act as a transcriptional coregulator of numerous nuclear receptors. GADD45A has also been reported to display a cytoprotective role by regulating inflammation, fibrosis and oxidative stress in several organs and tissues, and is regarded an important contributor for the development of heart failure. Overall data point to that GADD45A may play an important role in metabolic, neurodegenerative and cardiovascular diseases, and also autoimmune-related disorders. Thus, the potential mechanisms by which dysregulation of GADD45A activity may contribute to the progression of these diseases are also reviewed below.
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Affiliation(s)
- Xavier Palomer
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain
- Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain
- Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
| | - Jesús M Salvador
- Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain
| | - Christian Griñán-Ferré
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain
- Institut de Neurociències, Universitat de Barcelona (NeuroUB), Barcelona, Spain
- Spanish Biomedical Research Center in Neurodegenerative Diseases (CIBERNED)-Instituto de Salud Carlos III, Madrid, Spain
| | - Emma Barroso
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain
- Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain
- Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
| | - Mercè Pallàs
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain
- Institut de Neurociències, Universitat de Barcelona (NeuroUB), Barcelona, Spain
- Spanish Biomedical Research Center in Neurodegenerative Diseases (CIBERNED)-Instituto de Salud Carlos III, Madrid, Spain
| | - Manuel Vázquez-Carrera
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain
- Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain
- Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
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Zhang P, You N, Ding Y, Zhu W, Wang N, Xie Y, Huang W, Ren Q, Qin T, Fu R, Zhang L, Xiao Z, Cheng T, Ma X. Gadd45g insufficiency drives the pathogenesis of myeloproliferative neoplasms. Nat Commun 2024; 15:2989. [PMID: 38582902 PMCID: PMC10998908 DOI: 10.1038/s41467-024-47297-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 03/22/2024] [Indexed: 04/08/2024] Open
Abstract
Despite the identification of driver mutations leading to the initiation of myeloproliferative neoplasms (MPNs), the molecular pathogenesis of MPNs remains incompletely understood. Here, we demonstrate that growth arrest and DNA damage inducible gamma (GADD45g) is expressed at significantly lower levels in patients with MPNs, and JAK2V617F mutation and histone deacetylation contribute to its reduced expression. Downregulation of GADD45g plays a tumor-promoting role in human MPN cells. Gadd45g insufficiency in the murine hematopoietic system alone leads to significantly enhanced growth and self-renewal capacity of myeloid-biased hematopoietic stem cells, and the development of phenotypes resembling MPNs. Mechanistically, the pathogenic role of GADD45g insufficiency is mediated through a cascade of activations of RAC2, PAK1 and PI3K-AKT signaling pathways. These data characterize GADD45g deficiency as a novel pathogenic factor in MPNs.
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Affiliation(s)
- Peiwen Zhang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, 301600, China
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Na You
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, 301600, China
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Yiyi Ding
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, 301600, China
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Wenqi Zhu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, 301600, China
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Nan Wang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, 301600, China
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Yueqiao Xie
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, 301600, China
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Wanling Huang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, 301600, China
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Qian Ren
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, 301600, China
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Tiejun Qin
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, 301600, China
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Rongfeng Fu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, 301600, China
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Lei Zhang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
- Tianjin Institutes of Health Science, Tianjin, 301600, China.
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China.
| | - Zhijian Xiao
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
- Tianjin Institutes of Health Science, Tianjin, 301600, China.
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China.
| | - Tao Cheng
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
- Tianjin Institutes of Health Science, Tianjin, 301600, China.
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China.
- Department of Stem Cell and Regenerative Medicine, Peking Union Medical College, Tianjin, China.
| | - Xiaotong Ma
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
- Tianjin Institutes of Health Science, Tianjin, 301600, China.
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China.
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Silva KCS, Tambwe N, Mahfouz DH, Wium M, Cacciatore S, Paccez JD, Zerbini LF. Transcription Factors in Prostate Cancer: Insights for Disease Development and Diagnostic and Therapeutic Approaches. Genes (Basel) 2024; 15:450. [PMID: 38674385 PMCID: PMC11050257 DOI: 10.3390/genes15040450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 03/28/2024] [Accepted: 03/30/2024] [Indexed: 04/28/2024] Open
Abstract
Transcription factors (TFs) are proteins essential for the regulation of gene expression, and they regulate the genes involved in different cellular processes, such as proliferation, differentiation, survival, and apoptosis. Although their expression is essential in normal physiological conditions, abnormal regulation of TFs plays critical role in several diseases, including cancer. In prostate cancer, the most common malignancy in men, TFs are known to play crucial roles in the initiation, progression, and resistance to therapy of the disease. Understanding the interplay between these TFs and their downstream targets provides insights into the molecular basis of prostate cancer pathogenesis. In this review, we discuss the involvement of key TFs, including the E26 Transformation-Specific (ETS) Family (ERG and SPDEF), NF-κB, Activating Protein-1 (AP-1), MYC, and androgen receptor (AR), in prostate cancer while focusing on the molecular mechanisms involved in prostate cancer development. We also discuss emerging diagnostic strategies, early detection, and risk stratification using TFs. Furthermore, we explore the development of therapeutic interventions targeting TF pathways, including the use of small molecule inhibitors, gene therapies, and immunotherapies, aimed at disrupting oncogenic TF signaling and improving patient outcomes. Understanding the complex regulation of TFs in prostate cancer provides valuable insights into disease biology, which ultimately may lead to advancing precision approaches for patients.
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Affiliation(s)
- Karla C. S. Silva
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town 7925, South Africa; (K.C.S.S.); (N.T.); (D.H.M.); (M.W.); (S.C.); (J.D.P.)
| | - Nadine Tambwe
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town 7925, South Africa; (K.C.S.S.); (N.T.); (D.H.M.); (M.W.); (S.C.); (J.D.P.)
- Integrative Biomedical Sciences Division, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
| | - Dalia H. Mahfouz
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town 7925, South Africa; (K.C.S.S.); (N.T.); (D.H.M.); (M.W.); (S.C.); (J.D.P.)
| | - Martha Wium
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town 7925, South Africa; (K.C.S.S.); (N.T.); (D.H.M.); (M.W.); (S.C.); (J.D.P.)
- Integrative Biomedical Sciences Division, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
| | - Stefano Cacciatore
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town 7925, South Africa; (K.C.S.S.); (N.T.); (D.H.M.); (M.W.); (S.C.); (J.D.P.)
- Integrative Biomedical Sciences Division, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
| | - Juliano D. Paccez
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town 7925, South Africa; (K.C.S.S.); (N.T.); (D.H.M.); (M.W.); (S.C.); (J.D.P.)
| | - Luiz F. Zerbini
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town 7925, South Africa; (K.C.S.S.); (N.T.); (D.H.M.); (M.W.); (S.C.); (J.D.P.)
- Integrative Biomedical Sciences Division, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
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Chen L, Fang C, Yuan X, Liu M, Wu P, Zhong L, Chen Z. Has-miR-300-GADD45B promotes melanoma growth via cell cycle. Aging (Albany NY) 2023; 15:13920-13943. [PMID: 38070141 PMCID: PMC10756120 DOI: 10.18632/aging.205276] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 10/16/2023] [Indexed: 12/21/2023]
Abstract
Response to oncogenic factors like UV, GADD45 family in skin participates in scavenging ROS, DNA repair and cell cycle control. Because of this, the previous study of the chronic UVB injury model has found that hsa-miR-300 can conduct intercellular transport by exosomes and target regulation of GADD45B. Whether the hsa-miR-300-GADD45B still regulates tumor development by cell cycle pathway is unclear. Through transcriptomic analysis of primary (n=39) and metastatic (n=102) melanoma, it was confirmed that in metastatic samples, some of the 97 down-regulated genes participate in maintaining skin homeostasis while 42 up-regulated genes were enriched in cancer-related functions. Furthermore, CDKN1A, CDKN2A, CXCR4 and RAD51 in the melanoma pathway, were also differentially expressed between normal skin and melanoma. CDKN1A and CDKN2A were also found to be involved in TP53-dependent cell cycle regulation. In conclusion, it was speculated that CDKN1A, CDKN2A, TP53, GADD45B and hsa-miR-300 may have regulatory relationships. It was demonstrated that there is a bidirectional regulation between hsa-miR-300 and TP53. In addition, miR-300 can regulate CDKN1A by GADD45B/TP53 and promote melanoma growth by accelerating the cell cycle transition from G1/S to G2 phase.
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Affiliation(s)
- Long Chen
- Department of Burn Plastic and Cosmetology, Affiliated Fuling Hospital, Chongqing University, Chongqing 408099, China
- College of Bioengineering, Chongqing University, Chongqing 400000, China
- Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu 610500, Sichuan, China
- Non-Coding RNA and Drug Discovery Key Laboratory of Sichuan Province, Chengdu Medical College, Chengdu 610500, Sichuan, China
| | - Chenglong Fang
- Department of Rehabilitation, LinYi People’s Hospital, Linyi 276000, Shandong, China
| | - Xiaoxue Yuan
- College of Bioengineering, Chongqing University, Chongqing 400000, China
| | - Mengqi Liu
- College of Bioengineering, Chongqing University, Chongqing 400000, China
| | - Ping Wu
- Department of Burn Plastic and Cosmetology, Affiliated Fuling Hospital, Chongqing University, Chongqing 408099, China
| | - Li Zhong
- College of Bioengineering, Chongqing University, Chongqing 400000, China
| | - Zhiyong Chen
- Department of Burn Plastic and Cosmetology, Affiliated Fuling Hospital, Chongqing University, Chongqing 408099, China
- College of Bioengineering, Chongqing University, Chongqing 400000, China
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Vava A, Paccez JD, Wang Y, Gu X, Bhasin MK, Myers M, Soares NC, Libermann TA, Zerbini LF. DCUN1D1 Is an Essential Regulator of Prostate Cancer Proliferation and Tumour Growth That Acts through Neddylation of Cullin 1, 3, 4A and 5 and Deregulation of Wnt/Catenin Pathway. Cells 2023; 12:1973. [PMID: 37566052 PMCID: PMC10417424 DOI: 10.3390/cells12151973] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 07/21/2023] [Accepted: 07/24/2023] [Indexed: 08/12/2023] Open
Abstract
Defective in cullin neddylation 1 domain containing 1 (DCUN1D1) is an E3 ligase for the neddylation, a post-translational process similar to and occurring in parallel to ubiquitin proteasome pathway. Although established as an oncogene in a variety of squamous cell carcinomas, the precise role of DCUN1D1 in prostate cancer (PCa) has not been previously explored thoroughly. Here, we investigated the role of DCUN1D1 in PCa and demonstrated that DCUN1D1 is upregulated in cell lines as well as human tissue samples. Inhibition of DCUN1D1 significantly reduced PCa cell proliferation and migration and remarkably inhibited xenograft formation in mice. Applying both genomics and proteomics approaches, we provide novel information about the DCUN1D1 mechanism of action. We identified CUL3, CUL4B, RBX1, CAND1 and RPS19 proteins as DCUN1D1 binding partners. Our analysis also revealed the dysregulation of genes associated with cellular growth and proliferation, developmental, cell death and cancer pathways and the WNT/β-catenin pathway as potential mechanisms. Inhibition of DCUN1D1 leads to the inactivation of β-catenin through its phosphorylation and degradation which inhibits the downstream action of β-catenin, reducing its interaction with Lef1 in the Lef1/TCF complex that regulates Wnt target gene expression. Together our data point to an essential role of the DCUN1D1 protein in PCa which can be explored for potential targeted therapy.
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Affiliation(s)
- Akhona Vava
- Cancer Genomics Group, International Centre for Genetic Engineering and Biotechnology, Cape Town 7925, South Africa; (A.V.); (J.D.P.)
- Division of Chemical and Systems Biology, Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town 7925, South Africa
| | - Juliano D. Paccez
- Cancer Genomics Group, International Centre for Genetic Engineering and Biotechnology, Cape Town 7925, South Africa; (A.V.); (J.D.P.)
| | - Yihong Wang
- Department of Pathology and Laboratory Medicine, Warren Alpert School of Medicine, Brown University, Providence, RI 02912, USA;
| | - Xuesong Gu
- BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; (X.G.); (T.A.L.)
| | - Manoj K. Bhasin
- Department of Pediatrics Bioinformatics, Emory University School of Medicine, Atlanta, GA 30322, USA;
| | - Michael Myers
- Protein Networks Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), 34149 Trieste, Italy;
| | - Nelson C. Soares
- Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah P.O. Box 26666, United Arab Emirates;
- Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 26666, United Arab Emirates
- Laboratory of Proteomics, Department of Human Genetics, National Institute of Health, Doutor Ricardo Jorge (INSA), 1649-016 Lisbon, Portugal
- Centre for Toxicogenomics and Human Health (ToxOmics), NOVA/School/Faculdade de Lisboa, 1169-056 Lisbon, Portugal
| | - Towia A. Libermann
- BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; (X.G.); (T.A.L.)
| | - Luiz F. Zerbini
- Cancer Genomics Group, International Centre for Genetic Engineering and Biotechnology, Cape Town 7925, South Africa; (A.V.); (J.D.P.)
