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1
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Mohapatra S, Winkle M, Ton AN, Nguyen D, Calin GA. The Role of Non-Coding RNAs in Chromosomal Instability in Cancer. J Pharmacol Exp Ther 2023; 384:10-19. [PMID: 36167417 PMCID: PMC9827503 DOI: 10.1124/jpet.122.001357] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/22/2022] [Accepted: 08/17/2022] [Indexed: 01/12/2023] Open
Abstract
Chromosomal instability (CIN) is characterized by an increased frequency of changes in chromosome structure or number and is regarded as a hallmark of cancer. CIN plays a prevalent role in tumorigenesis and cancer progression by assisting the cancer cells' phenotypic adaptation to stress, which have been tightly linked to therapy resistance and metastasis. Both CIN-inducing and CIN-repressing agents are being clinically tested for the treatment of cancer to increase CIN levels to unsustainable levels leading to cell death or to decrease CIN levels to limit the development of drug resistance, respectively. Non-coding RNAs (ncRNAs) including microRNAs and long ncRNAs (lncRNAs) have been fundamentally implicated in CIN. The miR-22, miR-26a, miR-28, and miR-186 target important checkpoint proteins involved in mediating chromosomal stability and their expression modulation has been directly related to CIN occurrence. lncRNAs derived from telomeric, centrosomal, and enhancer regions play an important role in mediating genome stability, while specific lncRNA transcripts including genomic instability inducing RNA called Ginir, P53-responsive lncRNA termed as GUARDIN, colon cancer-associated transcript 2, PCAT2, and ncRNA activated by DNA damage called NORAD have been shown to act within CIN-associated pathways. In this review, we discuss how these ncRNAs either maintain or disrupt the stability of chromosomes and how these mechanisms could be exploited for novel therapeutic approaches targeting CIN in cancer patients. SIGNIFICANCE STATEMENT: Chromosomal instability increases tumor heterogeneity and thereby assists the phenotypic adaptation of cancer cells, causing therapy resistance and metastasis. Several microRNAs and long non-coding RNAs that have been causally linked to chromosomal instability could represent novel therapeutic targets. Understanding the role of non-coding RNAs in regulating different genes involved in driving chromosomal instability will give insights into how non-coding RNAs can be utilized toward modifying chemotherapeutic regimens in different cancers.
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Affiliation(s)
- Swati Mohapatra
- Department of Translational Molecular Pathology (S.M., M.W., A.N.T., G.A.C.), UT Health Graduate School of Biomedical Sciences (S.M.), Program in Molecular Genetic Technology, School of Health Professions (A.N.T.), and Center for RNA Interference and Non-Coding RNAs (G.A.C.), The University of Texas MD Anderson Cancer Center, Houston, Texas; and Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts (D.N.)
| | - Melanie Winkle
- Department of Translational Molecular Pathology (S.M., M.W., A.N.T., G.A.C.), UT Health Graduate School of Biomedical Sciences (S.M.), Program in Molecular Genetic Technology, School of Health Professions (A.N.T.), and Center for RNA Interference and Non-Coding RNAs (G.A.C.), The University of Texas MD Anderson Cancer Center, Houston, Texas; and Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts (D.N.)
| | - Anh N Ton
- Department of Translational Molecular Pathology (S.M., M.W., A.N.T., G.A.C.), UT Health Graduate School of Biomedical Sciences (S.M.), Program in Molecular Genetic Technology, School of Health Professions (A.N.T.), and Center for RNA Interference and Non-Coding RNAs (G.A.C.), The University of Texas MD Anderson Cancer Center, Houston, Texas; and Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts (D.N.)
| | - Dien Nguyen
- Department of Translational Molecular Pathology (S.M., M.W., A.N.T., G.A.C.), UT Health Graduate School of Biomedical Sciences (S.M.), Program in Molecular Genetic Technology, School of Health Professions (A.N.T.), and Center for RNA Interference and Non-Coding RNAs (G.A.C.), The University of Texas MD Anderson Cancer Center, Houston, Texas; and Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts (D.N.)
| | - George A Calin
- Department of Translational Molecular Pathology (S.M., M.W., A.N.T., G.A.C.), UT Health Graduate School of Biomedical Sciences (S.M.), Program in Molecular Genetic Technology, School of Health Professions (A.N.T.), and Center for RNA Interference and Non-Coding RNAs (G.A.C.), The University of Texas MD Anderson Cancer Center, Houston, Texas; and Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts (D.N.)
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González-Borja I, Alors-Pérez E, Amat I, Alonso L, Viyuela-García C, Goñi S, Reyes JC, Ceballos-Chávez M, Hernández-García I, Sánchez-Frías ME, Santamaría E, Razquin S, Arjona-Sánchez Á, Arrazubi V, Pérez-Sanz J, Vera R, Fernández-Irigoyen J, Castaño JP, Viúdez A. Deciphering CHFR Role in Pancreatic Ductal Adenocarcinoma. Front Med (Lausanne) 2021; 8:720128. [PMID: 34869418 PMCID: PMC8639583 DOI: 10.3389/fmed.2021.720128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 10/04/2021] [Indexed: 12/09/2022] Open
Abstract
Checkpoint with forkhead-associated and ring finger domains (CHFR) has been proposed as a predictive and prognosis biomarker for different tumor types, but its role in pancreatic ductal adenocarcinoma (PDAC) remains unknown. The aim of this study was two-pronged: to review the role of CHFR in PDAC and evaluating CHFR as a potential predictive biomarker in this disease. For this purpose, we first explored the CHFR messenger (m)RNA expression and promoter methylation through the TCGA database. Secondly, the CHFR expression and promoter methylation were prospectively evaluated in a cohort of patients diagnosed with borderline (n = 19) or resectable (n = 16) PDAC by immunohistochemistry (IHC), methylation specific-PCR (MSP), and pyrosequencing. The results from the TCGA database showed significant differences in terms of progression-free survival (PFS) and overall survival (OS) based on the CHFR mRNA expression, which was likely independent from the promoter methylation. Importantly, our results showed that in primarily resected patients and also the entire cohort, a higher CHFR expression as indicated by the higher IHC staining intensity might identify patients with longer disease-free survival (DFS) and OS, respectively. Similarly, in the same cohorts, patients with lower methylation levels by pyrosequencing showed significantly longer OS than patients without this pattern. Both, the CHFR expression intensity and its promoter methylation were established as independent prognostic factors for PFS and OS in the entire cohort. In contrast, no significant differences were found between different methylation patterns for CHFR and the response to taxane-based neoadjuvant treatment. These results suggest the potential role of the higher expression of CHFR and the methylation pattern of its promoter as potential prognostic biomarkers in PDAC, thus warranting further comprehensive studies to extend and confirm our preliminary findings.
