Decreased Expression of Fructose-1,6- Bisphosphatase

Total Page:16

File Type:pdf, Size:1020Kb

Decreased Expression of Fructose-1,6- Bisphosphatase Published OnlineFirst April 6, 2016; DOI: 10.1158/0008-5472.CAN-15-2601 Cancer Molecular and Cellular Pathobiology Research Decreased Expression of Fructose-1,6- bisphosphatase Associates with Glucose Metabolism and Tumor Progression in Hepatocellular Carcinoma Hidenari Hirata1,2,3, Keishi Sugimachi1, Hisateru Komatsu1, Masami Ueda1,Takaaki Masuda1, Ryutaro Uchi1, Shotaro Sakimura1, Sho Nambara1, Tomoko Saito1, Yoshiaki Shinden1, Tomohiro Iguchi1, Hidetoshi Eguchi1, Shuhei Ito1, Kotaro Terashima2, Katsumi Sakamoto2, Masakazu Hirakawa2, Hiroshi Honda3, and Koshi Mimori1 Abstract Fructose-1,6-bisphosphatase (FBP1), the rate-limiting enzyme promoter methylation and copy-number loss of FBP1 were inde- in gluconeogenesis, is reduced in expression in certain cancers pendently associated with decreased FBP1 expression. Similarly, where it has been hypothesized to act as a tumor suppressor, FBP1 downregulation in HCC cell lines was also associated with including in hepatocellular carcinoma (HCC). Here, we report copy-number loss. HCC specimens exhibiting low expression of functional evidence supporting this hypothesis, providing a pre- FBP1 had a highly malignant phenotype, including large tumor clinical rationale to develop FBP1 as a therapeutic target for HCC size, poor differentiation, impaired gluconeogenesis, and enhanced treatment. Three independent cohorts totaling 594 cases of HCC aerobic glycolysis. The effects of FBP1 expression on prognosis and were analyzed to address clinical significance. Lower FBP1 expres- glucose metabolism were confirmed by gene set enrichment anal- sion associated with advanced tumor stage, poor overall survival, ysis. Overall, our findings established that FBP1 downregulation in and higher tumor recurrence rates. In HCC cell lines, where HCC contributed to tumor progression and poor prognosis by endogenous FBP1 expression is low, engineering its ectopic over- altering glucose metabolism, and they rationalize further study of expression inhibited tumor growth and intracellular glucose FBP1 as a prognostic biomarker and therapeutic target in HCC uptake by reducing aerobic glycolysis. In patient specimens, patients. Cancer Res; 76(11); 3265–76. Ó2016 AACR. Introduction cytes (3). A recent study reported the loss of gluconeogenic capacity in HCC (4). Moreover, the switch from aerobic glycolysis Hepatocellular carcinoma (HCC) is one of the most prevalent to gluconeogenesis may be an effective treatment in patients with cancers worldwide and is associated with a high mortality rate (1). HCC (5). Nevertheless, the role of impaired gluconeogenesis in Therefore, identification of useful biomarkers predicting clinical HCC progression is still poorly understood. outcomes and molecular targets for treatment is required. Altered The tumor-suppressive function of the fructose-1,6-bisphospha- glucose metabolism, particularly aerobic glycolysis, is one of the tase (FBP1) gene, which encodes a rate-limiting gluconeogenic hallmarks of cancers, including HCC (2), supporting the notion enzyme, has been reported in certain cancers. Loss of FBP1 that the molecules involved in altered glucose metabolism may be expression has been shown to promote tumor progression by potential biomarkers and therapeutic targets. Many studies have enhancing aerobic glycolysis, thereby resulting in poor prognosis examined aerobic glycolysis in various cancers; however, gluco- in patients with clear cell renal cell carcinoma (ccRCC; ref. 6) and neogenesis has not been studied extensively. Gluconeogenesis is breast cancer (7). With regard to HCC, in vitro experiments have also thought to play an important role in tumor progression in shown that FBP1 expression is silenced by promoter methylation HCC because gluconeogenesis mainly occurs in normal hepato- and that ectopic FBP1 expression inhibits anchorage-dependent growth of a cell line through cell-cycle arrest (8). However, the role 1Department of Surgery, Kyushu University Beppu Hospital, Beppu, of FBP1 in altered glucose metabolism has not been assessed in Japan. 