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Vaill M, Kawanishi K, Varki N, Gagneux P, Varki A. Comparative physiological anthropogeny: exploring molecular underpinnings of distinctly human phenotypes. Physiol Rev 2023; 103:2171-2229. [PMID: 36603157 PMCID: PMC10151058 DOI: 10.1152/physrev.00040.2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 12/26/2022] [Accepted: 12/28/2022] [Indexed: 01/06/2023] Open
Abstract
Anthropogeny is a classic term encompassing transdisciplinary investigations of the origins of the human species. Comparative anthropogeny is a systematic comparison of humans and other living nonhuman hominids (so-called "great apes"), aiming to identify distinctly human features in health and disease, with the overall goal of explaining human origins. We begin with a historical perspective, briefly describing how the field progressed from the earliest evolutionary insights to the current emphasis on in-depth molecular and genomic investigations of "human-specific" biology and an increased appreciation for cultural impacts on human biology. While many such genetic differences between humans and other hominids have been revealed over the last two decades, this information remains insufficient to explain the most distinctive phenotypic traits distinguishing humans from other living hominids. Here we undertake a complementary approach of "comparative physiological anthropogeny," along the lines of the preclinical medical curriculum, i.e., beginning with anatomy and considering each physiological system and in each case considering genetic and molecular components that are relevant. What is ultimately needed is a systematic comparative approach at all levels from molecular to physiological to sociocultural, building networks of related information, drawing inferences, and generating testable hypotheses. The concluding section will touch on distinctive considerations in the study of human evolution, including the importance of gene-culture interactions.
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Affiliation(s)
- Michael Vaill
- Center for Academic Research and Training in Anthropogeny, University of California, San Diego, La Jolla, California
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California
- Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California
| | - Kunio Kawanishi
- Center for Academic Research and Training in Anthropogeny, University of California, San Diego, La Jolla, California
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California
- Department of Experimental Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Nissi Varki
- Center for Academic Research and Training in Anthropogeny, University of California, San Diego, La Jolla, California
- Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California
- Department of Pathology, University of California, San Diego, La Jolla, California
| | - Pascal Gagneux
- Center for Academic Research and Training in Anthropogeny, University of California, San Diego, La Jolla, California
- Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California
- Department of Pathology, University of California, San Diego, La Jolla, California
| | - Ajit Varki
- Center for Academic Research and Training in Anthropogeny, University of California, San Diego, La Jolla, California
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California
- Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California
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(–)-Xanthatin as a Killer of Human Breast Cancer MCF-7 Mammosphere Cells: A Comparative Study with Salinomycin. Curr Issues Mol Biol 2022; 44:3849-3858. [PMID: 36135176 PMCID: PMC9497939 DOI: 10.3390/cimb44090264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 08/20/2022] [Accepted: 08/22/2022] [Indexed: 11/17/2022] Open
Abstract
Experimental evidence accumulated by our research group and others strongly suggests that (–)-xanthatin, a xanthanolide sesquiterpene lactone, exhibits anti-proliferative effects on human breast cancer cells (in vitro) as well as anti-tumor effects in experimental animals (in vivo). In cancer biology, it is now critically important for anti-cancer agents to selectively target cancer stem cells (CSCs) in order to overcome cancer therapeutic resistance and recurrence. However, it has not yet been established whether (–)-xanthatin abrogates the formation of breast CSCs. In the present study, we utilized chemically synthesized pure (–)-xanthatin and a culture system to obtain mammospheres from human breast cancer MCF-7 cells, which are a CSC-enriched population. We herein demonstrated for the first time that (–)-xanthatin exhibited the ability to kill mammospheres, similar to salinomycin, an established selective killer of CSCs. A possible anti-proliferative mechanism toward mammospheres by (–)-xanthatin is discussed.
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9
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Chandramouly G. Gadd45 in DNA Demethylation and DNA Repair. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1360:55-67. [PMID: 35505162 DOI: 10.1007/978-3-030-94804-7_4] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Growth arrest and DNA damage 45 (Gadd45) family genes, Gadd45A, Gadd45B, and GADD45 G are implicated as stress sensors that are rapidly induced upon genotoxic/physiological stress. They are involved in regulation of various cellular functions such as DNA repair, senescence, and cell cycle control. Gadd45 family of genes serve as tumor suppressors in response to different stimuli and defects in Gadd45 pathway can give rise to oncogenesis. More recently, Gadd45 has been shown to promote gene activation by demethylation and this function is important for transcriptional regulation and differentiation during development. Gadd45 serves as an adaptor for DNA repair factors to promote removal of 5-methylcytosine from DNA at gene specific loci. Therefore, Gadd45 serves as a powerful link between DNA repair and epigenetic gene regulation.
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Affiliation(s)
- Gurushankar Chandramouly
- Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA.
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10
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Humayun A, Fornace AJ. GADD45 in Stress Signaling, Cell Cycle Control, and Apoptosis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1360:1-22. [PMID: 35505159 DOI: 10.1007/978-3-030-94804-7_1] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
GADD45 is a gene family consisting of GADD45A, GADD45B, and GADD45G that is often induced by DNA damage and other stress signals associated with growth arrest and apoptosis. Many of these roles are carried out via signaling mediated by p38 mitogen-activated protein kinases (MAPKs). The GADD45 proteins can contribute to p38 activation either by activation of upstream kinase(s) or by direct interaction, as well as suppression of p38 activity in certain cases. In vivo, there are important tissue and cell type specific differences in the roles for GADD45 in MAPK signaling. In addition to being p53-regulated, GADD45A has also been found to contribute to p53 activation via p38. Like other stress and signaling proteins, GADD45 proteins show complex regulation and numerous effectors. More recently, aberrant GADD45 expression has been found in several human cancers, but the mechanisms behind these findings largely remain to be understood.
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Affiliation(s)
- Arslon Humayun
- Lombardi Comprehensive Cancer Center, Washington, DC, USA
| | - Albert J Fornace
- Lombardi Comprehensive Cancer Center, Washington, DC, USA.
- Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC, USA.
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11
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Feng J, Li S, Zhang B, Duan N, Zhou R, Yan S, Elango J, Liu N, Wu W. FGFC1 Exhibits Anti-Cancer Activity via Inhibiting NF-κB Signaling Pathway in EGFR-Mutant NSCLC Cells. Mar Drugs 2022; 20:md20010076. [PMID: 35049931 PMCID: PMC8781927 DOI: 10.3390/md20010076] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 01/07/2022] [Accepted: 01/10/2022] [Indexed: 12/29/2022] Open
Abstract
FGFC1, an active compound isolated from the culture of marine fungi Stachybotrys longispora FG216, elicits fibrinolytic, anti-oxidative, and anti-inflammatory activity. We have previously reported that FGFC1 inhibited the proliferation, migration, and invasion of the non-small cell lung cancer (NSCLC) cells in vitro. However, the precise mechanisms of FGFC1 on NSCLC and its anti-cancer activity in vivo remains unclear. Hence, this study was focused to investigate the effects and regulatory mechanisms of FGFC1 on two NSCLC cell lines, EGFR-mutant PC9 (ex19del) and EGFR wild-type H1299. Results suggested that FGFC1 significantly inhibited proliferation, colony formation, as well as triggered G0/G1 arrest and apoptosis of PC9 cells in a dose- and time-dependent manner, but no obvious inhibitory effects were observed in H1299 cells. Subsequently, transcriptome analysis revealed that FGFC1 significantly down-regulated 28 genes related to the NF-κB pathway, including IL-6, TNF-α, and ICAM-1 in the PC9 cells. We further confirmed that FGFC1 decreased the expression of protein p-IKKα/β, p-p65, p-IκB, IL-6, and TNF-α. Moreover, NF-κB inhibitor PDTC could strengthen the effects of FGFC1 on the expression of CDK4, Cyclin D1, cleaved-PARP-1, and cleaved-caspase-3 proteins, suggesting that the NF-κB pathway plays a major role in FGFC1-induced cell cycle arrest and apoptosis. Correspondingly, the nuclear translocation of p-p65 was also suppressed by FGFC1 in PC9 cells. Finally, the intraperitoneal injection of FGFC1 remarkably inhibited PC9 xenograft growth and decreased the expression of Ki-67, p-p65, IL-6, and TNF-α in tumors. Our results indicated that FGFC1 exerted anti-cancer activity in PC9 cells via inhibiting the NF-κB signaling pathway, providing a possibility for FGFC1 to be used as a lead compound for the treatment of NSCLC in the future.
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Affiliation(s)
- Jingwen Feng
- Department of Marine Bio-Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China; (J.F.); (B.Z.); (N.D.); (R.Z.); (S.Y.); (J.E.)
| | - Songlin Li
- Research Centre of the Ministry of Agriculture and Rural Affairs on Environmental Ecology and Fish Nutrition, Shanghai Ocean University, Shanghai 201306, China;
| | - Bing Zhang
- Department of Marine Bio-Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China; (J.F.); (B.Z.); (N.D.); (R.Z.); (S.Y.); (J.E.)
| | - Namin Duan
- Department of Marine Bio-Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China; (J.F.); (B.Z.); (N.D.); (R.Z.); (S.Y.); (J.E.)
| | - Rui Zhou
- Department of Marine Bio-Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China; (J.F.); (B.Z.); (N.D.); (R.Z.); (S.Y.); (J.E.)
| | - Shike Yan
- Department of Marine Bio-Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China; (J.F.); (B.Z.); (N.D.); (R.Z.); (S.Y.); (J.E.)
| | - Jeevithan Elango
- Department of Marine Bio-Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China; (J.F.); (B.Z.); (N.D.); (R.Z.); (S.Y.); (J.E.)
| | - Ning Liu
- Department of Marine Bio-Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China; (J.F.); (B.Z.); (N.D.); (R.Z.); (S.Y.); (J.E.)
- Engineering Research Center of Aquatic Product Processing & Preservation, Shanghai Ocean University, Shanghai 201306, China
- Correspondence: (N.L.); (W.W.)
| | - Wenhui Wu
- Department of Marine Bio-Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China; (J.F.); (B.Z.); (N.D.); (R.Z.); (S.Y.); (J.E.)
- Engineering Research Center of Aquatic Product Processing & Preservation, Shanghai Ocean University, Shanghai 201306, China
- Correspondence: (N.L.); (W.W.)
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12
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Patel K, Murray MG, Whelan KA. Roles for GADD45 in Development and Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1360:23-39. [DOI: 10.1007/978-3-030-94804-7_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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13
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Gadd45 in Normal Hematopoiesis and Leukemia. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1360:41-54. [DOI: 10.1007/978-3-030-94804-7_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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14
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Shin GT, Park JE, Lee MJ. MAGEH1 interacts with GADD45G and induces renal tubular cell apoptosis. PLoS One 2021; 16:e0260135. [PMID: 34788311 PMCID: PMC8598065 DOI: 10.1371/journal.pone.0260135] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 11/03/2021] [Indexed: 12/05/2022] Open
Abstract
BACKGROUND Melanoma-associated antigen H1 (MAGEH1) is a protein that belongs to melanoma-associated antigen (MAGE) superfamily. Growth arrest and DNA damage 45G (GADD45G) is a member of the DNA damage-inducible gene family which responds to environmental stresses. We have previously shown that GADD45G is a protein that promotes apoptosis of renal tubular cells in response to a nephrotoxic injury. In this study, we show evidence that MAGEH1 interacts with GADD45G and is involved in the induction of nephrotoxin-induced apoptosis of renal tubular cells. METHODS Primary human renal tubular epithelial (HRE) cells and human kidney 2 (HK-2) cells were used in this study. To produce stable cell lines in which MAGEH1 expression was silenced, HRE cells were transduced with a lentiviral vector encoding a single guide RNA construct targeting the MAGEH1 gene. To knockdown GADD45G expression in HRE cells, a vector containing short hairpin RNA (shRNA) was used. We used short interfering RNAs (siRNA) to achieve transient silencing of genes in HK-2 cells. Recombinant adenoviruses were synthesized to overexpress MAGEH1 and GADD45G proteins. Human protein microarray was used to identify proteins that binds to GADD45G. Co-immunoprecipitation assays were then performed to confirm microarray results. Cell death was induced by cyclosporine A (CsA). Real-time quantitative PCR assay was used to evaluate gene expression levels. The degree of apoptosis and necrosis of cultured cells was evaluated by flow cytometry. Expression levels of caspases were examined using western blot analysis. RESULTS We found that GADD45G bound to one protein spotted in the protein microarray, which was subsequently identified as MAGEH1. We confirmed the interaction between GADD45G and MAGEH1 protein using the co-immunoprecipitation assay. MAGEH1 gene expression was not altered by CsA-induced cytotoxic injury, whereas GADD45G gene expression was increased significantly upon CsA treatment. MAGEH1 expression was significantly downregulated in GADD45G knockdown HRE stable cells suggesting that MAGEH1 expression may be dependent on GADD45G expression. CsA-induced apoptosis was significantly reduced in MAGEH1 knockdown HRE stable cells which led to an increased survival of these cells. Similar results were observed in GADD45G knockdown HRE stable cells. Accordingly, CsA-induced apoptosis was significantly decreased in MAGEH1 siRNA and GADD45G siRNA transfected HK-2 cells. CsA-induced activation of caspase-7 and caspase-9 was inhibited in MAGEH1 knockdown HRE stable cells, and similarly in GADD45G knockdown HRE stable cells. CONCLUSIONS To the best of our knowledge, this is the first study to show that MAGEH1 interacts with GADD45G and that MAGEH1 is involved in caspase-dependent apoptosis of renal tubular cells induced by nephrotoxic drugs.