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Affiliation(s)
- Iranzu González-Borja
- OncobionaTras Lab, Navarrabiomed, Complejo Hospitalario de Navarra, Universidad Pública de Navarra, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain
| | - Emilia Alors-Pérez
- Hormones and Cancer Group, Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain.,Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain.,Reina Sofia University Hospital, Córdoba, Spain.,Centro de Investigación Biomédica en Red (CIBER) Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain
| | - Irene Amat
- Pathology Department, Complejo Hospitalario de Navarra, Pamplona, Spain
| | - Laura Alonso
- Pathology Department, Complejo Hospitalario de Navarra, Pamplona, Spain
| | - Cristina Viyuela-García
- Hormones and Cancer Group, Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain.,Reina Sofia University Hospital, Córdoba, Spain.,Surgery Service, Reina Sofia University Hospital, Córdoba, Spain
| | - Saioa Goñi
- OncobionaTras Lab, Navarrabiomed, Complejo Hospitalario de Navarra, Universidad Pública de Navarra, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain
| | - José C Reyes
- Centro Andaluz de Biología Molecular y Medicina Regenerativa, Consejo Superior de Investigaciones Científicas-Universidad de Sevilla-Universidad Pablo de Olavide, Seville, Spain
| | - María Ceballos-Chávez
- Centro Andaluz de Biología Molecular y Medicina Regenerativa, Consejo Superior de Investigaciones Científicas-Universidad de Sevilla-Universidad Pablo de Olavide, Seville, Spain
| | | | - Marina E Sánchez-Frías
- Hormones and Cancer Group, Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain.,Reina Sofia University Hospital, Córdoba, Spain.,Pathology Service, Reina Sofia University Hospital, Córdoba, Spain
| | - Enrique Santamaría
- Proteomics Platform, Clinical Neuroproteomics Unit, Navarrabiomed, Complejo Hospitalario de Navarra, Universidad Pública de Navarra, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain
| | - Socorro Razquin
- Pathology Department, Complejo Hospitalario de Navarra, Pamplona, Spain
| | - Álvaro Arjona-Sánchez
- Hormones and Cancer Group, Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain.,Reina Sofia University Hospital, Córdoba, Spain.,Surgery Service, Reina Sofia University Hospital, Córdoba, Spain
| | - Virginia Arrazubi
- Medical Oncology Department, Complejo Hospitalario de Navarra, Pamplona, Spain
| | - Jairo Pérez-Sanz
- OncobionaTras Lab, Navarrabiomed, Complejo Hospitalario de Navarra, Universidad Pública de Navarra, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain
| | - Ruth Vera
- Medical Oncology Department, Complejo Hospitalario de Navarra, Pamplona, Spain
| | - Joaquín Fernández-Irigoyen
- Proteomics Platform, Clinical Neuroproteomics Unit, Navarrabiomed, Complejo Hospitalario de Navarra, Universidad Pública de Navarra, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain
| | - Justo P Castaño
- Hormones and Cancer Group, Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain.,Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain.,Reina Sofia University Hospital, Córdoba, Spain.,Centro de Investigación Biomédica en Red (CIBER) Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain
| | - Antonio Viúdez
- OncobionaTras Lab, Navarrabiomed, Complejo Hospitalario de Navarra, Universidad Pública de Navarra, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain.,Medical Oncology Department, Complejo Hospitalario de Navarra, Pamplona, Spain.,Medical Affairs Services, ICON plc, North Wales, PA, United States
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Chen X, Lin J, Chen Q, Liao X, Wang T, Li S, Mao L, Li Z. Identification of a Novel Epigenetic Signature CHFR as a Potential Prognostic Gene Involved in Metastatic Clear Cell Renal Cell Carcinoma. Front Genet 2021; 12:720979. [PMID: 34539751 PMCID: PMC8440929 DOI: 10.3389/fgene.2021.720979] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Accepted: 08/02/2021] [Indexed: 01/21/2023] Open
Abstract
Metastasis is the main cause of clear cell renal cell carcinoma (ccRCC) treatment failure, and the key genes involved in ccRCC metastasis remain largely unknown. We analyzed the ccRCC datasets in The Cancer Genome Atlas database, comparing primary and metastatic ccRCC tumor records in search of tumor metastasis-associated genes, and then carried out overall survival, Cox regression, and receiver operating characteristic (ROC) analyses to obtain potential prognostic markers. Comprehensive bioinformatics analysis was performed to verify that the checkpoint with forkhead associated and ring finger domains (CHFR) gene is a reliable candidate oncogene, which is overexpressed in ccRCC metastatic tumor tissue, and that high expression levels of CHFR indicate a poor prognosis. A detailed analysis of the methylation of CHFR in ccRCC tumors showed that three sites within 200 bp of the transcription initiation site were significantly associated with prognosis and that hypomethylation was associated with increased CHFR gene expression levels. Knockdown of CHFR in ccRCC cells inhibited cell proliferation, colony formation, and migration ability. In summary, our findings suggest that the epigenetic signature on CHFR gene is a novel prognostic feature; furthermore, our findings offer theoretical support for the study of metastasis-related genes in ccRCC and provided new insights for the clinical treatment of the disease.
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Affiliation(s)
- Xiangling Chen
- Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), Shenzhen, China.,Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), Shenzhen, China.,Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Jiatian Lin
- Department of Minimally Invasive Intervention, Peking University Shenzhen Hospital, Shenzhen, China
| | | | - Ximian Liao
- Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), Shenzhen, China.,Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), Shenzhen, China
| | - Tongyu Wang
- Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), Shenzhen, China.,Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), Shenzhen, China
| | - Shi Li
- Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), Shenzhen, China.,Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), Shenzhen, China
| | - Longyi Mao
- Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), Shenzhen, China.,Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), Shenzhen, China
| | - Zesong Li
- Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), Shenzhen, China.,Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), Shenzhen, China
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4
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Robinson N, Brown H, Antoun E, Godfrey KM, Hanson MA, Lillycrop KA, Crozier SR, Murray R, Pearce MS, Relton CL, Albani V, McKay JA. Childhood DNA methylation as a marker of early life rapid weight gain and subsequent overweight. Clin Epigenetics 2021; 13:8. [PMID: 33436068 PMCID: PMC7805168 DOI: 10.1186/s13148-020-00952-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 10/19/2020] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND High early postnatal weight gain has been associated with childhood adiposity; however, the mechanism remains unknown. DNA methylation is a hypothesised mechanism linking early life exposures and subsequent disease. However, epigenetic changes associated with high early weight gain have not previously been investigated. Our aim was to investigate the associations between early weight gain, peripheral blood DNA methylation, and subsequent overweight/obese. Data from the UK Avon Longitudinal study of Parents and Children (ALSPAC) cohort were used to estimate associations between early postnatal weight gain and epigenome-wide DNA CpG site methylation (Illumina 450 K Methylation Beadchip) in blood in childhood (n = 125) and late adolescence (n = 96). High weight gain in the first year (a change in weight z-scores > 0.67), both unconditional (rapid weight gain) and conditional on birthweight (rapid thrive), was related to individual CpG site methylation and across regions using the meffil pipeline, with and without adjustment for cell type proportions, and with 5% false discovery rate correction. Variation in methylation at high weight gain-associated CpG sites was then examined with regard to body composition measures in childhood and adolescence. Replication of the differentially methylated CpG sites was sought using whole-blood DNA samples from 104 children from the UK Southampton Women's Survey. RESULTS Rapid infant weight gain was associated with small (+ 1% change) increases in childhood methylation (age 7) for two distinct CpG sites (cg01379158 (NT5M) and cg11531579 (CHFR)). Childhood methylation at one of these CpGs (cg11531579) was also higher in those who experienced rapid weight gain and were subsequently overweight/obese in adolescence (age 17). Rapid weight gain was not associated with differential DNA methylation in adolescence. Childhood methylation at the cg11531579 site was also suggestively associated with rapid weight gain in the replication cohort. CONCLUSIONS This study identified associations between rapid weight gain in infancy and small increases in childhood methylation at two CpG sites, one of which was replicated and was also associated with subsequent overweight/obese. It will be important to determine whether loci are markers of early rapid weight gain across different, larger populations. The mechanistic relevance of these differentially methylated sites requires further investigation.