2Department of Radiology, Kyushu University Beppu Hospital, HCC. Furthermore, no studies have investigated whether aberrant 3 Beppu, Japan. Department of Clinical Radiology, Graduate School of FBP1 expression affects clinical outcomes in patients with HCC. Medical Sciences, Kyushu University, Fukuoka, Japan. Therefore, the objective of this study was to examine the Note: Supplementary data for this article are available at Cancer Research function and clinical significance of FBP1 expression in HCC. Online (http://cancerres.aacrjournals.org/). Through analysis of three independent large cohorts of HCC Corresponding Author: Koshi Mimori, Kyushu University Beppu Hospital, 4546 cases, the present study evaluated whether aberrant FBP1 expres- Tsurumihara, Beppu 8740838, Japan. Phone: 81-977-27-1650; Fax: 81-977-27- sion was associated with tumor progression and prognosis in 1651, E-mail: [email protected] patients with HCC. We also elucidated the genetic and epigenetic doi: 10.1158/0008-5472.CAN-15-2601 mechanisms regulating FBP1 expression and investigated the role Ó2016 American Association for Cancer Research. of FBP1 expression in altered glucose metabolism. www.aacrjournals.org 3265 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst April 6, 2016; DOI: 10.1158/0008-5472.CAN-15-2601 Hirata et al. Materials and Methods Encyclopedia (CCLE; ref. 10) from cBioPortal For Cancer Geno- mics (http://www.cbioportal.org/index.do; ref. 11). Of the 967 Patients and sample collection human cancer cell lines in the CCLE database, FBP1 expression One hundred eighteen patients with HCC who underwent profiles were available for 27 liver cancer cell lines. A z-score hepatic resection at Kyushu University Beppu Hospital and affil- threshold of 2 was used as the cutoff value. For the analysis of iated hospitals between 2000 and 2004 were enrolled in this copy-number alterations, data were available for 23 liver cancer study. Resected tumor tissues and paired normal liver tissues were cell lines (Supplementary Table S1). Moreover, FBP1 promoter immediately stored in RNAlater (Ambion), frozen in liquid methylation status was determined using the results of methyl- nitrogen, and kept at –80C until RNA extraction. A 5-year ation-specific PCR, as described in a previous report (8), or follow-up was conducted after operation. The median follow-up methylation array data from GEO database accession numbers for the 118 patients was 59.5 months (range, 3.0–60 months). GSE60753 (12) and GSE67485 (13). Data on promoter methyl- Patients were staged according to the seventh edition of the ation profiles were available for 7 liver cancer cell lines (Supple- International Union against Cancer TNM classification system. mentary Table S2). Of the 118 HCC patients, paired normal liver tissues were avail- able for 115 patients. All protocols were approved by the Ethics Western blotting analysis and Indications Committee of Kyushu University. Written Proteins were detected using antibodies against FBP1 informed consent was obtained from all patients. (SAB1405798; Sigma-Aldrich), thioredoxin-interacting protein (TXNIP; K0204-3; Medical & Biological Laboratories), and b-actin Cell culture (Santa Cruz Biotechnology). The methods are described in detail HuH7 and HepG2 cells authenticated by short tandem repeat in the Supplementary Materials and Methods. profiling using the PowerPlex 1.2 System (Promega) were obtained from the cell bank of RIKEN BioResource Center (Tsu- Sphere formation assays kuba, Japan) in 2015. Cells were used within 6 months of Detailed methods are provided in the Supplementary Materials culturing after resuscitation. Details are provided in the Supple- and Methods. mentary Materials and Methods. Xenograft studies Construction of an FBP1 expression lentiviral vector Five-week-old female BALB/c nu/nu mice were obtained from FBP1 fi A full-length cDNA insert of human was ampli ed by SLC, Inc. and maintained under specific pathogen-free condi- PCR. Lentiviruses were generated by transfection of HEK293T cells tions. All animal procedures were performed in compliance with with pCMV-VSV-G-RSV-Rev, pCAG-HIVgp, and either CSII-CMV- the Guidelines for the Care and Use of Experimental Animals 0 Nhe 0 FBP1 or CSII-CMV-MCS (empty) plasmid DNAs (5 I and 3 established by the Committee for Animal Experimentation of Xba I sites) using Lipofectamine 2000 (Invitrogen) following the Kyushu University. A total of 5  106 cells (empty vector control manufacturer's protocol. Forty-eight hours after transfection, the cells or HuH7 cells stably expressing FBP1) in 150 mL of phos- lentivirus-containing supernatant was collected and passed phate-buffered saline were injected subcutaneously into both m fi through a 0.45- m lter. Infections were then carried out by flanks of the mice. Tumor size was measured every 3 to 4 days incubating cells with medium containing the lentiviral superna- with a digital caliper and calculated using the following formula: tant for 48 hours. tumor volume ¼ length  width2  0.5. RNA preparation and quantitative real-time RT-PCR Quantification of metabolites Detailed methods are provided in the Supplementary Materials Intracellular glucose uptake was determined by 2-(N-[7-nitro- and Methods. benz-2-oxa-1,3-diazol-4-yl]amino)-2-deoxy-D-glucose (2-NBDG), a fluorescently-tagged glucose derivative, using a Glucose Uptake Analysis of public clinical datasets and gene set