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Affiliation(s)
- Gyu-Tae Shin
- Department of Nephrology, Ajou University School of Medicine, Suwon, Korea
| | - Ji Eun Park
- Department of Nephrology, Ajou University School of Medicine, Suwon, Korea
| | - Min-Jeong Lee
- Department of Nephrology, Ajou University School of Medicine, Suwon, Korea
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15
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GADD45g acts as a novel tumor suppressor and its activation confers new combination regimens for the treatment of AML. Blood 2021; 138:464-479. [PMID: 33945602 DOI: 10.1182/blood.2020008229] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 04/07/2021] [Indexed: 11/20/2022] Open
Abstract
Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy for which there is an unmet need for novel treatment strategies. Here, we characterize the growth arrest and DNA damage-inducible gene gamma (GADD45g) as a novel tumor suppressor in AML. We show that GADD45g is preferentially silenced in AML, especially in AML with FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations and mixed-lineage leukemia (MLL)-rearrangements, and reduced expression of GADD45g is correlated with poor prognosis in AML patients. Upregulation of GADD45g impairs homologous recombination (HR) DNA repair, leading to DNA damage accumulation, and dramatically induces apoptosis, differentiation, growth arrest and increases sensitivity of AML cells to chemotherapeutic drugs, without affecting normal cells. In addition, GADD45g is epigenetically silenced by histone deacetylation in AML, and its expression is further downregulated by oncogenes FLT3-ITD and MLL-AF9 in patients carrying these genetic abnormalities. Combination of histone deacetylase 1/2 inhibitor Romidepsin with FLT3 tyrosine kinase inhibitor AC220 or bromodomain inhibitor JQ1 exert synergistic anti-leukemic effects on FLT3-ITD+ and MLL-AF9+ AML, respectively, by dually activating GADD45g. These findings uncover hitherto unreported evidence for the selective anti-leukemia role of GADD45g and provide novel strategies for the treatment of FLT3-ITD+ and MLL-AF9+ AML.
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16
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Wang B, Liang C, Liu H, Lin J, Wang B, Fan K, Ren Z, Wang B, Li T, Qi K, Tian X. The expression of mouse double minute 2 homolog and P73 had no correlation with growth arrest DNA damage-inducible gene 45α in patients with non-small-cell lung carcinoma: A STROBE-compliant study. Medicine (Baltimore) 2019; 98:e17944. [PMID: 31860949 PMCID: PMC6940057 DOI: 10.1097/md.0000000000017944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
To investigate the difference in messenger ribonucleic acid (mRNA) and protein expression of growth arrest DNA damage-inducible gene 45α (GADD45α), mouse double minute 2 homolog (MDM2), and P73 in cancer and cancer-adjacent tissues in patients with non-small-cell lung carcinoma (NSCLC).We compared the mRNA expression of GADD45α and MDM2 and the protein expression of GADD45α, MDM2, and P73 in lung cancer and cancer-adjacent tissues in NSCLC patients by quantitative real-time PCR, immunohistochemistry (IHC), and Western Blot (WB). We analyzed GADD45α, MDM2, and P73 expression in patients with different pathological types of NSCLC, and the correlation of these genes with gender, smoking history, and TNM/T stages.IHC results suggested that MDM2 protein expression significantly increased in cancer tissues in female patients (P = .01), but not in male patients. In addition, WB results indicated that P73 protein expression significantly decreased in cancer tissues in patients with adenocarcinoma (P = .03), but not squamous carcinoma.MDM2 and P73 protein levels were differentially regulated in cancer and cancer-adjacient tissues in patients with sub types of NSCLC. There was no significant difference in GADD45α expression between cancer and cancer-adjacent tissues in NSCLC patients.
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Affiliation(s)
- Bo Wang
- Department of Thoracic Surgery, Chinese PLA General Hospital, Beijing
| | - Chaoyang Liang
- Department of Thoracic Surgery, Hainan Hospital of PLA General Hospital, Haitangwan, Sanya
| | - Huifeng Liu
- Department of Thoracic Surgery, PLA 309 Hospital, Haidian District, Beijing, China
| | - Jixing Lin
- Department of Thoracic Surgery, Hainan Hospital of PLA General Hospital, Haitangwan, Sanya
| | - Bailin Wang
- Department of Thoracic Surgery, Hainan Hospital of PLA General Hospital, Haitangwan, Sanya
| | - Kaijie Fan
- Department of Thoracic Surgery, Chinese PLA General Hospital, Beijing
| | - Zhipeng Ren
- Department of Thoracic Surgery, Chinese PLA General Hospital, Beijing
| | - Bin Wang
- Department of Thoracic Surgery, Chinese PLA General Hospital, Beijing
| | - Tong Li
- Department of Thoracic Surgery, Chinese PLA General Hospital, Beijing
| | - Kang Qi
- Department of Thoracic Surgery, Chinese PLA General Hospital, Beijing
| | - Xiaodong Tian
- Department of Thoracic Surgery, Hainan Hospital of PLA General Hospital, Haitangwan, Sanya
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17
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Doan RN, Shin T, Walsh CA. Evolutionary Changes in Transcriptional Regulation: Insights into Human Behavior and Neurological Conditions. Annu Rev Neurosci 2019; 41:185-206. [PMID: 29986162 DOI: 10.1146/annurev-neuro-080317-062104] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Understanding the biological basis for human-specific cognitive traits presents both immense challenges and unique opportunities. Although the question of what makes us human has been investigated with several different methods, the rise of comparative genomics, epigenomics, and medical genetics has provided tools to help narrow down and functionally assess the regions of the genome that seem evolutionarily relevant along the human lineage. In this review, we focus on how medical genetic cases have provided compelling functional evidence for genes and loci that appear to have interesting evolutionary signatures in humans. Furthermore, we examine a special class of noncoding regions, human accelerated regions (HARs), that have been suggested to show human-lineage-specific divergence, and how the use of clinical and population data has started to provide functional information to examine these regions. Finally, we outline methods that provide new insights into functional noncoding sequences in evolution.
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Affiliation(s)
- Ryan N Doan
- Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts 02115, USA; .,Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Boston, Massachusetts 02115, USA.,Howard Hughes Medical Institute, Boston Children's Hospital, Boston, Massachusetts 02115, USA
| | - Taehwan Shin
- Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts 02115, USA; .,Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Boston, Massachusetts 02115, USA
| | - Christopher A Walsh
- Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts 02115, USA; .,Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Boston, Massachusetts 02115, USA.,Howard Hughes Medical Institute, Boston Children's Hospital, Boston, Massachusetts 02115, USA.,Departments of Pediatrics and Neurology, Harvard Medical School, Boston, Massachusetts 02138, USA
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18
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Zhou L, Zhang Y, Leng Y, Dai Y, Kmieciak M, Kramer L, Sharma K, Wang Y, Craun W, Grant S. The IAP antagonist birinapant potentiates bortezomib anti-myeloma activity in vitro and in vivo. J Hematol Oncol 2019; 12:25. [PMID: 30845975 PMCID: PMC6407248 DOI: 10.1186/s13045-019-0713-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Accepted: 02/26/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Mechanisms by which Smac mimetics (SMs) interact with proteasome inhibitors (e.g., bortezomib) are largely unknown, particularly in multiple myeloma (MM), a disease in which bortezomib represents a mainstay of therapy. METHODS Interactions between the clinically relevant IAP (inhibitor of apoptosis protein) antagonist birinapant (TL32711) and the proteasome inhibitor bortezomib were investigated in multiple myeloma (MM) cell lines and primary cells, as well as in vivo models. Induction of apoptosis and changes in gene and protein expression were monitored using MM cell lines and confirmed in primary MM cell populations. Genetically modified cells (e.g., exhibiting shRNA knockdown or ectopic expression) were employed to evaluate the functional significance of birinapant/bortezomib-induced changes in protein levels. A MM xenograft model was used to evaluate the in vivo activity of the birinapant/bortezomib regimen. RESULTS Birinapant and bortezomib synergistically induced apoptosis in diverse cell lines, including bortezomib-resistant cells (PS-R). The regimen robustly downregulated cIAP1/2 but not the canonical NF-κB pathway, reflected by p65 phosphorylation and nuclear accumulation. In contrast, the bortezomib/birinapant regimen upregulated TRAF3, downregulated TRAF2, and diminished p52 processing and BCL-XL expression, consistent with disruption of the non-canonical NF-κB pathway. TRAF3 knockdown, ectopic TRAF2, or BCL-XL expression significantly diminished birinapant/bortezomib toxicity. The regimen sharply increased extrinsic apoptotic pathway activation, and cells expressing dominant-negative FADD or caspase-8 displayed markedly reduced birinapant/bortezomib sensitivity. Primary CD138+ (n = 43) and primitive MM populations (CD138-/19+/20+/27+; n = 31) but not normal CD34+ cells exhibited significantly enhanced toxicity with combined treatment (P < 0.0001). The regimen was also fully active in the presence of HS-5 stromal cells or growth factors (e.g., IL-6 and VEGF). Finally, the regimen was well tolerated and significantly increased survival (P < 0.05 and P < 0.001) compared to single agents in a MM xenograft model. Combined treatment also downregulated cIAP1/2 and p52 while increasing PARP cleavage in MM cells in vivo. CONCLUSIONS Our data suggest that birinapant and bortezomib interact synergistically in MM cells, including those resistant to bortezomib, through inactivation of the non-canonical NF-κB and activation of the extrinsic apoptotic pathway both in vitro and in vivo. They also argue that a strategy combining cIAP antagonists and proteasome inhibitors warrants attention in MM.
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Affiliation(s)
- Liang Zhou
- Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University, P.O. Box 980035, Richmond, VA, 23298, USA
| | - Yu Zhang
- Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University, P.O. Box 980035, Richmond, VA, 23298, USA
| | - Yun Leng
- Department of Hematology, Beijing Chaoyang Hospital of Capital Medical University, Beijing, China
| | - Yun Dai
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Maciej Kmieciak
- Massey Cancer Center, Virginia Commonwealth University Health Sciences Center, Richmond, VA, USA
| | - Lora Kramer
- Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University, P.O. Box 980035, Richmond, VA, 23298, USA
| | - Kanika Sharma
- Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University, P.O. Box 980035, Richmond, VA, 23298, USA
| | - Yan Wang
- Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University, P.O. Box 980035, Richmond, VA, 23298, USA
- Department of General Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - William Craun
- Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University, P.O. Box 980035, Richmond, VA, 23298, USA
| | - Steven Grant
- Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University, P.O. Box 980035, Richmond, VA, 23298, USA.
- Massey Cancer Center, Virginia Commonwealth University Health Sciences Center, Richmond, VA, USA.