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Affiliation(s)
- N Robinson
- Population Health Sciences, Newcastle University Medical School, Newcastle University, Newcastle upon Tyne, UK.
| | - H Brown
- Population Health Sciences, Newcastle University Medical School, Newcastle University, Newcastle upon Tyne, UK
| | - Elie Antoun
- Institute of Developmental Sciences, Biological Sciences and NIHR Southampton Biomedical Research Centre, University of Southampton, Southampton, UK
| | - Keith M Godfrey
- MRC Lifecourse Epidemiology Unit and NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Mark A Hanson
- Institute of Developmental Sciences, Biological Sciences and NIHR Southampton Biomedical Research Centre, University of Southampton, Southampton, UK
| | - Karen A Lillycrop
- Institute of Developmental Sciences, Biological Sciences and NIHR Southampton Biomedical Research Centre, University of Southampton, Southampton, UK
| | - Sarah R Crozier
- MRC Lifecourse Epidemiology Unit and NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Robert Murray
- Institute of Developmental Sciences, Biological Sciences and NIHR Southampton Biomedical Research Centre, University of Southampton, Southampton, UK
| | - M S Pearce
- Population Health Sciences, Newcastle University Medical School, Newcastle University, Newcastle upon Tyne, UK
| | - C L Relton
- MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - V Albani
- Population Health Sciences, Newcastle University Medical School, Newcastle University, Newcastle upon Tyne, UK
| | - J A McKay
- Department of Applied Sciences, Northumbria University, Newcastle upon Tyne, UK
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Yang S, He F, Dai M, Pan J, Wang J, Ye B. CHFR promotes the migration of human gastric cancer cells by inducing epithelial-to-mesenchymal transition in a HDAC1-dependent manner. Onco Targets Ther 2019; 12:1075-1084. [PMID: 30799937 PMCID: PMC6369853 DOI: 10.2147/ott.s191016] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Background Previous studies have illustrated that checkpoint with forkhead-associated and ring finger domains (CHFR) was frequently silenced in several cancer types due to promoter hypermethylation and functions as a tumor suppressor gene. However, the data from the public dataset reveal that CHFR is highly expressed in human gastric cancer specimens, and the biological function of CHFR in gastric cancer is still not well understood. Materials and methods The clinical association between CHFR expression and the overall survival of gastric cancer patients as well as cancer metastasis was analyzed according to public datasets. The CHFR expression in clinical specimens and human gastric cancer cell lines was detected by immunohistochemistry and Western blotting, respectively. Gain (overexpression) and loss (silencing) of function experiments were used to elucidate the role of CHFR in gastric cancer. The migration ability of gastric cancer cells was determined by wound healing and transwell assays. Cell cycle distribution was analyzed using fluorescence-activated cell sorting experiment. The expression of the proteins in cancer cells was measured using Western blot analysis. Results According to the analysis from Kaplan–Meier plotter dataset, CHFR expression was negatively associated with overall survival of gastric cancer patients. Our data revealed that exogenous expression of CHFR not only arrested cell cycle but also led to dramatically enhanced cell migration, while silencing of CHFR significantly inhibited cell migration in gastric cancer cells. This result is consistent with the data from the Human Cancer Metastasis Dataset, in which CHFR level is found to significantly increase in metastatic gastric cancer. The overexpression of CHFR promoted epithelial–mesenchymal transition (EMT) in both SGC-7901 and AGS cells, while HDAC1 was inhibited. Interestingly, suberoylanilide hydroxamic acid, a HDAC1 antagonist, could effectively increase cell migration in both cell lines via enhancement of EMT. Conclusion Our data indicated that CHFR exerted positive effects on cell migration of human gastric cancer by promoting EMT via downregulating HDAC1.
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Affiliation(s)
- Shangwen Yang
- Department of Gastroenterology, The Fifth Affiliated Hospital of Wenzhou Medical University and Lishui Municipal Central Hospital, Lishui 323000, Zhejiang Province, China,
| | - Feiyun He
- Department of Gastroenterology, Lishui Chinese Medicine Hospital, Lishui 323000, Zhejiang Province, China
| | - Mugen Dai
- Department of Gastroenterology, The Fifth Affiliated Hospital of Wenzhou Medical University and Lishui Municipal Central Hospital, Lishui 323000, Zhejiang Province, China,
| | - Jundi Pan
- Department of Gastroenterology, The Fifth Affiliated Hospital of Wenzhou Medical University and Lishui Municipal Central Hospital, Lishui 323000, Zhejiang Province, China,
| | - Jianbo Wang
- Department of Gastroenterology, The Fifth Affiliated Hospital of Wenzhou Medical University and Lishui Municipal Central Hospital, Lishui 323000, Zhejiang Province, China,
| | - Bin Ye
- Department of Gastroenterology, The Fifth Affiliated Hospital of Wenzhou Medical University and Lishui Municipal Central Hospital, Lishui 323000, Zhejiang Province, China,
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Cullati SN, Gould KL. Spatiotemporal regulation of the Dma1-mediated mitotic checkpoint coordinates mitosis with cytokinesis. Curr Genet 2019; 65:663-668. [PMID: 30600396 DOI: 10.1007/s00294-018-0921-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 12/14/2018] [Accepted: 12/15/2018] [Indexed: 11/26/2022]
Abstract
During cell division, the timing of mitosis and cytokinesis must be ordered to ensure that each daughter cell receives a complete, undamaged copy of the genome. In fission yeast, the septation initiation network (SIN) is responsible for this coordination, and a mitotic checkpoint dependent on the E3 ubiquitin ligase Dma1 and the protein kinase CK1 controls SIN signaling to delay cytokinesis when there are errors in mitosis. The participation of kinases and ubiquitin ligases in cell cycle checkpoints that maintain genome integrity is conserved from yeast to human, making fission yeast an excellent model system in which to study checkpoint mechanisms. In this review, we highlight recent advances and remaining questions related to checkpoint regulation, which requires the synchronized modulation of protein ubiquitination, phosphorylation, and subcellular localization.
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Wade BE, Zhao J, Ma J, Hart CM, Sutliff RL. Hypoxia-induced alterations in the lung ubiquitin proteasome system during pulmonary hypertension pathogenesis. Pulm Circ 2018; 8:2045894018788267. [PMID: 29927354 PMCID: PMC6146334 DOI: 10.1177/2045894018788267] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Pulmonary hypertension (PH) is a clinical disorder characterized by sustained
increases in pulmonary vascular resistance and pressure that can lead to right
ventricular (RV) hypertrophy and ultimately RV failure and death. The molecular
pathogenesis of PH remains incompletely defined, and existing treatments are
associated with suboptimal outcomes and persistent morbidity and mortality.
Reports have suggested a role for the ubiquitin proteasome system (UPS) in PH,
but the extent of UPS-mediated non-proteolytic protein alterations during PH
pathogenesis has not been previously defined. To further examine UPS
alterations, the current study employed C57BL/6J mice exposed to normoxia or
hypoxia for 3 weeks. Lung protein ubiquitination was evaluated by mass
spectrometry to identify differentially ubiquitinated proteins relative to
normoxic controls. Hypoxia stimulated differential ubiquitination of 198
peptides within 131 proteins (p < 0.05). These proteins were
screened to identify candidates within pathways involved in PH pathogenesis.
Some 51.9% of the differentially ubiquitinated proteins were implicated in at
least one known pathway contributing to PH pathogenesis, and 13% were involved
in three or more PH pathways. Anxa2, App, Jak1, Lmna, Pdcd6ip, Prkch1, and Ywhah
were identified as mediators in PH pathways that undergo differential
ubiquitination during PH pathogenesis. To our knowledge, this is the first study
to report global changes in protein ubiquitination in the lung during PH
pathogenesis. These findings suggest signaling nodes that are dynamically
regulated by the UPS during PH pathogenesis. Further exploration of these
differentially ubiquitinated proteins and related pathways can provide new
insights into the role of the UPS in PH pathogenesis.
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Affiliation(s)
- Brandy E Wade
- Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Atlanta Veterans' Affairs and Emory University Medical Centers, Decatur, Georgia, USA
| | - Jingru Zhao
- Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Atlanta Veterans' Affairs and Emory University Medical Centers, Decatur, Georgia, USA
| | - Jing Ma
- Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Atlanta Veterans' Affairs and Emory University Medical Centers, Decatur, Georgia, USA
| | - C Michael Hart
- Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Atlanta Veterans' Affairs and Emory University Medical Centers, Decatur, Georgia, USA
| | - Roy L Sutliff
- Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Atlanta Veterans' Affairs and Emory University Medical Centers, Decatur, Georgia, USA
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The inhibition of UBC13 expression and blockage of the DNMT1-CHFR-Aurora A pathway contribute to paclitaxel resistance in ovarian cancer. Cell Death Dis 2018; 9:93. [PMID: 29367628 PMCID: PMC5833742 DOI: 10.1038/s41419-017-0137-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Revised: 09/03/2017] [Accepted: 11/08/2017] [Indexed: 12/14/2022]
Abstract
Paclitaxel is widely used as a first-line chemotherapeutic drug for patients with ovarian cancer and other solid cancers, but drug resistance occurs frequently, resulting in ovarian cancer still presenting as the highest lethality among all gynecological tumors. Here, using DIGE quantitative proteomics, we identified UBC13 as down-regulated in paclitaxel-resistant ovarian cancer cells, and it was further revealed by immunohistochemical staining that UBC13 low-expression was associated with poorer prognosis and shorter survival of the patients. Through gene function experiments, we found that paclitaxel exposure induced UBC13 down-regulation, and the enforced change in UBC13 expression altered the sensitivity to paclitaxel. Meanwhile, the reduction of UBC13 increased DNMT1 levels by attenuating its ubiquitination, and the up-regulated DNMT1 enhanced the CHFR promoter DNA methylation levels, leading to a reduction of CHFR expression, and an increased in the levels of Aurora A. Our findings revealed a novel function for UBC13 in regulating paclitaxel sensitivity through a DNMT1-CHFR-Aurora A pathway in ovarian cancer cells. UBC13 could potentially be employed as a therapeutic molecular drug for reversing paclitaxel resistance in ovarian cancer patients.