Recommended publications
  • The Switch from Fermentation to Respiration in Saccharomyces Cerevisiae Is Regulated by the Ert1 Transcriptional Activator/Repressor
    INVESTIGATION The Switch from Fermentation to Respiration in Saccharomyces cerevisiae Is Regulated by the Ert1 Transcriptional Activator/Repressor Najla Gasmi,* Pierre-Etienne Jacques,† Natalia Klimova,† Xiao Guo,§ Alessandra Ricciardi,§ François Robert,†,** and Bernard Turcotte*,‡,§,1 ‡Department of Medicine, *Department of Biochemistry, and §Department of Microbiology and Immunology, McGill University Health Centre, McGill University, Montreal, QC, Canada H3A 1A1, †Institut de recherches cliniques de Montréal, Montréal, QC, Canada H2W 1R7, and **Département de Médecine, Faculté de Médecine, Université de Montréal, QC, Canada H3C 3J7 ABSTRACT In the yeast Saccharomyces cerevisiae, fermentation is the major pathway for energy production, even under aerobic conditions. However, when glucose becomes scarce, ethanol produced during fermentation is used as a carbon source, requiring a shift to respiration. This adaptation results in massive reprogramming of gene expression. Increased expression of genes for gluconeogenesis and the glyoxylate cycle is observed upon a shift to ethanol and, conversely, expression of some fermentation genes is reduced. The zinc cluster proteins Cat8, Sip4, and Rds2, as well as Adr1, have been shown to mediate this reprogramming of gene expression. In this study, we have characterized the gene YBR239C encoding a putative zinc cluster protein and it was named ERT1 (ethanol regulated transcription factor 1). ChIP-chip analysis showed that Ert1 binds to a limited number of targets in the presence of glucose. The strongest enrichment was observed at the promoter of PCK1 encoding an important gluconeogenic enzyme. With ethanol as the carbon source, enrichment was observed with many additional genes involved in gluconeogenesis and mitochondrial function. Use of lacZ reporters and quantitative RT-PCR analyses demonstrated that Ert1 regulates expression of its target genes in a manner that is highly redundant with other regulators of gluconeogenesis.
    [Show full text]
  • Analysis of Gene Expression Data for Gene Ontology
    ANALYSIS OF GENE EXPRESSION DATA FOR GENE ONTOLOGY BASED PROTEIN FUNCTION PREDICTION A Thesis Presented to The Graduate Faculty of The University of Akron In Partial Fulfillment of the Requirements for the Degree Master of Science Robert Daniel Macholan May 2011 ANALYSIS OF GENE EXPRESSION DATA FOR GENE ONTOLOGY BASED PROTEIN FUNCTION PREDICTION Robert Daniel Macholan Thesis Approved: Accepted: _______________________________ _______________________________ Advisor Department Chair Dr. Zhong-Hui Duan Dr. Chien-Chung Chan _______________________________ _______________________________ Committee Member Dean of the College Dr. Chien-Chung Chan Dr. Chand K. Midha _______________________________ _______________________________ Committee Member Dean of the Graduate School Dr. Yingcai Xiao Dr. George R. Newkome _______________________________ Date ii ABSTRACT A tremendous increase in genomic data has encouraged biologists to turn to bioinformatics in order to assist in its interpretation and processing. One of the present challenges that need to be overcome in order to understand this data more completely is the development of a reliable method to accurately predict the function of a protein from its genomic information. This study focuses on developing an effective algorithm for protein function prediction. The algorithm is based on proteins that have similar expression patterns. The similarity of the expression data is determined using a novel measure, the slope matrix. The slope matrix introduces a normalized method for the comparison of expression levels throughout a proteome. The algorithm is tested using real microarray gene expression data. Their functions are characterized using gene ontology annotations. The results of the case study indicate the protein function prediction algorithm developed is comparable to the prediction algorithms that are based on the annotations of homologous proteins.