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Shin GT, Lee HJ, Park JE. Growth arrest and DNA damage 45γ is required for caspase-dependent renal tubular cell apoptosis. PLoS One 2019; 14:e0212818. [PMID: 30794682 PMCID: PMC6386268 DOI: 10.1371/journal.pone.0212818] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Accepted: 02/08/2019] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Growth Arrest and DNA Damage 45γ (GADD45γ) is a member of the DNA damage-inducible gene family which responds to environmental stresses. Apoptosis is a critical mode of renal tubular cell death in nephrotoxin-induced acute kidney injury. In this study, we investigated the role of GADD45γ in renal tubular cell apoptosis induced by nephrotoxic drugs. METHODS Primary human renal tubular epithelial (HRE) cells were used in this study. To derive stable cell lines in which GADD45γ expression was silenced, HRE cells were transduced with a plasmid encoding GADD45γ-specific shRNA. The recombinant adenovirus containing the GADD45γ gene was synthesized to overexpress GADD45γ protein. Cell death was induced by cisplatin and cyclosporine A (CsA). To prevent apoptotic cell death, pan-caspase inhibitor ZVAD-FMK was used. To prevent non-apoptotic cell death, necrostatin-1 and ferrostatin-1 were used. The degree of apoptosis and necrosis of cultured cells were evaluated by flow cytometry. RESULTS Expression of the GADD45γ gene was significantly upregulated in response to treatment with CsA and cisplatin. Apoptosis and necrosis induced by these drugs were significantly reduced by silencing of GADD45γ, and significantly augmented by the overexpression of GADD45γ. The activation of caspase-3 and caspase-7 as well as caspase-9 induced by cisplatin or CsA was reduced by silencing of GADD45γ, and was augmented by the overexpression of GADD45γ, indicating that caspase activation is dependent on the expression of GADD45γ. ZVAD-FMK significantly inhibited apoptosis induced by cisplatin or CsA, indicating a role of caspases in mediating apoptotic cell death. ZVAD-FMK was effective to prevent necrosis as well, indicating that the observed necrosis was a secondary event following apoptosis at least in part. CONCLUSIONS To our knowledge, this is the first study to show that GADD45γ is required for the caspase-dependent apoptosis of renal tubular cells induced by nephrotoxic drugs.
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Affiliation(s)
- Gyu-Tae Shin
- Department of Nephrology, Ajou University School of Medicine, Suwon, Korea
| | - Hwa Joung Lee
- Department of Nephrology, Ajou University School of Medicine, Suwon, Korea
| | - Ji Eun Park
- Department of Nephrology, Ajou University School of Medicine, Suwon, Korea
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Paccez JD, Duncan K, Sekar D, Correa RG, Wang Y, Gu X, Bashin M, Chibale K, Libermann TA, Zerbini LF. Dihydroartemisinin inhibits prostate cancer via JARID2/miR-7/miR-34a-dependent downregulation of Axl. Oncogenesis 2019; 8:14. [PMID: 30783079 PMCID: PMC6381097 DOI: 10.1038/s41389-019-0122-6] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2018] [Revised: 11/16/2018] [Accepted: 01/28/2019] [Indexed: 01/24/2023] Open
Abstract
Axl expression is deregulated in several cancer types, predicts poor overall patient survival and is linked to resistance to drug therapy. Here, we evaluated a library of natural compounds for inhibitors of Axl and identified dihydroartemisinin, the active principle of the anti-malarial drug artemisinin, as an Axl-inhibitor in prostate cancer. Dihydroartemisinin blocks Axl expression leading to apoptosis, decrease in cell proliferation, migration, and tumor development of prostate cancer cells. Dihydroartemisinin treatment synergizes with docetaxel, a standard of care in metastatic prostate cancer increasing overall survival of mice with human xenografts. Dihydroartemisinin control of miR-34a and miR-7 expression leads to inhibition of Axl expression in a process at least partially dependent on regulation of chromatin via methylation of histone H3 lysine 27 residues by Jumonji, AT-rich interaction domain containing 2 (JARID2), and the enhancer of zeste homolog 2. Our discovery of a previously unidentified miR-34a/miR-7/JARID2 pathway controlling dihydroartemisinin effects on Axl expression and inhibition of cancer cell proliferation, migration, invasion, and tumor formation provides new molecular mechanistic insights into dihydroartemisinin anticancer effect on prostate cancer with potential therapeutic implications.
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Affiliation(s)
- Juliano D Paccez
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town, South Africa
- Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa
| | - Kristal Duncan
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town, South Africa
| | - Durairaj Sekar
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town, South Africa
- Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa
| | - Ricardo G Correa
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Yihong Wang
- Department of Pathology and Laboratory Medicine, Warren Alpert School of Medicine, Brown University, Providence, RI, USA
| | - Xuesong Gu
- BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Manoj Bashin
- BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Kelly Chibale
- South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
| | - Towia A Libermann
- BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Luiz F Zerbini
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town, South Africa.
- Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa.
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21
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Zhang L, Song D, Zhu B, Wang X. The role of nuclear matrix protein HNRNPU in maintaining the architecture of 3D genome. Semin Cell Dev Biol 2018; 90:161-167. [PMID: 29981443 DOI: 10.1016/j.semcdb.2018.07.006] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Accepted: 07/03/2018] [Indexed: 02/07/2023]
Abstract
The complexity of higher eukaryote genomes is far from being explained by linear information. There is a need to understand roles of genome regulation at the organism level through defining a comprehensive profile of chromosomal organization. Chromosome conformation capture (3C)-based studies reveal that higher-order of chromatin include not only long-range chromatin loops, but also compartments and topologically associating domains as the basis of genome structure and functions. However, the molecular machinery how the genome is spatially organized is still inadequate. Exciting progress has been made with the development of today's technology, we find that heterogeneous nuclear ribonucleoprotein U, initially identified as a structural nuclear protein, plays important role in three-dimensional (3D) genome organization by high-throughput assays. The disruption of this protein not only results in compartment switching on of the genome, it also reduces of TAD boundary strengths at borders between two types of compartments, and regulates chromatin loop by decrease its intensities. In addition, HNRNPU mainly binds to active chromatin. Most of HNRNPU peaks is consistent with CTCF or RAD21.It also plays an irreplaceable role in the processes of mitosis. This review aims to discuss the role of HNRNPU in maintaining the 3D chromatin architecture, as well as the recent development and human diseases involved in this nuclear matrix (NM)-associated protein.
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Affiliation(s)
- Linlin Zhang
- Zhongshan Hospital Institute of Clinical Science, Fudan University Medical School, Shanghai Institute of Clinical Bioinformatics, Shanghai, China
| | - Dongli Song
- Zhongshan Hospital Institute of Clinical Science, Fudan University Medical School, Shanghai Institute of Clinical Bioinformatics, Shanghai, China
| | - Bijun Zhu
- Zhongshan Hospital Institute of Clinical Science, Fudan University Medical School, Shanghai Institute of Clinical Bioinformatics, Shanghai, China
| | - Xiangdong Wang
- Zhongshan Hospital Institute of Clinical Science, Fudan University Medical School, Shanghai Institute of Clinical Bioinformatics, Shanghai, China.
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22
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Wu T, Wang G, Chen W, Zhu Z, Liu Y, Huang Z, Huang Y, Du P, Yang Y, Liu CY, Cui L. Co-inhibition of BET proteins and NF-κB as a potential therapy for colorectal cancer through synergistic inhibiting MYC and FOXM1 expressions. Cell Death Dis 2018; 9:315. [PMID: 29472532 PMCID: PMC5833769 DOI: 10.1038/s41419-018-0354-y] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2017] [Revised: 01/18/2018] [Accepted: 01/19/2018] [Indexed: 12/22/2022]
Abstract
The bromodomain and extra-terminal domain inhibitors (BETi) are promising epigenetic drugs for the treatment of various cancers through suppression of oncogenic transcription factors. However, only a subset of colorectal cancer (CRC) cells response to BETi. We investigate additional agents that could be combined with BETi to overcome this obstacle. JQ1-resistant CRC cells were used for screening of the effective combination therapies with JQ1. RNA-seq was performed to explore the mechanism of synergistic effect. The efficacy of combinational treatment was tested in the CRC cell line- and patient-derived xenograft (PDX) models. In BETi-sensitive CRC cells, JQ1 also impaired tumor angiogenesis through the c-myc/miR-17-92/CTGF+THBS1 axis. CTGF knockdown moderately counteracted anti-angiogenic effect of JQ1 and led to partially attenuated tumor regression. JQ1 decreased c-myc expression and NF-κB activity in BETi-sensitive CRC cells but not in resistant cells. Bortezomib synergistically sensitized BETi-resistant cells to the JQ1 treatment, and JQ1+Bortezomib induced G2/M arrest in CRC cells. Mechanistically, inhibition of NF-κB by Bortezomib or NF-κB inhibitor or IKK1/2 siRNA all rendered BETi-resistant cells more sensitive to BETi by synergistic repression of c-myc, which in turn induces GADD45s’ expression, and by synergistic repression of FOXM1 which in turn inhibit G2/M checkpoint genes’ expression. Activation of NF-κB by IκBα siRNA induced resistance to JQ1 in BETi-sensitive CRC cells. Last, JQ1+Bortezomib inhibited tumor growth and angiogenesis in CRC cell line xenograft model and four PDX models. Our results indicate that anti-angiogenic effect of JQ1 plays a vital role in therapeutic effect of JQ1 in CRC, and provide a rationale for combined inhibition of BET proteins and NF-κB as a potential therapy for CRC.
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Affiliation(s)
- Tingyu Wu
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Colorectal Cancer Research Center, Shanghai, China
| | - Guanghui Wang
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Colorectal Cancer Research Center, Shanghai, China
| | - Wei Chen
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Colorectal Cancer Research Center, Shanghai, China
| | - Zhehui Zhu
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Colorectal Cancer Research Center, Shanghai, China
| | - Yun Liu
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Zhenyu Huang
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Colorectal Cancer Research Center, Shanghai, China
| | - Yuji Huang
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Colorectal Cancer Research Center, Shanghai, China
| | - Peng Du
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Colorectal Cancer Research Center, Shanghai, China
| | - Yili Yang
- Suzhou Institute of Systems Medicine, Center for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China
| | - Chen-Ying Liu
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. .,Shanghai Colorectal Cancer Research Center, Shanghai, China.
| | - Long Cui
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. .,Shanghai Colorectal Cancer Research Center, Shanghai, China.
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23
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Liang P, Saqib HSA, Zhang X, Zhang L, Tang H. Single-Base Resolution Map of Evolutionary Constraints and Annotation of Conserved Elements across Major Grass Genomes. Genome Biol Evol 2018; 10:473-488. [PMID: 29378032 PMCID: PMC5798027 DOI: 10.1093/gbe/evy006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/08/2018] [Indexed: 12/20/2022] Open
Abstract
Conserved noncoding sequences (CNSs) are evolutionarily conserved DNA sequences that do not encode proteins but may have potential regulatory roles in gene expression. CNS in crop genomes could be linked to many important agronomic traits and ecological adaptations. Compared with the relatively mature exon annotation protocols, efficient methods are lacking to predict the location of noncoding sequences in the plant genomes. We implemented a computational pipeline that is tailored to the comparisons of plant genomes, yielding a large number of conserved sequences using rice genome as the reference. In this study, we used 17 published grass genomes, along with five monocot genomes as well as the basal angiosperm genome of Amborella trichopoda. Genome alignments among these genomes suggest that at least 12.05% of the rice genome appears to be evolving under constraints in the Poaceae lineage, with close to half of the evolutionarily constrained sequences located outside protein-coding regions. We found evidence for purifying selection acting on the conserved sequences by analyzing segregating SNPs within the rice population. Furthermore, we found that known functional motifs were significantly enriched within CNS, with many motifs associated with the preferred binding of ubiquitous transcription factors. The conserved elements that we have curated are accessible through our public database and the JBrowse server. In-depth functional annotations and evolutionary dynamics of the identified conserved sequences provide a solid foundation for studying gene regulation, genome evolution, as well as to inform gene isolation for cereal biologists.
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Affiliation(s)
- Pingping Liang
- Key Laboratory of Genetics, Breeding and Multiple Utilization of Corps, Center for Genomics and Biotechnology, Ministry of Education; Fujian Provincial Key Laboratory of Haixia Applied Plant Systems Biology, Fujian Agriculture and Forestry University, Fuzhou, China
- Key Laboratory of the Ministry of Education for Coastal and Wetland Ecosystems, College of the Environment and Ecology, Xiamen University, China
| | - Hafiz Sohaib Ahmed Saqib
- Institute of Applied Ecology, Fujian Agriculture and Forestry University, Fuzhou, China
- State Key Laboratory of Ecological Pest Control for Fujian and Taiwan Crops, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Xingtan Zhang
- Key Laboratory of Genetics, Breeding and Multiple Utilization of Corps, Center for Genomics and Biotechnology, Ministry of Education; Fujian Provincial Key Laboratory of Haixia Applied Plant Systems Biology, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Liangsheng Zhang
- Key Laboratory of Genetics, Breeding and Multiple Utilization of Corps, Center for Genomics and Biotechnology, Ministry of Education; Fujian Provincial Key Laboratory of Haixia Applied Plant Systems Biology, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Haibao Tang
- Key Laboratory of Genetics, Breeding and Multiple Utilization of Corps, Center for Genomics and Biotechnology, Ministry of Education; Fujian Provincial Key Laboratory of Haixia Applied Plant Systems Biology, Fujian Agriculture and Forestry University, Fuzhou, China
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24
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Levchenko A, Kanapin A, Samsonova A, Gainetdinov RR. Human Accelerated Regions and Other Human-Specific Sequence Variations in the Context of Evolution and Their Relevance for Brain Development. Genome Biol Evol 2018; 10:166-188. [PMID: 29149249 PMCID: PMC5767953 DOI: 10.1093/gbe/evx240] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/14/2017] [Indexed: 12/24/2022] Open
Abstract
The review discusses, in a format of a timeline, the studies of different types of genetic variants, present in Homo sapiens, but absent in all other primate, mammalian, or vertebrate species, tested so far. The main characteristic of these variants is that they are found in regions of high evolutionary conservation. These sequence variations include single nucleotide substitutions (called human accelerated regions), deletions, and segmental duplications. The rationale for finding such variations in the human genome is that they could be responsible for traits, specific to our species, of which the human brain is the most remarkable. As became obvious, the vast majority of human-specific single nucleotide substitutions are found in noncoding, likely regulatory regions. A number of genes, associated with these human-specific alleles, often through novel enhancer activity, were in fact shown to be implicated in human-specific development of certain brain areas, including the prefrontal cortex. Human-specific deletions may remove regulatory sequences, such as enhancers. Segmental duplications, because of their large size, create new coding sequences, like new functional paralogs. Further functional study of these variants will shed light on evolution of our species, as well as on the etiology of neurodevelopmental disorders.