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Zhou JD, Zhang TJ, Li XX, Ma JC, Guo H, Wen XM, Yao DM, Zhang W, Lin J, Qian J. Methylation-independent CHFR expression is a potential biomarker affecting prognosis in acute myeloid leukemia. J Cell Physiol 2018; 233:4707-4714. [PMID: 29115660 DOI: 10.1002/jcp.26253] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2017] [Accepted: 09/29/2017] [Indexed: 12/29/2022]
Affiliation(s)
- Jing-Dong Zhou
- Department of Hematology; Affiliated People's Hospital of Jiangsu University; Zhenjiang Jiangsu P.R. China
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City; Zhenjiang Jiangsu P.R. China
| | - Ting-Juan Zhang
- Department of Hematology; Affiliated People's Hospital of Jiangsu University; Zhenjiang Jiangsu P.R. China
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City; Zhenjiang Jiangsu P.R. China
| | - Xi-Xi Li
- Department of Hematology; Affiliated People's Hospital of Jiangsu University; Zhenjiang Jiangsu P.R. China
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City; Zhenjiang Jiangsu P.R. China
| | - Ji-Chun Ma
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City; Zhenjiang Jiangsu P.R. China
- Laboratory Center; Affiliated People's Hospital of Jiangsu University; Zhenjiang Jiangsu P.R. China
| | - Hong Guo
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City; Zhenjiang Jiangsu P.R. China
- Laboratory Center; Affiliated People's Hospital of Jiangsu University; Zhenjiang Jiangsu P.R. China
| | - Xiang-Mei Wen
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City; Zhenjiang Jiangsu P.R. China
- Laboratory Center; Affiliated People's Hospital of Jiangsu University; Zhenjiang Jiangsu P.R. China
| | - Dong-Ming Yao
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City; Zhenjiang Jiangsu P.R. China
- Laboratory Center; Affiliated People's Hospital of Jiangsu University; Zhenjiang Jiangsu P.R. China
| | - Wei Zhang
- Department of Hematology; Affiliated People's Hospital of Jiangsu University; Zhenjiang Jiangsu P.R. China
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City; Zhenjiang Jiangsu P.R. China
| | - Jiang Lin
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City; Zhenjiang Jiangsu P.R. China
- Laboratory Center; Affiliated People's Hospital of Jiangsu University; Zhenjiang Jiangsu P.R. China
| | - Jun Qian
- Department of Hematology; Affiliated People's Hospital of Jiangsu University; Zhenjiang Jiangsu P.R. China
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City; Zhenjiang Jiangsu P.R. China
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10
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Leveraging Epigenetics to Enhance the Cellular Response to Chemotherapies and Improve Tumor Immunogenicity. Adv Cancer Res 2018; 138:1-39. [PMID: 29551125 DOI: 10.1016/bs.acr.2018.02.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Cancer chemotherapeutic drugs have greatly advanced our ability to successfully treat a variety of human malignancies. The different forms of stress produced by these agents in cancer cells result in both cell autonomous and cell nonautonomous effects. Desirable cell autonomous effects include reduced proliferative potential, cellular senescence, and cell death. More recently recognized cell nonautonomous effects, usually in the form of stimulating an antitumor immune response, have significant roles in therapeutic efficiency for a select number of chemotherapies. Unfortunately, the success of these therapeutics is not universal as not all tumors respond to treatment, and those that do respond will frequently relapse into therapy-resistant disease. Numerous strategies have been developed to sensitize tumors toward chemotherapies as a means to either improve initial responses, or serve as a secondary treatment strategy for therapy-resistant disease. Recently, targeting epigenetic regulators has emerged as a viable method of sensitizing tumors to the effects of chemotherapies, many of which are cytotoxic. In this review, we summarize these strategies and propose a path for future progress.
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11
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Cuomo D, Porreca I, Cobellis G, Tarallo R, Nassa G, Falco G, Nardone A, Rizzo F, Mallardo M, Ambrosino C. Carcinogenic risk and Bisphenol A exposure: A focus on molecular aspects in endoderm derived glands. Mol Cell Endocrinol 2017; 457:20-34. [PMID: 28111205 DOI: 10.1016/j.mce.2017.01.027] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Revised: 01/16/2017] [Accepted: 01/17/2017] [Indexed: 02/07/2023]
Abstract
Epidemiological and experimental evidence associates the exposure to Bisphenol A with the increase of cancer risk in several organs, including prostate. BPA targets different pathways involved in carcinogenicity including the Nuclear Receptors (i.e. estrogen and androgen receptors), stress regulated proteins and, finally, epigenetic changes. Here, we analyse BPA-dependent carcinogenesis in endoderm-derived glands, thyroid, liver, pancreas and prostate focusing on cell signalling, DNA damage repair pathways and epigenetic modifications. Mainly, we gather molecular data evidencing harmful effects at doses relevant for human risk (low-doses). Since few molecular data are available, above all for the pancreas, we analysed transcriptomic data generated in our laboratory to suggest possible mechanisms of BPA carcinogenicity in endoderm-derived glands, discussing the role of nuclear receptors and stress/NF-kB pathways. We evidence that an in vitro toxicogenomic approach might suggest mechanisms of toxicity applicable to cells having the same developmental origin. Although we cannot draw firm conclusions, published data summarized in this review suggest that exposure to BPA, primarily during the developmental stages, represents a risk for carcinogenesis of endoderm-derived glands.
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Affiliation(s)
- Danila Cuomo
- IRGS, Biogem, Via Camporeale, 83031 Ariano Irpino, Avellino, Italy; Department of Science and Technology, University of Sannio, via Port'Arsa 11, 82100 Benevento, Italy
| | | | - Gilda Cobellis
- Department of Experimental Medicine, Sez. Bozzatti, II University of Naples, 80138 Napoli, Italy
| | - Roberta Tarallo
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry "Schola Medica Salernitana", University of Salerno, 84081 Baronissi, SA, Italy
| | - Giovanni Nassa
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry "Schola Medica Salernitana", University of Salerno, 84081 Baronissi, SA, Italy; Genomix4Life srl, Department of Medicine, Surgery and Dentistry "Schola Medica Salernitana", University of Salerno, Baronissi, SA, Italy
| | - Geppino Falco
- Department of Biology, University of Naples "Federico II", Napoli, Italy
| | - Antonio Nardone
- Department of Public Health, University of Naples "Federico II", Napoli, Italy
| | - Francesca Rizzo
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry "Schola Medica Salernitana", University of Salerno, 84081 Baronissi, SA, Italy
| | - Massimo Mallardo
- Molecular Medicine and Medical Biotechnologies, University of Naples "Federico II", Napoli, Italy
| | - Concetta Ambrosino
- Department of Science and Technology, University of Sannio, via Port'Arsa 11, 82100 Benevento, Italy.