    [Show full text]
  • Role of RUNX1 in Aberrant Retinal Angiogenesis Jonathan D
    Page 1 of 25 Diabetes Identification of RUNX1 as a mediator of aberrant retinal angiogenesis Short Title: Role of RUNX1 in aberrant retinal angiogenesis Jonathan D. Lam,†1 Daniel J. Oh,†1 Lindsay L. Wong,1 Dhanesh Amarnani,1 Cindy Park- Windhol,1 Angie V. Sanchez,1 Jonathan Cardona-Velez,1,2 Declan McGuone,3 Anat O. Stemmer- Rachamimov,3 Dean Eliott,4 Diane R. Bielenberg,5 Tave van Zyl,4 Lishuang Shen,1 Xiaowu Gai,6 Patricia A. D’Amore*,1,7 Leo A. Kim*,1,4 Joseph F. Arboleda-Velasquez*1 Author affiliations: 1Schepens Eye Research Institute/Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, 20 Staniford St., Boston, MA 02114 2Universidad Pontificia Bolivariana, Medellin, Colombia, #68- a, Cq. 1 #68305, Medellín, Antioquia, Colombia 3C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114 4Retina Service, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, 243 Charles St., Boston, MA 02114 5Vascular Biology Program, Boston Children’s Hospital, Department of Surgery, Harvard Medical School, 300 Longwood Ave., Boston, MA 02115 6Center for Personalized Medicine, Children’s Hospital Los Angeles, Los Angeles, 4650 Sunset Blvd, Los Angeles, CA 90027, USA 7Department of Pathology, Harvard Medical School, 25 Shattuck St., Boston, MA 02115 Corresponding authors: Joseph F. Arboleda-Velasquez: [email protected] Ph: (617) 912-2517 Leo Kim: [email protected] Ph: (617) 912-2562 Patricia D’Amore: [email protected] Ph: (617) 912-2559 Fax: (617) 912-0128 20 Staniford St. Boston MA, 02114 † These authors contributed equally to this manuscript Word Count: 1905 Tables and Figures: 4 Diabetes Publish Ahead of Print, published online April 11, 2017 Diabetes Page 2 of 25 Abstract Proliferative diabetic retinopathy (PDR) is a common cause of blindness in the developed world’s working adult population, and affects those with type 1 and type 2 diabetes mellitus.
    [Show full text]
  • Clinical and Molecular Characterization of Patients with Fructose 1,6-Bisphosphatase Deficiency
    Article Clinical and Molecular Characterization of Patients with Fructose 1,6-Bisphosphatase Deficiency Niu Li 1,†, Guoying Chang 2,†, Yufei Xu 1, Yu Ding 2, Guoqiang Li 1, Tingting Yu 1, Yanrong Qing 1, Juan Li 2, Yiping Shen 1,3, Jian Wang 1,* and Xiumin Wang 2,* 1 Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China; [email protected] (N.L.); [email protected] (Y.X.); [email protected] (G.L.); [email protected] (T.Y.); [email protected] (Y.Q.); [email protected] (Y.S.) 2 Department of Endocrinology and Metabolism, Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China; [email protected] (G.C.); [email protected] (Y.D.); [email protected] (J.L.) 3 Department of Laboratory Medicine, Boston Children’s Hospital, Boston, MA 02115, USA * Correspondence: [email protected] (J.W.); [email protected] (X.W.); Tel.: +86-21-3862-6161 (J.W. & X.W.); Fax: +86-21-5875-6923 (J.W. & X.W.) † These authors contributed equally to this work. Academic Editor: William Chi-shing Cho Received: 26 February 2017; Accepted: 17 April 2017; Published: 18 April 2017 Abstract: Fructose-1,6-bisphosphatase (FBPase) deficiency is a rare, autosomal recessive inherited disease caused by the mutation of the FBP1 gene, the incidence is estimated to be between 1/350,000 and 1/900,000. The symptoms of affected individuals are non-specific and are easily confused with other metabolic disorders.