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Affiliation(s)
- Anastasia Levchenko
- Institute of Translational Biomedicine, Saint Petersburg State University, Russia
| | - Alexander Kanapin
- Institute of Translational Biomedicine, Saint Petersburg State University, Russia
- Department of Oncology, University of Oxford, United Kingdom
| | - Anastasia Samsonova
- Institute of Translational Biomedicine, Saint Petersburg State University, Russia
- Department of Oncology, University of Oxford, United Kingdom
| | - Raul R Gainetdinov
- Institute of Translational Biomedicine, Saint Petersburg State University, Russia
- Skolkovo Institute of Science and Technology, Skolkovo, Moscow, Russia
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25
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Deng H, Kuang P, Cui H, Luo Q, Liu H, Lu Y, Fang J, Zuo Z, Deng J, Li Y, Wang X, Zhao L. Sodium fluoride induces apoptosis in mouse splenocytes by activating ROS-dependent NF-κB signaling. Oncotarget 2017; 8:114428-114441. [PMID: 29383091 PMCID: PMC5777703 DOI: 10.18632/oncotarget.22826] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Accepted: 11/09/2017] [Indexed: 12/26/2022] Open
Abstract
In this study, we investigated the roles of reactive oxygen species (ROS) and nuclear factor-κB (NF-κB) signaling in sodium fluoride-induced DNA damage and apoptosis in mouse splenocytes. Intragastric administration of 12, 24 or 48 mg/kg sodium fluoride resulted in a time- and dose-dependent increase in DNA fragmentation and apoptosis in mouse splenocytes on days 21 and 42. High ROS levels correlated with increased levels of phosphorylated IκB kinase and NF-κB p65 and decreased levels of inhibitory kappa B protein in splenocytes from mice treated with sodium fluoride. Moreover, splenocytes from sodium fluoride-treated mice showed high expression of pro-apoptotic proteins, including Bim, Bax, Bak, caspase-3 and poly ADP-ribose polymerase, and low expression of the anti-apoptotic proteins BcL-2 and BcL-xL. These results show that sodium fluoride induces apoptosis in mouse splenocytes by enhancing ROS-dependent NF-κB signaling.
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Affiliation(s)
- Huidan Deng
- College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China
| | - Ping Kuang
- College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China
| | - Hengmin Cui
- College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China
- Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China
| | - Qin Luo
- College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China
| | - Huan Liu
- College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China
| | - Yujiao Lu
- College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China
| | - Jing Fang
- College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China
- Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China
| | - Zhicai Zuo
- College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China
- Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China
| | - Junliang Deng
- College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China
- Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China
| | - Yinglun Li
- College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China
- Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China
| | - Xun Wang
- College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China
- Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China
| | - Ling Zhao
- College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China
- Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China
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26
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Tamura RE, Paccez JD, Duncan KC, Morale MG, Simabuco FM, Dillon S, Correa RG, Gu X, Libermann TA, Zerbini LF. GADD45α and γ interaction with CDK11p58 regulates SPDEF protein stability and SPDEF-mediated effects on cancer cell migration. Oncotarget 2017; 7:13865-79. [PMID: 26885618 PMCID: PMC4924684 DOI: 10.18632/oncotarget.7355] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Accepted: 01/28/2016] [Indexed: 01/02/2023] Open
Abstract
The epithelium-specific Ets transcription factor, SPDEF, plays a critical role in metastasis of prostate and breast cancer cells. While enhanced SPDEF expression blocks migration and invasion, knockdown of SPDEF expression enhances migration, invasion, and metastasis of cancer cells. SPDEF expression and activation is tightly regulated in cancer cells; however, the precise mechanism of SPDEF regulation has not been explored in detail. In this study we provide evidence that the cell cycle kinase CDK11p58, a protein involved in G2/M transition and degradation of several transcription factors, directly interacts with and phosphorylates SPDEF on serine residues, leading to subsequent ubiquitination and degradation of SPDEF through the proteasome pathway. As a consequence of CDK11p58 mediated degradation of SPDEF, this loss of SPDEF protein results in increased prostate cancer cell migration and invasion. In contrast, knockdown of CDK11p58 protein expression by interfering RNA or SPDEF overexpression inhibit migration and invasion of cancer cells. We demonstrate that CDK11p58 mediated degradation of SPDEF is attenuated by Growth Arrest and DNA damage-inducible 45 (GADD45) α and, two proteins inducing G2/M cell cycle arrest. We show that GADD45 α and γ, directly interact with CDK11p58 and thereby inhibit CDK11p58 activity, and consequentially SPDEF phosphorylation and degradation, ultimately reducing prostate cancer cell migration and invasion. Our findings provide new mechanistic insights into the complex regulation of SPDEF activity linked to cancer metastasis and characterize a previously unidentified SPDEF/CDK11p58/GADD45α/γ pathway that controls SPDEF protein stability and SPDEF-mediated effects on cancer cell migration and invasion.
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Affiliation(s)
- Rodrigo E Tamura
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Medical Biochemistry Division, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Juliano D Paccez
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Medical Biochemistry Division, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Kristal C Duncan
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Medical Biochemistry Division, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Mirian G Morale
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Medical Biochemistry Division, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Fernando M Simabuco
- BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Simon Dillon
- BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Ricardo G Correa
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Xuesong Gu
- BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Towia A Libermann
- BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Luiz F Zerbini
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Medical Biochemistry Division, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
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27
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Cai F, Chen M, Zha D, Zhang P, Zhang X, Cao N, Wang J, He Y, Fan X, Zhang W, Fu Z, Lai Y, Hua ZC, Zhuang H. Curcumol potentiates celecoxib-induced growth inhibition and apoptosis in human non-small cell lung cancer. Oncotarget 2017; 8:115526-115545. [PMID: 29383179 PMCID: PMC5777791 DOI: 10.18632/oncotarget.23308] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Accepted: 12/05/2017] [Indexed: 01/01/2023] Open
Abstract
Combinatorial therapies that target multiple signaling pathways may provide improved therapeutic responses over monotherapies. Celecoxib and curcumol are two highly hydrophobic drugs which show bioavailability problems due to their poor aqueous solubility. In the present study, we evaluated the effects of celecoxib and curcumol alone and in combination on cell proliferation, invasion, migration, cell cycle and apoptosis induction in non-small cell lung cancer (NSCLC) cells using in vitro and in vivo experiments. Our data showed that the sensitivity of a combined therapy using low concentration of celecoxib and curcumol was higher than that of celecoxib or curcumol alone. Suppression of NF-κB transcriptional activity, activation of caspase-9/caspase-3, cell cycle G1 arrest, and inhibition of survival MAPK and PI3K/AKT signaling pathway contributed to the synergistic effects of this combination therapy for induction of apoptosis. Additionally, either celecoxib alone or in combination with curcumol inhibited NSCLC cell migration and invasion by suppressing FAK and matrix metalloproteinase-9 activities. Furthermore, the combined treatment reduced tumor volume and weight in xenograft mouse model, and significantly decreased tumor metastasis nodules in lung tissues by tail vein injection. Our results confirm and provide mechanistic insights into the prominent anti-proliferative activities of celecoxib and/or curcumol on NSCLC cells, which provide a rationale for further detailed preclinical and potentially clinical studies of this combination for the therapy of lung cancer.
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Affiliation(s)
- Fangfang Cai
- The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China
| | - Minghui Chen
- The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.,State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China
| | - Daolong Zha
- The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China
| | - Peng Zhang
- State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China
| | - Xiangyu Zhang
- The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China
| | - Nini Cao
- The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China
| | - Jishuang Wang
- State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China
| | - Yan He
- State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China
| | - Xinxin Fan
- State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China
| | - Wenjing Zhang
- State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China
| | - Zhongping Fu
- State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China
| | - Yueyang Lai
- The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.,Nanjing Industrial Innovation Center for Pharmaceutical Biotechnology, Nanjing, China
| | - Zi-Chun Hua
- The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.,State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China
| | - Hongqin Zhuang
- The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China
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28
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Hou XJ, Zhao QD, Jing YY, Han ZP, Yang X, Wei LX, Zheng YT, Xie F, Zhang BH. Methylation mediated Gadd45β enhanced the chemosensitivity of hepatocellular carcinoma by inhibiting the stemness of liver cancer cells. Cell Biosci 2017; 7:63. [PMID: 29225771 PMCID: PMC5717842 DOI: 10.1186/s13578-017-0189-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Accepted: 11/06/2017] [Indexed: 12/21/2022] Open
Abstract
Background Defects of the growth arrest DNA damage-inducible gene 45β (Gadd45β) play an important role in the progression of tumor and confer resistance to chemotherapy. However, the role of Gadd45β in the apoptosis of hepatocellular carcinoma is still not clear. Purpose of this study was to explore the effect of Gadd45β on the apoptosis of liver cancer cells, and the possible mechanism was examined. Result In this study, we first confirmed the decreased expression of Gadd45β in human liver cancer tissues and human liver cancer cell lines, when compared to the peri-tumor liver tissue and normal liver cells. And, it was found that Gadd45β could inhibit the stemness of liver cancer cells, enhancing the apoptosis of cancer cells induced by chemotherapy. Furthermore, the results showed that HCC tissues and cell lines showed a higher methylation status in Gadd45β promoter than that in peri-tumor tissues and normal liver cells. Methylation was then reversed by pretreatment of SMMC-7721 and Hep-3B with 5-azacytidine which is the DNA methyltransferase inhibitor. And the 5-azacytidine decreased the stemness of SMMC-7721 and Hep-3B, enhanced the sensitivity of SMMC-7721 and Hep-3B to cisplatin. Conclusions Methylation mediated Gadd45β expression inhibited the stemness of liver cancer cells, promoting the chemotherapy-induced apoptosis. Thus Gadd45β may be the potential target for enhancing the chemosensitivity of human hepatocellular carcinoma.
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Affiliation(s)
- Xiao-Juan Hou
- Department of Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, NO. 225 Changhai Road, Shanghai, 200438 China
| | - Qiu-Dong Zhao
- Department of Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, NO. 225 Changhai Road, Shanghai, 200438 China
| | - Ying-Ying Jing
- Department of Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, NO. 225 Changhai Road, Shanghai, 200438 China
| | - Zhi-Peng Han
- Department of Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, NO. 225 Changhai Road, Shanghai, 200438 China
| | - Xue Yang
- Department of Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, NO. 225 Changhai Road, Shanghai, 200438 China
| | - Li-Xin Wei
- Department of Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, NO. 225 Changhai Road, Shanghai, 200438 China
| | - Yu-Ting Zheng
- Department of Biliary Tract Surgery Department III, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Feng Xie
- Department of Biliary Tract Surgery Department III, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Bai-He Zhang
- Department of Biliary Tract Surgery Department III, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China
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29
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Hassani S, Khaleghian A, Ahmadian S, Alizadeh S, Alimoghaddam K, Ghavamzadeh A, Ghaffari SH. Redistribution of cell cycle by arsenic trioxide is associated with demethylation and expression changes of cell cycle related genes in acute promyelocytic leukemia cell line (NB4). Ann Hematol 2017; 97:83-93. [DOI: 10.1007/s00277-017-3163-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2017] [Accepted: 10/24/2017] [Indexed: 01/11/2023]
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30
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Li L, Yin JY, He FZ, Huang MS, Zhu T, Gao YF, Chen YX, Zhou DB, Chen X, Sun LQ, Zhang W, Zhou HH, Liu ZQ. Long noncoding RNA SFTA1P promoted apoptosis and increased cisplatin chemosensitivity via regulating the hnRNP-U-GADD45A axis in lung squamous cell carcinoma. Oncotarget 2017; 8:97476-97489. [PMID: 29228625 PMCID: PMC5722577 DOI: 10.18632/oncotarget.22138] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Accepted: 08/24/2017] [Indexed: 01/05/2023] Open
Abstract
Chemotherapeutic insensitivity remains one of the major obstacles in clinical treatment of lung squamous cell carcinoma (LSCC). Recently, increasing evidence has suggested that long non-coding RNAs (lncRNAs) promote tumorigenesis in many cancer types. However, the potential biological roles and regulatory mechanisms of lncRNAs in response to cisplatin treatment are poorly understood. Here, we found that lncRNA SFTA1P (surfactant associated 1, pseudogene), highly expressed in lung, was down-regulated in LSCC tissues and could be induced upon cisplatin treatment in LSCC cells. Elevated SFTA1P induced apoptosis and enhanced the sensitivity to cisplatin of LSCC cells. We further identified that hnRNP-U (heterogeneous nuclear ribonucleoprotein U) was down-regulated in LSCCs and positively correlated with patients' poor prognosis as well as SFTA1P. Mechanistic studies revealed that SFTA1P could up-regulate hnRNP-U expression. In addition, we identified that hnRNP-U enhanced cisplatin-induced apoptosis through up-regulation of GADD45A, high expression of which was correlated with good prognosis in LSCC patients. Our findings demonstrated that SFTA1P might serve as a useful biomarker for LSCC diagnosis and a predictor for cisplatin chemotherapy response in patients with LSCC.