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12
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Luebeck EG, Curtius K, Hazelton WD, Maden S, Yu M, Thota PN, Patil DT, Chak A, Willis JE, Grady WM. Identification of a key role of widespread epigenetic drift in Barrett's esophagus and esophageal adenocarcinoma. Clin Epigenetics 2017; 9:113. [PMID: 29046735 PMCID: PMC5644061 DOI: 10.1186/s13148-017-0409-4] [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: 05/25/2017] [Accepted: 09/24/2017] [Indexed: 12/13/2022] Open
Abstract
Background Recent studies have identified age-related changes in DNA methylation patterns in normal and cancer tissues in a process that is called epigenetic drift. However, the evolving patterns, functional consequences, and dynamics of epigenetic drift during carcinogenesis remain largely unexplored. Here we analyze the evolution of epigenetic drift patterns during progression from normal squamous esophagus tissue to Barrett’s esophagus (BE) to esophageal adenocarcinoma (EAC) using 173 tissue samples from 100 (nonfamilial) BE patients, along with publically available datasets including The Cancer Genome Atlas (TCGA). Results Our analysis reveals extensive methylomic drift between normal squamous esophagus and BE tissues in nonprogressed BE patients, with differential drift affecting 4024 (24%) of 16,984 normally hypomethylated cytosine-guanine dinucleotides (CpGs) occurring in CpG islands. The majority (63%) of islands that include drift CpGs are associated with gene promoter regions. Island CpGs that drift have stronger pairwise correlations than static islands, reflecting collective drift consistent with processive DNA methylation maintenance. Individual BE tissues are extremely heterogeneous in their distribution of methylomic drift and encompass unimodal low-drift to bimodal high-drift patterns, reflective of differences in BE tissue age. Further analysis of longitudinally collected biopsy samples from 20 BE patients confirm the time-dependent evolution of these drift patterns. Drift patterns in EAC are similar to those in BE, but frequently exhibit enhanced bimodality and advanced mode drift. To better understand the observed drift patterns, we developed a multicellular stochastic model at the CpG island level. Importantly, we find that nonlinear feedback in the model between mean island methylation and CpG methylation rates is able to explain the widely heterogeneous collective drift patterns. Using matched gene expression and DNA methylation data in EAC from TCGA and other publically available data, we also find that advanced methylomic drift is correlated with significant transcriptional repression of ~ 200 genes in important regulatory and developmental pathways, including several checkpoint and tumor suppressor-like genes. Conclusions Taken together, our findings suggest that epigenetic drift evolution acts to significantly reduce the expression of developmental genes that may alter tissue characteristics and improve functional adaptation during BE to EAC progression. Electronic supplementary material The online version of this article (10.1186/s13148-017-0409-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- E Georg Luebeck
- Program in Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 USA
| | - Kit Curtius
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ UK
| | - William D Hazelton
- Program in Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 USA
| | - Sean Maden
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 USA
| | - Ming Yu
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 USA
| | - Prashanthi N Thota
- Department of Gastroenterology, Digestive Disease & Surgery Institute, Cleveland Clinic, Cleveland, OH 44195 USA
| | - Deepa T Patil
- Department of Pathology, Cleveland Clinic, Cleveland, OH 44195 USA
| | - Amitabh Chak
- University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106 USA
| | - Joseph E Willis
- University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106 USA
| | - William M Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 USA.,Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195 USA
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13
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Abstract
SUMMARYEpigenetic changes are present in all human cancers and are now known to cooperate with genetic alterations to drive the cancer phenotype. These changes involve DNA methylation, histone modifiers and readers, chromatin remodelers, microRNAs, and other components of chromatin. Cancer genetics and epigenetics are inextricably linked in generating the malignant phenotype; epigenetic changes can cause mutations in genes, and, conversely, mutations are frequently observed in genes that modify the epigenome. Epigenetic therapies, in which the goal is to reverse these changes, are now one standard of care for a preleukemic disorder and form of lymphoma. The application of epigenetic therapies in the treatment of solid tumors is also emerging as a viable therapeutic route.
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Affiliation(s)
- Stephen B Baylin
- Cancer Biology Program, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21287
| | - Peter A Jones
- Van Andel Research Institute, Grand Rapids, Michigan 49503
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14
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Gao L, Liu F, Zhang H, Sun J, Ma Y. CHFRhypermethylation, a frequent event in acute myeloid leukemia, is independently associated with an adverse outcome. Genes Chromosomes Cancer 2015; 55:158-68. [PMID: 26542416 DOI: 10.1002/gcc.22322] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2015] [Revised: 09/22/2015] [Accepted: 09/23/2015] [Indexed: 12/19/2022] Open
Affiliation(s)
- Li Gao
- Department of Hematology, China-Japan Friendship Hospital, Beijing, China
| | - Fang Liu
- Department of Hematology and Oncology, The First Affiliated Hospital of Chinese PLA General Hospital, Beijing, China
- Department of Oncology, Chinese PLA General Hospital, Beijing, China
| | - Hui Zhang
- Department of Hematology, China-Japan Friendship Hospital, Beijing, China
| | - Junzhong Sun
- Department of Hematology and Oncology, The First Affiliated Hospital of Chinese PLA General Hospital, Beijing, China
| | - Yigai Ma
- Department of Hematology, China-Japan Friendship Hospital, Beijing, China
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15
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Burroughs AM, Zhang D, Aravind L. The eukaryotic translation initiation regulator CDC123 defines a divergent clade of ATP-grasp enzymes with a predicted role in novel protein modifications. Biol Direct 2015; 10:21. [PMID: 25976611 PMCID: PMC4431377 DOI: 10.1186/s13062-015-0053-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Accepted: 04/07/2015] [Indexed: 12/26/2022] Open
Abstract
Abstract Deciphering the origin of uniquely eukaryotic features of sub-cellular systems, such as the translation apparatus, is critical in reconstructing eukaryogenesis. One such feature is the highly conserved, but poorly understood, eukaryotic protein CDC123, which regulates the abundance of the eukaryotic translation initiation eIF2 complex and binds one of its components eIF2γ. We show that the eukaryotic protein CDC123 defines a novel clade of ATP-grasp enzymes distinguished from all other members of the superfamily by a RAGNYA domain with two conserved lysines (henceforth the R2K clade). Combining the available biochemical and genetic data on CDC123 with the inferred enzymatic function, we propose that the eukaryotic CDC123 proteins are likely to function as ATP-dependent protein-peptide ligases which modify proteins by ribosome-independent addition of an oligopeptide tag. We also show that the CDC123 family emerged first in bacteria where it appears to have diversified along with the two other families of the R2K clade. The bacterial CDC123 family members are of two distinct types, one found as part of type VI secretion systems which deliver polymorphic toxins and the other functioning as potential effectors delivered to amoeboid eukaryotic hosts. Representatives of the latter type have also been independently transferred to phylogenetically unrelated amoeboid eukaryotes and their nucleo-cytoplasmic large DNA viruses. Similarly, the two other prokaryotic R2K clade families are also proposed to participate in biological conflicts between bacteriophages and their hosts. These findings add further evidence to the recently proposed hypothesis that the horizontal transfer of enzymatic effectors from the bacterial endosymbionts of the stem eukaryotes played a fundamental role in the emergence of the characteristically eukaryotic regulatory systems and sub-cellular structures. Reviewers This article was reviewed by Michael Galperin and Sandor Pongor. Electronic supplementary material The online version of this article (doi:10.1186/s13062-015-0053-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- A Maxwell Burroughs
- National Center for Biotechnology Information, National Library of Medicine, Bethesda, MD, 20894, USA.
| | - Dapeng Zhang
- National Center for Biotechnology Information, National Library of Medicine, Bethesda, MD, 20894, USA.
| | - L Aravind
- National Center for Biotechnology Information, National Library of Medicine, Bethesda, MD, 20894, USA.