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Affiliation(s)
- Ling Li
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, P. R. China
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, P. R. China
| | - Ji-Ye Yin
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, P. R. China
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, P. R. China
| | - Fa-Zhong He
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, P. R. China
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, P. R. China
| | - Ma-Sha Huang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, P. R. China
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, P. R. China
| | - Tao Zhu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, P. R. China
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, P. R. China
| | - Yuan-Feng Gao
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, P. R. China
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, P. R. China
| | - Yi-Xin Chen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, P. R. China
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, P. R. China
| | - Dong-Bo Zhou
- Department of Gerontology, Xiangya Hospital, Central South University, Changsha 410008, P. R. China
| | - Xiang Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, P. R. China
| | - Lun-Quan Sun
- Center for Molecular Medicine, Xiangya Hospital, Key Laboratory of Molecular Radiation Oncology of Hunan Province, Central South University, Changsha 410008, P. R. China
| | - Wei Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, P. R. China
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, P. R. China
| | - Hong-Hao Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, P. R. China
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, P. R. China
| | - Zhao-Qian Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, P. R. China
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, P. R. China
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31
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Vert A, Castro J, Ribó M, Benito A, Vilanova M. Activating transcription factor 3 is crucial for antitumor activity and to strengthen the antiviral properties of Onconase. Oncotarget 2017; 8:11692-11707. [PMID: 28035074 PMCID: PMC5355296 DOI: 10.18632/oncotarget.14302] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2016] [Accepted: 11/30/2016] [Indexed: 12/18/2022] Open
Abstract
Onconase is a ribonuclease that presents both antitumor and antiviral properties linked to its ribonucleolytic activity and represents a new class of RNA-damaging drugs. It has reached clinical trials for the treatment of several cancers and human papilloma virus warts. Onconase targets different RNAs in the cell cytosol but Onconase-treated cells present features that are different from a simple arrest of protein synthesis. We have used microarray-derived transcriptional profiling to identify Onconase-regulated genes in two ovarian cancer cell lines (NCI/ADR-RES and OVCAR-8). RT-qPCR analyses have confirmed the microarray findings. We have identified a network of up-regulated genes implicated in different signaling pathways that may explain the cytotoxic effects exerted by Onconase. Among these genes, activating transcription factor 3 (ATF3) plays a central role in the key events triggered by Onconase in treated cancer cells that finally lead to apoptosis. This mechanism, mediated by ATF3, is cell-type independent. Up-regulation of ATF3 may also explain the antiviral properties of this ribonuclease because this factor is involved in halting viral genome replication, keeping virus latency or preventing viral oncogenesis. Finally, Onconase-regulated genes are different from those affected by nuclear-directed ribonucleases.
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Affiliation(s)
- Anna Vert
- Laboratori d'Enginyeria de Proteïnes, Departament de Biologia, Facultat de Ciències, Universitat de Girona, Campus de Montilivi, 17003, Girona, Spain.,Institut d'Investigació Biomèdica de Girona Josep Trueta, (IdIBGi), Girona, Spain
| | - Jessica Castro
- Laboratori d'Enginyeria de Proteïnes, Departament de Biologia, Facultat de Ciències, Universitat de Girona, Campus de Montilivi, 17003, Girona, Spain.,Institut d'Investigació Biomèdica de Girona Josep Trueta, (IdIBGi), Girona, Spain
| | - Marc Ribó
- Laboratori d'Enginyeria de Proteïnes, Departament de Biologia, Facultat de Ciències, Universitat de Girona, Campus de Montilivi, 17003, Girona, Spain.,Institut d'Investigació Biomèdica de Girona Josep Trueta, (IdIBGi), Girona, Spain
| | - Antoni Benito
- Laboratori d'Enginyeria de Proteïnes, Departament de Biologia, Facultat de Ciències, Universitat de Girona, Campus de Montilivi, 17003, Girona, Spain.,Institut d'Investigació Biomèdica de Girona Josep Trueta, (IdIBGi), Girona, Spain
| | - Maria Vilanova
- Laboratori d'Enginyeria de Proteïnes, Departament de Biologia, Facultat de Ciències, Universitat de Girona, Campus de Montilivi, 17003, Girona, Spain.,Institut d'Investigació Biomèdica de Girona Josep Trueta, (IdIBGi), Girona, Spain
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32
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Sadowska A, Nynca A, Ruszkowska M, Paukszto L, Myszczynski K, Orlowska K, Swigonska S, Molcan T, Jastrzebski JP, Ciereszko RE. Transcriptional profiling of porcine granulosa cells exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. CHEMOSPHERE 2017; 178:368-377. [PMID: 28340459 DOI: 10.1016/j.chemosphere.2017.03.055] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Revised: 03/06/2017] [Accepted: 03/12/2017] [Indexed: 06/06/2023]
Abstract
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a toxic man-made chemical compound contaminating the environment. An exposure of living organisms to TCDD may result in numerous disorders, including reproductive pathologies. The aim of the current study was to examine the effects of TCDD on the transcriptome of porcine granulosa cell line AVG-16. By employing next-generation sequencing (NGS) we aimed to identify genes potentially involved in the mechanism of TCDD action and toxicity in porcine granulosa cells. The AVG-16 cells were treated with TCDD (100 nM) for 3, 12 or 24 h, and afterwards total cellular RNA was isolated and sequenced. In TCDD-treated cells we identified 141 differentially expressed genes (DEGs; padjusted < 0.05 and log2 fold change ≥1.0). The DEGs were assigned to GO term, covering biological processes, molecular functions and cellular components. Due to the large number of genes with altered expression, in the current study we analyzed only the genes involved in follicular growth, development and functioning. The obtained results showed that TCDD may affect ovarian follicle fate by influencing granulosa cell cycle, proliferation and DNA repair. The demonstrated over-time changes in the quantity and quality of genes being affected by TCDD treatment showed that the effects of TCDD on granulosa cells changed dramatically between 3-, 12- and 24-h of cell culture. This finding indicate that timing of gene expression measurement is critical for drawing correct conclusions on detailed relationships between the TCDD-affected genes and resulting intracellular processes. These conclusions have to be confirmed and extended by research involving proteomic and functional studies.
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Affiliation(s)
- Agnieszka Sadowska
- Department of Animal Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Poland.
| | - Anna Nynca
- Laboratory of Molecular Diagnostics, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Poland
| | - Monika Ruszkowska
- Department of Animal Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Poland
| | - Lukasz Paukszto
- Department of Plant Physiology, Genetics and Biotechnology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Poland
| | - Kamil Myszczynski
- Department of Botany and Nature Protection, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Poland
| | - Karina Orlowska
- Department of Animal Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Poland
| | - Sylwia Swigonska
- Laboratory of Molecular Diagnostics, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Poland
| | - Tomasz Molcan
- Department of Animal Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Poland
| | - Jan P Jastrzebski
- Department of Plant Physiology, Genetics and Biotechnology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Poland
| | - Renata E Ciereszko
- Department of Animal Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Poland; Laboratory of Molecular Diagnostics, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Poland
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Li D, Dai C, Zhou Y, Yang X, Zhao K, Xiao X, Tang S. Effect of GADD45a on olaquindox-induced apoptosis in human hepatoma G2 cells: Involvement of mitochondrial dysfunction. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2016; 46:140-146. [PMID: 27458702 DOI: 10.1016/j.etap.2016.07.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Revised: 07/15/2016] [Accepted: 07/18/2016] [Indexed: 06/06/2023]
Abstract
Olaquindox, a quinoxaline 1, 4-dioxide derivative, has been widely used as a feed additive for promoting animal growth in China. The aim of present study was to investigate the effect of grow arrest and DNA damage 45 alpha (GADD45a) on olaquindox-induced apoptosis in HepG2 cells. The result showed that olaquindox induced the decrease of cell viability in a dose dependent manner. Compared to the control group, olaquindox treatment at 400 and 800μg/mL increased the expression level of GADD45a protein and reactive oxygen species (ROS) production, decreased mitochondrial membrane potential (MMP), and subsequently increased the expression of Bax while decreased the expression of Bcl-2, leading to the release of cytochrome c (Cyt c). However, knockdown of GADD45a enhanced olaquindox-induced ROS production, disrupted MMP and subsequently caused Cyt c release, then further increased olaquindox- induced cell apoptosis by increasing the activities of caspase-9, caspase-3, and poly (ADP-ribose) polymerase (PARP). In conclusion, the results revealed that GADD45a played a critical role in olaquindox-induced apoptosis in HepG2 cells, which may embrace the regulatory ability on the mitochondrial apoptosis pathway.
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Affiliation(s)
- Daowen Li
- Department of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No. 2, Haidian District, Beijing, PR China
| | - Chongshan Dai
- Department of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No. 2, Haidian District, Beijing, PR China
| | - Yan Zhou
- Department of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No. 2, Haidian District, Beijing, PR China
| | - Xiayun Yang
- Department of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No. 2, Haidian District, Beijing, PR China
| | - Kena Zhao
- Department of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No. 2, Haidian District, Beijing, PR China
| | - Xilong Xiao
- Department of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No. 2, Haidian District, Beijing, PR China
| | - Shusheng Tang
- Department of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No. 2, Haidian District, Beijing, PR China.
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34
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Ou DL, Shyue SK, Lin LI, Feng ZR, Liou JY, Fan HH, Lee BS, Hsu C, Cheng AL. Growth arrest DNA damage-inducible gene 45 gamma expression as a prognostic and predictive biomarker in hepatocellular carcinoma. Oncotarget 2016; 6:27953-65. [PMID: 26172295 PMCID: PMC4695037 DOI: 10.18632/oncotarget.4446] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2015] [Accepted: 06/19/2015] [Indexed: 12/29/2022] Open
Abstract
Growth arrest DNA damage-inducible gene 45 (GADD45) family proteins play a crucial role in regulating cellular stress responses and apoptosis. The present study explored the prognostic and predictive role of GADD45γ in hepatocellular carcinoma (HCC) treatment. GADD45γ expression in HCC cells was examined using quantitative reverse transcription-PCR (qRT-PCR) and Western blotting. The control of GADD45γ transcription was examined using a luciferase reporter assay and chromatin immunoprecipitation. The in vivo induction of GADD45γ was performed using adenoviral transfer. The expression of GADD45γ in HCC tumor tissues from patients who had undergone curative resection was measured using qRT-PCR. Sorafenib induced expression of GADD45γ mRNA and protein, independent of its RAF kinase inhibitor activity. GADD45γ induction was more prominent in sorafenib-sensitive HCC cells (Huh-7 and HepG2, IC50 6–7 μM) than in sorafenib-resistant HCC cells (Hep3B, Huh-7R, and HepG2R, IC50 12–15 μM). Overexpression of GADD45γ reversed sorafenib resistance in vitro and in vivo, whereas GADD45γ expression knockdown by using siRNA partially abrogated the proapoptotic effects of sorafenib on sorafenib-sensitive cells. Overexpression of survivin in HCC cells abolished the antitumor enhancement between GADD45γ overexpression and sorafenib treatment, suggesting that survivin is a crucial mediator of antitumor effects of GADD45γ. GADD45γ expression decreased in tumors from patients with HCC who had undergone curative surgery, and low GADD45γ expression was an independent prognostic factor for poor survival, in addition to old age and vascular invasion. The preceding data indicate that GADD45γ suppression is a poor prognostic factor in patients with HCC and may help predict sorafenib efficacy in HCC.
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Affiliation(s)
- Da-Liang Ou
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan.,National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Song-Kun Shyue
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Liang-In Lin
- Graduate Institute of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Zi-Rui Feng
- National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan.,Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - Jun-Yang Liou
- Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan
| | - Hsiang-Hsuan Fan
- National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan.,Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - Bin-Shyun Lee
- National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan.,Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - Chiun Hsu
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan.,Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Ann-Lii Cheng
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan.,Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
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Hong L, Sun QF, Xu TY, Wu YH, Zhang H, Fu RQ, Cai FJ, Zhou QQ, Zhou K, Du QW, Zhang D, Xu S, Ding JG. New role and molecular mechanism of Gadd45a in hepatic fibrosis. World J Gastroenterol 2016; 22:2779-2788. [PMID: 26973416 PMCID: PMC4778000 DOI: 10.3748/wjg.v22.i9.2779] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2015] [Revised: 08/04/2015] [Accepted: 11/09/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the role of Gadd45a in hepatic fibrosis and the transforming growth factor (TGF)-β/Smad signaling pathway.
METHODS: Wild-type male BALB/c mice were treated with CCl4 to induce a model of chronic liver injury. Hepatic stellate cells (HSCs) were isolated from the liver of BALB/c mice and were treated with small interfering RNAs (siRNAs) targeting Gadd45a or the pcDNA3.1-Gadd45a recombinant plasmid. Cellular α-smooth muscle actin (α-SMA), β-actin, type I collagen, phospho-Smad2, phospho-Smad3, Smad2, Smad3, and Smad4 were detected by Western blots. The mRNA levels of α-SMA, β-actin, and type I collagen were determined by quantitative real-time (qRT)-PCR analyses. Reactive oxygen species production was monitored by flow cytometry using 2,7-dichlorodihydrofluorescein diacetate. Gadd45a, Gadd45b, anti-Gadd45g, type I collagen, and SMA local expression in liver tissue were measured by histologic and immunohistochemical analyses.
RESULTS: Significant downregulation of Gadd45a, but not Gadd45b or Gadd45g, accompanied by activation of the TGF-β/Smad signaling pathways was detected in fibrotic liver tissues of mice and isolated HSCs with chronic liver injury induced by CCl4 treatment. Overexpression of Gadd45a reduced the expression of extracellular matrix proteins and α-SMA in HSCs, whereas transient knockdown of Gadd45a with siRNA reversed this process. Gadd45a inhibited the activity of a plasminogen activator inhibitor-1 promoter construct and (CAGA)9 MLP-Luc, an artificial Smad3/4-specific reporter, as well as reduced the phosphorylation and nuclear translocation of Smad3. Gadd45a showed protective effects by scavenging reactive oxygen species and upregulating antioxidant enzymes.
CONCLUSION: Gadd45a may counteract hepatic fibrosis by regulating the activation of HSCs via the inhibition of TGF-β/Smad signaling.
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Liu X, Deng Q, Luo X, Chen Y, Shan N, Qi H. Oxidative stress-induced Gadd45α inhibits trophoblast invasion and increases sFlt1/sEng secretions via p38 MAPK involving in the pathology of pre-eclampsia. J Matern Fetal Neonatal Med 2016; 29:3776-85. [PMID: 26809169 DOI: 10.3109/14767058.2016.1144744] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Pre-eclampsia (PE) is one of the most common pregnancy-related complications. We have previously reported that growth arrest and DNA damage-inducible 45 alpha (Gadd45α) is over-expressed in trophoblasts in pre-eclamptic placentas, with an excessive activation of p38 mitogen-activated protein kinase (MAPK) and increased levels of soluble Fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng) in maternal sera. Now we further investigate how Gadd45α regulates trophoblast functions and anti-angiogenesis factors secretions during placental development in patients with PE. METHODS Human placental villous explants were used to verify the effects of Gadd45α and p38 MAPK in placentation. Then HRT8/SVneo cells exposed to hypoxia/reoxygenation (H/R) were employed as an oxidative stress model to investigate the effects of Gadd45α on invasion and sFlt-1/sEng secretions. Through silencing Gadd45α with lentiviral vector-based short-hairpin RNA and inhibiting p38 MAPK with SB203580, we demonstrated that Gadd45α and its downstream p38 protein played roles in the pathology of pre-eclampsia. RESULTS Gadd45α was found to have increased expression in H/R-treated villous explants and HTR8/SVneo cells. Gadd45α knockdown or p38 blockage could promote trophoblast outgrowth and migration in H/R-exposed villous explants, and enhance the potentials of trophoblast migration/invasion and network formation in H/R-exposed HTR8/SVneo cells. These functional changes might be related to the increased activities of MMP2/9. Meanwhile, Gadd45α knockdown or p38 inhibition also decreases sFlt-1/sEng secretions via suppressing oxidative stress. CONCLUSIONS Oxidative stress-induced overexpression of Gadd45α might influence the activity of MMPs through activation of p38 MAPK signaling to affect the invasion of trophoblast cells, and increase the secretions of sFlt-1/sEng, which then participate in the pathogenesis of pre-eclampsia.
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Affiliation(s)
- Xiru Liu
- a Department of Obstetrics and Gynecology , the First Affiliated Hospital of Chongqing Medical University , Chongqing , China
| | - Qinyin Deng
- a Department of Obstetrics and Gynecology , the First Affiliated Hospital of Chongqing Medical University , Chongqing , China
| | - Xin Luo
- a Department of Obstetrics and Gynecology , the First Affiliated Hospital of Chongqing Medical University , Chongqing , China
| | - Ying Chen
- a Department of Obstetrics and Gynecology , the First Affiliated Hospital of Chongqing Medical University , Chongqing , China
| | - Nan Shan
- a Department of Obstetrics and Gynecology , the First Affiliated Hospital of Chongqing Medical University , Chongqing , China
| | - Hongbo Qi
- a Department of Obstetrics and Gynecology , the First Affiliated Hospital of Chongqing Medical University , Chongqing , China
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37
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Yuan A, Hsiao YJ, Chen HY, Chen HW, Ho CC, Chen YY, Liu YC, Hong TH, Yu SL, Chen JJW, Yang PC. Opposite Effects of M1 and M2 Macrophage Subtypes on Lung Cancer Progression. Sci Rep 2015; 5:14273. [PMID: 26399191 PMCID: PMC4585843 DOI: 10.1038/srep14273] [Citation(s) in RCA: 256] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Accepted: 08/24/2015] [Indexed: 12/11/2022] Open
Abstract
Macrophages in a tumor microenvironment have been characterized as M1- and M2-polarized subtypes. Here, we discovered the different macrophages' impacts on lung cancer cell A549. The M2a/M2c subtypes promoted A549 invasion and xenograft tumor growth. The M1 subtype suppressed angiogenesis. M1 enhanced the sensitivity of A549 to cisplatin and decreased the tube formation activity and cell viability of A549 cells by inducing apoptosis and senescence. Different macrophage subtypes regulated genes involved in the immune response, cytoskeletal remodeling, coagulation, cell adhesion, and apoptosis pathways in A549 cells, which was a pattern that correlated with the altered behaviors of the A549 cells. Furthermore, we found that the identified M1/M2 gene signatures were significantly correlated with the extended overall survival of lung cancer patients. These results suggest that M1/M2 gene expression signature may be used as a prognostic indicator for lung cancer patients, and M1/M2 polarization may be a target of investigation of immune-modulating therapies for lung cancer in the future.
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Affiliation(s)
- Ang Yuan
- Departments of Chest Medicine and Emergency Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Yi-Jing Hsiao
- Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Hsuan-Yu Chen
- Institute of Statistical Science, Academia Sinica, Taipei, Taiwan
| | - Huei-Wen Chen
- Graduate Institute of Toxicology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chao-Chi Ho
- Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yu-Yun Chen
- Graduate Institute of Toxicology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yi-Chia Liu
- Departments of Chest Medicine and Emergency Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Tsai-Hsia Hong
- Departments of Surgery, National Taiwan University Hospital, Taipei, Taiwan.,General Education Center, National Defense University, Taipei, Taiwan
| | - Sung-Liang Yu
- Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Department of Pathology, National Taiwan University College of Medicine, Taipei, Taiwan.,Center for Optoelectronic Biomedicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Jeremy J W Chen
- Institute of Biomedical Sciences, National Chung-Hsing University, Taichung, Taiwan.,Agricultural Biotechnology Center, National Chung-Hsing University, Taichung, Taiwan
| | - Pan-Chyr Yang
- Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
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38
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Reineke LC, Lloyd RE. The stress granule protein G3BP1 recruits protein kinase R to promote multiple innate immune antiviral responses. J Virol 2015; 89:2575-89. [PMID: 25520508 PMCID: PMC4325707 DOI: 10.1128/jvi.02791-14] [Citation(s) in RCA: 153] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2014] [Accepted: 12/08/2014] [Indexed: 11/20/2022] Open
Abstract
UNLABELLED Stress granules (SGs) are cytoplasmic storage sites containing translationally silenced mRNPs that can be released to resume translation after stress subsides. We previously showed that poliovirus 3C proteinase cleaves the SG-nucleating protein G3BP1, blocking the ability of cells to form SGs late in infection. Many other viruses also target G3BP1 and inhibit SG formation, but the reasons why these functions evolved are unclear. Previously, we also showed a link between G3BP1-induced SGs and protein kinase R (PKR)-mediated translational control, but the mechanism of PKR interplay with SG and the antiviral consequences are unknown. Here, we show that G3BP1 exhibits antiviral activity against several enteroviruses, whereas truncated G3BP1 that cannot form SGs does not. G3BP1-induced SGs are linked to activation of innate immune transcriptional responses through NF-κB and JNK. The G3BP1-induced SGs also recruit PKR and other antiviral proteins. We show that the PXXP domain within G3BP1 is essential for the recruitment of PKR to SGs, for eIF2α phosphorylation driven by PKR, and for nucleating SGs of normal composition. We also show that deletion of the PXXP domain in G3BP1 compromises its antiviral activity. These findings tie PKR activation to its recruitment to SGs by G3BP1 and indicate that G3BP1 promotes innate immune responses at both the transcriptional and translational levels and integrates cellular stress responses and innate immunity. IMPORTANCE Stress granules appear during virus infection, and their importance is not well understood. Previously, it was assumed that they were nonfunctional artifacts associated with cellular stress. PKR is a well-known antiviral protein; however, its regulation in cells is not well understood. Our work links cellular stress granules with activation of PKR and other innate immune pathways through the activity of G3BP1, a critical stress granule component. The ability of stress granules and G3BP1 to activate PKR and other innate immune transcriptional responses indicates that G3BP1 is an antiviral protein. This work helps to refine a longstanding paradigm indicating stress granules are inert structures and explains why G3BP1 is subverted by many viruses to promote a productive infection.
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Affiliation(s)
- Lucas C Reineke
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
| | - Richard E Lloyd
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
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Paccez JD, Duncan K, Vava A, Correa RG, Libermann TA, Parker MI, Zerbini LF. Inactivation of GSK3β and activation of NF-κB pathway via Axl represents an important mediator of tumorigenesis in esophageal squamous cell carcinoma. Mol Biol Cell 2015; 26:821-31. [PMID: 25568334 PMCID: PMC4342020 DOI: 10.1091/mbc.e14-04-0868] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Deregulation of Axl in esophageal squamous cell carcinoma (OSCC) with potential therapeutic implications is described for the first time. This paper also sheds light on the understanding of how Axl regulates OSCC development in vitro and in vivo. Axl expression leads to an Akt-dependent regulation of glycogen synthase kinase 3β activity and the nucluear factor kappaB (NF-κB) pathway, affecting the epithelial–mesenchymal transition. The receptor tyrosine kinase Axl has been described as an oncogene, and its deregulation has been implicated in the progression of several human cancers. While the role of Axl in esophageal adenocarcinoma has been addressed, there is no information about its role in esophageal squamous cell carcinoma (OSCC). In the current report, we identified, for the first time, deregulation of Axl expression in OSCC. Axl is consistently overexpressed in OSCC cell lines and human tumor samples, mainly in advanced stages of the disease. Blockage of Axl gene expression by small interfering RNA inhibits cell survival, proliferation, migration, and invasion in vitro and esophageal tumor growth in vivo. Additionally, repression of Axl expression results in Akt-dependent inhibition of pivotal genes involved in the nuclear factor-kappaB (NF-κB) pathway and in the induction of glycogen synthase kinase 3β (GSK3β) activity, resulting in loss of mesenchymal markers and induction of epithelial markers. Furthermore, treatment of esophageal cancer cells with the Akt inhibitor wortmannin inhibits NF-κB signaling, induces GSK3β activity, and blocks OSCC cell proliferation in an Axl-dependent manner. Taken together, our results establish a clear role for Axl in OSCC tumorigenesis with potential therapeutic implications.