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16
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Perdereau D, Cailliau K, Browaeys-Poly E, Lescuyer A, Carré N, Benhamed F, Goenaga D, Burnol AF. Insulin-induced cell division is controlled by the adaptor Grb14 in a Chfr-dependent manner. Cell Signal 2015; 27:798-806. [PMID: 25578860 DOI: 10.1016/j.cellsig.2015.01.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Accepted: 01/03/2015] [Indexed: 01/02/2023]
Abstract
Beyond its key role in the control of energy metabolism, insulin is also an important regulator of cell division and neoplasia. However, the molecular events involved in insulin-driven cell proliferation are not fully elucidated. Here, we show that the ubiquitin ligase Chfr, a checkpoint protein involved in G2/M transition, is a new effector involved in the control of insulin-induced cell proliferation. Chfr is identified as a partner of the molecular adapter Grb14, an inhibitor of insulin signalling. Using mammalian cell lines and the Xenopus oocyte as a model of G2/M transition, we demonstrate that Chfr potentiates the inhibitory effect of Grb14 on insulin-induced cell division. Insulin stimulates Chfr binding to the T220 residue of Grb14. Both Chfr binding site and Grb14 C-ter BPS-SH2 domain, mediating IR binding and inhibition, are required to prevent insulin-induced cell division. Targeted mutagenesis revealed that Chfr ligase activity and phosphorylation of its T39 residue, a target of Akt, are required to potentiate Grb14 inhibitory activity. In the presence of insulin, the binding of Chfr to Grb14 activates its ligase activity, leading to Aurora A and Polo-like kinase degradation and blocking cell division. Collectively, our results show that Chfr and Grb14 collaborate in a negative feedback loop controlling insulin-stimulated cell division.
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Affiliation(s)
- Dominique Perdereau
- INSERM, U1016, Institut Cochin, Paris, France; CNRS, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité; 24, Rue du Faubourg Saint Jacques, Paris 75014, France
| | - Katia Cailliau
- Laboratoire de Régulation des Signaux de Division, Université de Lille 1, UE 4479, IFR 147, Villeneuve d'Ascq 59655, France
| | - Edith Browaeys-Poly
- Laboratoire de Régulation des Signaux de Division, Université de Lille 1, UE 4479, IFR 147, Villeneuve d'Ascq 59655, France
| | - Arlette Lescuyer
- Laboratoire de Régulation des Signaux de Division, Université de Lille 1, UE 4479, IFR 147, Villeneuve d'Ascq 59655, France
| | - Nadège Carré
- INSERM, U1016, Institut Cochin, Paris, France; CNRS, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité; 24, Rue du Faubourg Saint Jacques, Paris 75014, France
| | - Fadila Benhamed
- INSERM, U1016, Institut Cochin, Paris, France; CNRS, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité; 24, Rue du Faubourg Saint Jacques, Paris 75014, France
| | - Diana Goenaga
- INSERM, U1016, Institut Cochin, Paris, France; CNRS, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité; 24, Rue du Faubourg Saint Jacques, Paris 75014, France
| | - Anne-Françoise Burnol
- INSERM, U1016, Institut Cochin, Paris, France; CNRS, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité; 24, Rue du Faubourg Saint Jacques, Paris 75014, France.
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17
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Song A, Ye J, Zhang K, Yu H, Gao Y, Wang H, Sun L, Xing X, Yang K, Zhao M. Aberrant expression of the CHFR prophase checkpoint gene in human B-cell non-Hodgkin lymphoma. Leuk Res 2015; 39:536-43. [PMID: 25798877 DOI: 10.1016/j.leukres.2015.02.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2014] [Revised: 01/22/2015] [Accepted: 02/15/2015] [Indexed: 10/23/2022]
Abstract
Checkpoint with FHA and Ring Finger (CHFR) is a checkpoint protein that reportedly initiates a cell cycle delay in response to microtubule stress during prophase in mitosis, which has become an interesting target for understanding cancer pathogenesis. Recently, aberrant methylation of the CHFR gene associated with gene silencing has been reported in several cancers. In the present study, we examined the expression of CHFR in B-cell non-Hodgkin lymphoma (B-NHL) in vitro and in vivo. Our results showed that the expression level of CHFR mRNA and protein was reduced in B-NHL tissue samples and B cell lines. Furthermore, CHFR methylation was detected in 39 of 122 B-NHL patients, which was not found in noncancerous reactive hyperplasia of lymph node (RH) tissues. CHFR methylation correlated with the reduced expression of CHFR, high International Prognostic Index (IPI) scores and later pathologic Ann Arbor stages of B-NHL. Treatment with demethylation reagent, 5-Aza-dC, could eliminate the hypermethylation of CHFR, enhance CHFR expression and cell apoptosis and inhibit the cell proliferation of Raji cells, which could be induced by high expression of CHFR in Raji cells. Our results indicated that aberrant methylation of CHFR may be associated with the pathogenesis, progression for B-NHL, which might be a novel molecular marker as prognosis and treatment for B-NHL.
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Affiliation(s)
- Aiqin Song
- Department of Pediatric Hematology, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, China.
| | - Junli Ye
- Department of Pathophysiology, Medical College of Qingdao University, Qingdao, Shangdong 266021, China
| | - Kunpeng Zhang
- Department of Pediatric Hematology, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, China
| | - Hongsheng Yu
- Department of Oncology, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, China
| | - Yanhua Gao
- Department of Hematology, Qingdao Women and Children's Medical Care Center, Qingdao, 266011, China
| | - Hongfang Wang
- Department of Pediatric Hematology, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, China
| | - Lirong Sun
- Department of Pediatric Hematology, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, China
| | - Xiaoming Xing
- Department of Pathology, Affiliated Hospital of Qingdao University, Qingdao, Shangdong 266003, China
| | - Kun Yang
- Center Laboratory, Affiliated Hospital of Qingdao University, Qingdao, Shangdong 266003, China
| | - Min Zhao
- Department of Pediatric Hematology, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, China
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18
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Miozzo M, Vaira V, Sirchia SM. Epigenetic alterations in cancer and personalized cancer treatment. Future Oncol 2015; 11:333-48. [DOI: 10.2217/fon.14.237] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
ABSTRACT Based on the pivotal importance of epigenetics for transcription regulation, it is not surprising that cancer is characterized by several epigenetic abnormalities. Conversely to genetic alterations, epigenetic changes are not permanent, thus represent opportunities for therapeutic strategies designed to reverse transcriptional abnormalities, and cancer is the first disease in which epigenetic therapies with chromatin remodeling agents were introduced. The role of miRNAs in gene regulation supports their potential as innovative therapeutic strategy. Recent evidences have proven that the environment can profoundly influence the epigenome: diet, smoking and alcohol consumption can negatively impact the expression profile. Given the plasticity of epigenetic marks, it is challenging the idea that the epigenetic alterations are ‘druggable’ sites using specific food components.
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Affiliation(s)
- Monica Miozzo
- Division of Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy
- Department of Pathophysiology & Transplantation, Università degli Studi di Milano, Milano, Italy
| | - Valentina Vaira
- Division of Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy
- Istituto Nazionale di Genetica Molecolare ‘Romeo ed Enrica Invernizzi’, Integrative Biology Unit, Milano, Italy
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19
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Noorlag R, van Kempen PMW, Moelans CB, de Jong R, Blok LER, Koole R, Grolman W, van Diest PJ, van Es RJJ, Willems SM. Promoter hypermethylation using 24-gene array in early head and neck cancer: better outcome in oral than in oropharyngeal cancer. Epigenetics 2014; 9:1220-7. [PMID: 25147921 DOI: 10.4161/epi.29785] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Silencing of tumor suppressor genes (TSGs) by DNA promoter hypermethylation is an early event in carcinogenesis and a potential target for personalized cancer treatment. In head and neck cancer, little is known about the role of promoter hypermethylation in survival. Using methylation specific multiplex ligation-dependent probe amplification (MS-MLPA) we investigated the role of promoter hypermethylation of 24 well-described genes (some of which are classic TSGs), which are frequently methylated in different cancer types, in 166 HPV-negative early oral squamous cell carcinomas (OSCC), and 51 HPV-negative early oropharyngeal squamous cell carcinomas (OPSCC) in relation to clinicopathological features and survival. Early OSCC showed frequent promoter hypermethylation in RARB (31% of cases), CHFR (20%), CDH13 (13%), DAPK1 (12%), and APC (10%). More hypermethylation (≥ 2 genes) independently correlated with improved disease specific survival (hazard ratio 0.17, P = 0.014) in early OSCC and could therefore be used as prognostic biomarker. Early OPSCCs showed more hypermethylation of CDH13 (58%), TP73 (14%), and total hypermethylated genes. Hypermethylation of two or more genes has a significantly different effect on survival in OPSCC compared with OSCC, with a trend toward worse instead of better survival. This could have a biological explanation, which deserves further investigation and could possibly lead to more stratified treatment in the future.
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Affiliation(s)
- Rob Noorlag
- Department of Oral and Maxillofacial Surgery; University Medical Center Utrecht; Utrecht, the Netherlands
| | - Pauline M W van Kempen
- Department of Otorhinolaryngology; University Medical Center Utrecht; Utrecht, the Netherlands
| | - Cathy B Moelans
- Department of Pathology; University Medical Center Utrecht; Utrecht, the Netherlands
| | - Rick de Jong
- Department of Pathology; University Medical Center Utrecht; Utrecht, the Netherlands
| | - Laura E R Blok
- Department of Pathology; University Medical Center Utrecht; Utrecht, the Netherlands
| | - Ronald Koole
- Department of Oral and Maxillofacial Surgery; University Medical Center Utrecht; Utrecht, the Netherlands
| | - Wilko Grolman
- Department of Otorhinolaryngology; University Medical Center Utrecht; Utrecht, the Netherlands
| | - Paul J van Diest
- Department of Pathology; University Medical Center Utrecht; Utrecht, the Netherlands
| | - Robert J J van Es
- Department of Oral and Maxillofacial Surgery; University Medical Center Utrecht; Utrecht, the Netherlands
| | - Stefan M Willems
- Department of Pathology; University Medical Center Utrecht; Utrecht, the Netherlands
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20
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Iida M, Banno K, Yanokura M, Nakamura K, Adachi M, Nogami Y, Umene K, Masuda K, Kisu I, Iwata T, Tanaka K, Aoki D. Candidate biomarkers for cervical cancer treatment: Potential for clinical practice (Review). Mol Clin Oncol 2014; 2:647-655. [PMID: 25054026 DOI: 10.3892/mco.2014.324] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2014] [Accepted: 03/05/2014] [Indexed: 12/14/2022] Open
Abstract
Cervical cancer ranks high among the causes of female cancer mortalities and is an important disease in developing and developed countries. Current diagnosis of cervical cancer depends on colposcopy, pathological diagnosis and preoperative diagnosis using methods, including magnetic resonance imaging and computed tomography. Advanced cervical cancer has a poor prognosis. The tumor marker squamous cell carcinoma is conventionally used for screening, but recent studies have revealed the mechanisms of carcinogenesis and the factors associated with a poor prognosis in cervical cancer. These include epigenetic biomarkers, with the methylation level of the checkpoint with forkhead and ring finger gene being potentially useful for predicting the malignancy of cervical cancer and sensitivity to treatment with paclitaxel. The extent of methylation of the Werner DNA helicase gene is also useful for determining sensitivity to an anticancer agent, CPT-11. In addition to epigenetic changes, the expression levels of hypoxia-inducible factor 1α subunit, epidermal growth factor receptor and cyclooxygenase-2 have been reported as possible biomarkers in cervical cancer. Novel prognostic factors, including angiogenic factors, fragile histidine triad, thymidylate synthase, glucose-related protein 58 and mucin antigens, have also been described, and hemoglobin and platelets may also be significant prognostic biomarkers. Utilization of these biomarkers may facilitate personalized treatment and improved outcomes in cervical cancer.
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Affiliation(s)
- Miho Iida
- Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo 160-8582, Japan
| | - Kouji Banno
- Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo 160-8582, Japan
| | - Megumi Yanokura
- Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo 160-8582, Japan
| | - Kanako Nakamura
- Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo 160-8582, Japan
| | - Masataka Adachi
- Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo 160-8582, Japan
| | - Yuya Nogami
- Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo 160-8582, Japan
| | - Kiyoko Umene
- Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo 160-8582, Japan
| | - Kenta Masuda
- Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo 160-8582, Japan
| | - Iori Kisu
- Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo 160-8582, Japan
| | - Takashi Iwata
- Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo 160-8582, Japan
| | - Kyoko Tanaka
- Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo 160-8582, Japan
| | - Daisuke Aoki
- Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo 160-8582, Japan
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21
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Overcoming inherent resistance to histone deacetylase inhibitors in multiple myeloma cells by targeting pathways integral to the actin cytoskeleton. Cell Death Dis 2014; 5:e1134. [PMID: 24651437 PMCID: PMC3973216 DOI: 10.1038/cddis.2014.98] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Revised: 01/22/2014] [Accepted: 02/10/2014] [Indexed: 01/05/2023]
Abstract
Histone deacetylase inhibitors (HDACi) are novel chemotherapeutics undergoing evaluation in clinical trials for the potential treatment of patients with multiple myeloma (MM). Although HDACi have demonstrable synergy when combined with proteasome inhibitors (PIs), recent evidence indicates that combination of HDACi and PI is beneficial only in a subset of patients with advanced MM, clearly indicating that other rational combinations should be explored. In this context we hypothesized that understanding the molecular signature associated with inherent resistance to HDACi would provide a basis for the identification of therapeutic combinations with improved clinical efficacy. Using human myeloma cell lines (HMCL) categorized as sensitive, intermediate or resistant to HDACi, gene expression profiling (GEP) and gene ontology enrichment analyses were performed to determine if a genetic signature associated with inherent resistance to HDACi-resistance could be identified. Correlation of GEP to increasing or decreasing sensitivity to HDACi indicated a unique 35-gene signature that was significantly enriched for two pathways – regulation of actin cytoskeleton and protein processing in endoplasmic reticulum. When HMCL and primary MM samples were treated with a combination of HDACi and agents targeting the signaling pathways integral to the actin cytoskeleton, synergistic cell death was observed in all instances, thus providing a rationale for combining these agents with HDACi for the treatment of MM to overcome resistance. This report validates a molecular approach for the identification of HDACi partner drugs and provides an experimental framework for the identification of novel therapeutic combinations for anti-MM treatment.
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22
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Suzuki Y, Miyagi Y, Yukawa N, Rino Y, Masuda M. Epigenetic silencing of checkpoint with fork-head associated and ring finger gene expression in esophageal cancer. Oncol Lett 2013; 7:69-73. [PMID: 24348823 PMCID: PMC3861576 DOI: 10.3892/ol.2013.1677] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2013] [Accepted: 10/31/2013] [Indexed: 01/02/2023] Open
Abstract
Checkpoint with fork-head associated and ring finger (CHFR) is a mitotic checkpoint gene with tumor-suppressor functions. Previous studies have described the hypermethylation of the CpG island in the promoter region as a key mechanism involved in silencing tumor suppressor genes. The epigenetic alterations regulating CHFR expression and the clinical significance of CHFR downregulation remain unclear. A total of 40 patients with esophageal squamous cell carcinoma who underwent primary resection were enrolled in this study. CHFR mRNA expression was quantified, followed by an evaluation of the methylation status using methylation-specific polymerase chain reaction (MSP) techniques in 29 patients. The correlation between CHFR expression and MSP status was then analyzed. In addition, the significance of CHFR expression was determined, with respect to clinicopathological features and overall survival. Aberrant hypermethylation of the CHFR gene was observed in 13 of 29 primary esophageal cancers. The CHFR expression levels of the methylated status samples was significantly lower than that of the unmethylated status samples (P=0.014). CHFR expression levels did not exhibit clinical significance with respect to the patient characteristics or overall survival. Hypermethylation of the CHFR gene is a common event in the development of primary esophageal cancer. CpG island hypermethylation of the promoter region in the CHFR gene is a key mechanism involved in silencing the CHFR gene in patients with esophageal cancer.