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Affiliation(s)
- Juliano D Paccez
- International Centre for Genetic Engineering and Biotechnology, Cape Town 7925, South Africa Division of Medical Biochemistry, University of Cape Town, Cape Town, South Africa
| | - Kristal Duncan
- International Centre for Genetic Engineering and Biotechnology, Cape Town 7925, South Africa Division of Medical Biochemistry, University of Cape Town, Cape Town, South Africa
| | - Akhona Vava
- International Centre for Genetic Engineering and Biotechnology, Cape Town 7925, South Africa Division of Medical Biochemistry, University of Cape Town, Cape Town, South Africa
| | | | - Towia A Libermann
- BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115
| | - M Iqbal Parker
- International Centre for Genetic Engineering and Biotechnology, Cape Town 7925, South Africa Division of Medical Biochemistry, University of Cape Town, Cape Town, South Africa
| | - Luiz F Zerbini
- International Centre for Genetic Engineering and Biotechnology, Cape Town 7925, South Africa Division of Medical Biochemistry, University of Cape Town, Cape Town, South Africa
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MacLeod AS, Rudolph R, Corriden R, Ye I, Garijo O, Havran WL. Skin-resident T cells sense ultraviolet radiation-induced injury and contribute to DNA repair. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2014; 192:5695-702. [PMID: 24808367 PMCID: PMC4048764 DOI: 10.4049/jimmunol.1303297] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Skin-resident T cells have been shown to play important roles in tissue homeostasis and wound repair, but their role in UV radiation (UVR)-mediated skin injury and subsequent tissue regeneration is less clear. In this study, we demonstrate that acute UVR rapidly activates skin-resident T cells in humans and dendritic epidermal γδ T cells (DETCs) in mice through mechanisms involving the release of ATP from keratinocytes. Following UVR, extracellular ATP leads to an increase in CD69 expression, proliferation, and IL-17 production, and to changes in DETC morphology. Furthermore, we find that the purinergic receptor P2X7 and caspase-1 are necessary for UVR-induced IL-1 production in keratinocytes, which increases IL-17 secretion by DETCs. IL-17, in turn, induces epidermal TNF-related weak inducer of apoptosis and growth arrest and DNA damage-associated gene 45, two molecules linked to the DNA repair response. Finally, we demonstrate that DETCs and human skin-resident T cells limit DNA damage in keratinocytes. Taken together, our findings establish a novel role for skin-resident T cells in the UVR-associated DNA repair response and underscore the importance of skin-resident T cells to overall skin regeneration.
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MESH Headings
- Animals
- Antigens, CD/genetics
- Antigens, CD/immunology
- Antigens, Differentiation, T-Lymphocyte/genetics
- Antigens, Differentiation, T-Lymphocyte/immunology
- DNA Repair/genetics
- DNA Repair/immunology
- DNA Repair/radiation effects
- Epidermis/immunology
- Epidermis/pathology
- Female
- Gene Expression Regulation/genetics
- Gene Expression Regulation/immunology
- Gene Expression Regulation/radiation effects
- Humans
- Interleukin-17/immunology
- Keratinocytes/immunology
- Keratinocytes/pathology
- Lectins, C-Type/genetics
- Lectins, C-Type/immunology
- Male
- Mice
- Mice, Knockout
- Receptors, Antigen, T-Cell, gamma-delta
- Regeneration/genetics
- Regeneration/immunology
- Regeneration/radiation effects
- T-Lymphocytes/immunology
- T-Lymphocytes/pathology
- Tumor Necrosis Factor-alpha/genetics
- Tumor Necrosis Factor-alpha/immunology
- Ultraviolet Rays/adverse effects
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Affiliation(s)
- Amanda S MacLeod
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037
| | - Ross Rudolph
- Division of Plastic Surgery, Scripps Clinic Torrey Pines, La Jolla, CA 92037; Division of Plastic Surgery, University of California San Diego, La Jolla, CA 92037; and
| | - Ross Corriden
- Division of Pharmacology and Drug Discovery, Department of Pediatrics, University of California San Diego, La Jolla, CA 92093
| | - Ivan Ye
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037
| | - Olivia Garijo
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037
| | - Wendy L Havran
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037;
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Liu X, Mu H, Luo X, Xiao X, Ding Y, Yin N, Deng Q, Qi H. Expression of Gadd45α in human early placenta and its role in trophoblast invasion. Placenta 2014; 35:370-7. [DOI: 10.1016/j.placenta.2014.03.020] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2014] [Revised: 03/21/2014] [Accepted: 03/27/2014] [Indexed: 01/04/2023]
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HDAC inhibitors induce apoptosis but not cellular senescence in Gadd45α-deficient E1A+Ras cells. Int J Biochem Cell Biol 2014; 51:102-10. [DOI: 10.1016/j.biocel.2014.03.031] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2013] [Revised: 03/10/2014] [Accepted: 03/28/2014] [Indexed: 11/22/2022]
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Modulatory effect of selenium on cell-cycle regulatory genes in the prostate adenocarcinoma cell line. J Appl Biomed 2014. [DOI: 10.1016/j.jab.2013.02.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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Han AL, Kumar S, Fok JY, Tyagi AK, Mehta K. Tissue transglutaminase expression promotes castration-resistant phenotype and transcriptional repression of androgen receptor. Eur J Cancer 2014; 50:1685-96. [PMID: 24656569 DOI: 10.1016/j.ejca.2014.02.014] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Revised: 01/28/2014] [Accepted: 02/15/2014] [Indexed: 01/08/2023]
Abstract
Many studies have supported a role for inflammation in prostate tumour growth. However, the contribution of inflammation to the development of castration-resistant prostate cancer remains largely unknown. Based on observations that aberrant expression of the proinflammatory protein tissue transglutaminase (TG2) is associated with development of drug resistance and metastatic phenotype in multiple cancer types, we determined TG2 expression in prostate cancer cells. Herein we report that human prostate cancer cell lines with low expression of androgen receptor (AR) had high basal levels of TG2 expression. Also, overexpression of TG2 negatively regulated AR mRNA and protein expression and attenuated androgen sensitivity of prostate cancer cells. TG2 expression in prostate cancer cells was associated with increased invasion and resistance to chemotherapy. Mechanistically, TG2 activated nuclear factor (NF)-κB and induced epithelial-mesenchymal transition. TG2/NF-κB-mediated decrease in AR expression resulted from transcriptional repression involving cis-interaction of NF-κB in a complex with TG2 with the 5'-untranslated region of AR. Negative regulation of AR could be partially abrogated by repression of TG2 or NF-κB (p65/RelA) by gene-specific small interfering RNA. These results suggested that a novel pathway links androgen dependence with TG2-regulated inflammatory signalling and hence may make TG2 a novel therapeutic target for the prevention and treatment of castration-resistant prostate cancer.
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Affiliation(s)
- Amy Lee Han
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
| | - Santosh Kumar
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
| | - Jansina Y Fok
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
| | - Amit K Tyagi
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
| | - Kapil Mehta
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States.
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Salvador JM, Brown-Clay JD, Fornace AJ. Gadd45 in stress signaling, cell cycle control, and apoptosis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2014; 793:1-19. [PMID: 24104470 DOI: 10.1007/978-1-4614-8289-5_1] [Citation(s) in RCA: 265] [Impact Index Per Article: 24.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The first identified Gadd45 gene, Gadd45a, encodes a ubiquitously expressed protein that is often induced by DNA damage and other stress signals associated with growth arrest and apoptosis. This protein and the other two members of this small gene family, Gadd45b and Gadd45g, have been implicated in a variety of the responses to cell injury including cell cycle checkpoints, apoptosis, and DNA repair. In vivo, many of the prominent roles for the Gadd45 proteins are associated with signaling mediated by p38 mitogen-activated protein kinases (MAPK). Gadd45 proteins can contribute to p38 activation either by activation of upstream kinase(s) or by direct interaction. In vivo, there are important tissue and cell-type-specific differences in the roles for Gadd45 in MAPK signaling. In addition to being p53-regulated, Gadd45a has been found to contribute to p53 activation via p38. Like other stress and signaling proteins, Gadd45 proteins show complex regulation and numerous effectors.
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Affiliation(s)
- Jesús M Salvador
- Department of Immunology and Oncology, Centro Nacional de Biotecnología, (CNB-CSIC) Lab 417, c/Darwin n 3, Campus Cantoblanco, 28049, Madrid, Spain
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Wu DG, Yu P, Li JW, Jiang P, Sun J, Wang HZ, Zhang LD, Wen MB, Bie P. Apigenin potentiates the growth inhibitory effects by IKK-β-mediated NF-κB activation in pancreatic cancer cells. Toxicol Lett 2014; 224:157-64. [DOI: 10.1016/j.toxlet.2013.10.007] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2013] [Revised: 10/04/2013] [Accepted: 10/10/2013] [Indexed: 12/22/2022]
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Kumar SR, Hosokawa M, Miyashita K. Fucoxanthin: a marine carotenoid exerting anti-cancer effects by affecting multiple mechanisms. Mar Drugs 2013; 11:5130-47. [PMID: 24351910 PMCID: PMC3877908 DOI: 10.3390/md11125130] [Citation(s) in RCA: 139] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2013] [Revised: 11/27/2013] [Accepted: 12/03/2013] [Indexed: 12/28/2022] Open
Abstract
Fucoxanthin is a marine carotenoid exhibiting several health benefits. The anti-cancer effect of fucoxanthin and its deacetylated metabolite, fucoxanthinol, is well documented. In view of its potent anti-carcinogenic activity, the need to understand the underlying mechanisms has gained prominence. Towards achieving this goal, several researchers have carried out studies in various cell lines and in vivo and have deciphered that fucoxanthin exerts its anti-proliferative and cancer preventing influence via different molecules and pathways including the Bcl-2 proteins, MAPK, NFκB, Caspases, GADD45, and several other molecules that are involved in either cell cycle arrest, apoptosis, or metastasis. Thus, in addition to decreasing the frequency of occurrence and growth of tumours, fucoxanthin has a cytotoxic effect on cancer cells. Some studies show that this effect is selective, i.e., fucoxanthin has the capability to target cancer cells only, leaving normal physiological cells unaffected/less affected. Hence, fucoxanthin and its metabolites show great promise as chemotherapeutic agents in cancer.
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Affiliation(s)
- Sangeetha Ravi Kumar
- Faculty of Fisheries Sciences, Hokkaido University, 3-1-1, Minato Cho, Hakodate, Hokkaido 041-8611, Japan.
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Basílio J, Hoeth M, Holper-Schichl YM, Resch U, Mayer H, Hofer-Warbinek R, de Martin R. TNFα-induced down-regulation of Sox18 in endothelial cells is dependent on NF-κB. Biochem Biophys Res Commun 2013; 442:221-6. [PMID: 24269235 DOI: 10.1016/j.bbrc.2013.11.030] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Accepted: 11/07/2013] [Indexed: 10/26/2022]
Abstract
The transcription factor Sox18 plays a role in angiogenesis, including lymphangiogenesis, where it is upregulated by growth factors and directs the expression of genes encoding, e.g., guidance molecules and a matrix metalloproteinase. Conversely, we found that in human umbilical vein endothelial cells (HUVEC) Sox18 is repressed by the pro-inflammatory mediator TNFα (as well as IL-1 and LPS). Since a common feature of these mediators is the activation of the NF-κB signaling pathway, we investigated whether Sox18 downregulation is dependent on this transcription factor. Transduction of HUVEC with an adenoviral vector directing the expression of the NF-κB inhibitor IκBα prevented the downregulation of Sox18. Transient transfections of Sox18 promoter reporter genes revealed that the downregulation takes place on the level of transcription, and that the p65/RelA subunit of NF-κB was operative. Furthermore, the responsible promoter region of Sox18 is located within -1.0kb from the transcriptional start site. The repression of Sox18 and its target genes may lead to altered formation of vessels in inflamed settings.
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Affiliation(s)
- José Basílio
- Department of Vascular Biology and Thrombosis Research, Medical University of Vienna, Lazarettg. 19, Vienna, Austria
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50
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Vlachostergios PJ, Voutsadakis IA, Papandreou CN. The role of ubiquitin-proteasome system in glioma survival and growth. Growth Factors 2013; 31:106-13. [PMID: 23688106 DOI: 10.3109/08977194.2013.799156] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
High-grade gliomas represent a group of aggressive brain tumors with poor prognosis due to an inherent capacity of persistent cell growth and survival. The ubiquitin-proteasome system (UPS) is an intracellular machinery responsible for protein turnover. Emerging evidence implicates various proteins targeted for degradation by the UPS in key survival and proliferation signaling pathways of these tumors. In this review, we discuss the involvement of UPS in the regulation of several mediators and effectors of these pathways in malignant gliomas.
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Affiliation(s)
- Panagiotis J Vlachostergios
- Department of Medical Oncology, Faculty of Medicine, School of Health Sciences, University of Thessaly, University Hospital of Larissa, Larissa, Greece.
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