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Affiliation(s)
- Yoshihiro Suzuki
- Department of Surgery, Hiratsuka Kyosai Hospital, Hiratsuka, Kanagawa 254-8502, Japan
| | - Yohei Miyagi
- Molecular Pathology and Genetics Division, Kanagawa Cancer Center, Yokohama, Kanagawa 241-0815, Japan
| | - Norio Yukawa
- Department of Surgery, Yokohama City University, Yokohama, Kanagawa 236-0004, Japan
| | - Yasushi Rino
- Department of Surgery, Yokohama City University, Yokohama, Kanagawa 236-0004, Japan
| | - Munetaka Masuda
- Department of Surgery, Yokohama City University, Yokohama, Kanagawa 236-0004, Japan
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23
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Kim JS, Kim EJ, Oh JS, Park IC, Hwang SG. CIP2A modulates cell-cycle progression in human cancer cells by regulating the stability and activity of Plk1. Cancer Res 2013; 73:6667-78. [PMID: 23983103 DOI: 10.1158/0008-5472.can-13-0888] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Abnormal cell-cycle control can lead to aberrant cell proliferation and cancer. The oncoprotein cancerous inhibitor of protein phosphatase 2A (CIP2A) is an inhibitor of protein phosphatase 2A (PP2A) that stabilizes c-Myc. However, the precise role of CIP2A in cell division is not understood. Herein, we show that CIP2A is required for mitotic progression by regulating the polo-like kinase (Plk1). With mitotic entry, CIP2A translocated from the cytoplasm to the nucleus, where it was enriched at spindle poles. CIP2A depletion delayed mitotic progression, resulting in mitotic abnormalities independent of PP2A activity. Unexpectedly, CIP2A interacted directly with the polo-box domain of Plk1 during mitosis. This interaction was required to maintain Plk1 stability by blocking APC/C-Cdh1-dependent proteolysis, thereby enhancing the kinase activity of Plk1 during mitosis. We observed strong correlation and in vivo interactions between these two proteins in multiple human cancer specimens. Overall, our results established a novel function for CIP2A in facilitating the stability and activity of the pivotal mitotic kinase Plk1 in cell-cycle progression and tumor development.
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Affiliation(s)
- Jae-Sung Kim
- Authors' Affiliations: Divisions of Radiation Cancer Research and Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul; and Department of Genetic Engineering, Sungkyunkwan University, Suwon, South Korea
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24
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Shinde SR, Gangula NR, Kavela S, Pandey V, Maddika S. TOPK and PTEN participate in CHFR mediated mitotic checkpoint. Cell Signal 2013; 25:2511-7. [PMID: 24012691 PMCID: PMC3819987 DOI: 10.1016/j.cellsig.2013.08.013] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2013] [Accepted: 08/24/2013] [Indexed: 01/15/2023]
Abstract
Mitotic progression is regulated by co-ordinated action of several proteins and is crucial for the maintenance of genomic stability. CHFR (Check point protein with FHA and RING domains) is an E3 ubiquitin ligase and a checkpoint protein that regulates entry into mitosis. But the molecular players involved in CHFR mediated mitotic checkpoint are not completely understood. In this study, we identified TOPK/PBK, a serine/threonine kinase and PTEN, a lipid phosphatase to play an important role in CHFR mediated mitotic transitions. We demonstrated that CHFR ubiquitinates and regulates TOPK levels, which is essential for its checkpoint function. Moreover, TOPK phosphorylates and inactivates PTEN, which in turn activates Akt that leads to proper G2/M progression. Collectively, our results reveal TOPK and PTEN as new players in CHFR mediated mitotic checkpoint.
TOPK is identified as a novel CHFR associated protein. TOPK is a substrate of CHFR. TOPK participates in CHFR mediated mitotic stress check point. PTEN is phosphorylated by TOPK and is required for mitotic entry.
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Affiliation(s)
- Swapnil R Shinde
- Laboratory of Cell Death & Cell Survival, Centre for DNA Fingerprinting and Diagnostics (CDFD), Nampally, Hyderabad 500001, India
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25
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Nikonova AS, Astsaturov I, Serebriiskii IG, Dunbrack RL, Golemis EA. Aurora A kinase (AURKA) in normal and pathological cell division. Cell Mol Life Sci 2013; 70:661-87. [PMID: 22864622 PMCID: PMC3607959 DOI: 10.1007/s00018-012-1073-7] [Citation(s) in RCA: 331] [Impact Index Per Article: 27.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2012] [Revised: 06/05/2012] [Accepted: 06/21/2012] [Indexed: 12/20/2022]
Abstract
Temporally and spatially controlled activation of the Aurora A kinase (AURKA) regulates centrosome maturation, entry into mitosis, formation and function of the bipolar spindle, and cytokinesis. Genetic amplification and mRNA and protein overexpression of Aurora A are common in many types of solid tumor, and associated with aneuploidy, supernumerary centrosomes, defective mitotic spindles, and resistance to apoptosis. These properties have led Aurora A to be considered a high-value target for development of cancer therapeutics, with multiple agents currently in early-phase clinical trials. More recently, identification of additional, non-mitotic functions and means of activation of Aurora A during interphase neurite elongation and ciliary resorption have significantly expanded our understanding of its function, and may offer insights into the clinical performance of Aurora A inhibitors. Here we review the mitotic and non-mitotic functions of Aurora A, discuss Aurora A regulation in the context of protein structural information, and evaluate progress in understanding and inhibiting Aurora A in cancer.
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Affiliation(s)
- Anna S. Nikonova
- Program in Developmental Therapeutics, Fox Chase Cancer Center, W406, 333 Cottman Ave., Philadelphia, PA 19111 USA
| | - Igor Astsaturov
- Program in Developmental Therapeutics, Fox Chase Cancer Center, W406, 333 Cottman Ave., Philadelphia, PA 19111 USA
| | - Ilya G. Serebriiskii
- Program in Developmental Therapeutics, Fox Chase Cancer Center, W406, 333 Cottman Ave., Philadelphia, PA 19111 USA
| | - Roland L. Dunbrack
- Program in Developmental Therapeutics, Fox Chase Cancer Center, W406, 333 Cottman Ave., Philadelphia, PA 19111 USA
| | - Erica A. Golemis
- Program in Developmental Therapeutics, Fox Chase Cancer Center, W406, 333 Cottman Ave., Philadelphia, PA 19111 USA
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26
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Hernández-Ortega S, Bru S, Ricco N, Ramírez S, Casals N, Jiménez J, Isasa M, Crosas B, Clotet J. Defective in mitotic arrest 1 (Dma1) ubiquitin ligase controls G1 cyclin degradation. J Biol Chem 2012; 288:4704-14. [PMID: 23264631 DOI: 10.1074/jbc.m112.426593] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Progression through the G(1) phase of the cell cycle is controlled by diverse cyclin-dependent kinases (CDKs) that might be associated to numerous cyclin isoforms. Given such complexity, regulation of cyclin degradation should be crucial for coordinating progression through the cell cycle. In Saccharomyces cerevisiae, SCF is the only E3 ligase known to date to be involved in G(1) cyclin degradation. Here, we report the design of a genetic screening that uncovered Dma1 as another E3 ligase that targets G(1) cyclins in yeast. We show that the cyclin Pcl1 is ubiquitinated in vitro and in vivo by Dma1, and accordingly, is stabilized in dma1 mutants. We demonstrate that Pcl1 must be phosphorylated by its own CDK to efficiently interact with Dma1 and undergo degradation. A nonphosphorylatable version of Pcl1 accumulates throughout the cell cycle, demonstrating the physiological relevance of the proposed mechanism. Finally, we present evidence that the levels of Pcl1 and Cln2 are independently controlled in response to nutrient availability. This new previously unknown mechanism for G(1) cyclin degradation that we report here could help elucidate the specific roles of the redundant CDK-cyclin complexes in G(1).
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Affiliation(s)
- Sara Hernández-Ortega
- Departament de Ciències Bàsiques, Universitat Internacional de Catalunya, 08017 Barcelona, Spain
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