    [Show full text]
  • Product Description SALSA® MLPA® Probemix P255-B1 ALDOB-FBP1 to Be Used with the MLPA General Protocol
    Product description version B1-01; Issued 14 January 2021 Product Description SALSA® MLPA® Probemix P255-B1 ALDOB-FBP1 To be used with the MLPA General Protocol. Version B1 No Changes. Catalogue numbers: P255-025R: SALSA MLPA Probemix P255 ALDOB-FBP1, 25 reactions. P255-050R: SALSA MLPA Probemix P255 ALDOB-FBP1, 50 reactions. P255-100R: SALSA MLPA Probemix P255 ALDOB-FBP1, 100 reactions. To be used in combination with a SALSA MLPA reagent kit and Coffalyser.Net data analysis software. MLPA reagent kits are either provided with FAM or Cy5.0 dye-labelled PCR primer, suitable for Applied Biosystems and Beckman/SCIEX capillary sequencers, respectively (see www.mrcholland.com). Certificate of Analysis Information regarding storage conditions, quality tests, and a sample electropherogram from the current sales lot is available at www.mrcholland.com. Precautions and warnings For professional use only. Always consult the most recent product description AND the MLPA General Protocol before use: www.mrcholland.com. It is the responsibility of the user to be aware of the latest scientific knowledge of the application before drawing any conclusions from findings generated with this product. General information The SALSA MLPA Probemix P255-B1 ALDOB-FBP1 is a research use only (RUO) assay for the detection of deletions or duplications in the ALDOB and FBP1, which are associated with Hereditary fructose intolerance. Hereditary fructose intolerance (HFI) is a rare recessive inherited disorder of carbohydrate metabolism, caused by catalytic deficiency of the aldolase B enzyme (ALDOB). The ALDOB enzyme plays a key role in glycolysis and gluconeogenesis and, in mammals, is preferentially expressed in the liver.
    [Show full text]
  • Datasheet: 0200-0058 Product Details
    Datasheet: 0200-0058 Description: MOUSE ANTI FOLATE BINDING PROTEIN Specificity: FOLATE BINDING PROTEIN Other names: FBP Format: Purified Product Type: Monoclonal Antibody Clone: SF75 (BGN/1210/75) Isotype: IgG2b Quantity: 0.2 mg Product Details Applications This product has been reported to work in the following applications. This information is derived from testing within our laboratories, peer-reviewed publications or personal communications from the originators. Please refer to references indicated for further information. For general protocol recommendations, please visit www.bio-rad-antibodies.com/protocols. Yes No Not Determined Suggested Dilution ELISA Where this product has not been tested for use in a particular technique this does not necessarily exclude its use in such procedures. Suggested working dilutions are given as a guide only. It is recommended that the user titrates the product for use in their own system using the appropriate negative/positive controls. Target Species Bovine Product Form Purified IgG - liquid Preparation Prepared by Protein A chromatography Buffer Solution Phosphate buffered saline Preservative 0.09% Sodium Azide (NaN ) Stabilisers 3 Approx. Protein IgG concentration 1.0mg/ml Concentrations Immunogen Purified Folate Binding Protein from bovine milk. External Database UniProt: Links P02702 Related reagents Entrez Gene: 432398 FBP1 Related reagents Page 1 of 3 Specificity Mouse anti Bovine folate binding protein antibody, clone SF75 recognizes folate binding protein isolated from bovine milk. Cross reactivity with folate binding proteins from other sources has not been determined. Soluble folate binding protein from milk serves to accumulate and stabilize reduced folate compounds in the milk and aid in the absorbtion of folates by the intestinal mucosa of neonates.
    [Show full text]
  • Far Upstream Element Binding Protein 1: a Commander of Transcription, Translation and Beyond
    Oncogene (2013) 32, 2907–2916 & 2013 Macmillan Publishers Limited All rights reserved 0950-9232/13 www.nature.com/onc REVIEW Far upstream element binding protein 1: a commander of transcription, translation and beyond J Zhang and QM Chen The far upstream binding protein 1 (FBP1) was first identified as a DNA-binding protein that regulates c-Myc gene transcription through binding to the far upstream element (FUSE) in the promoter region 1.5 kb upstream of the transcription start site. FBP1 collaborates with TFIIH and additional transcription factors for optimal transcription of the c-Myc gene. In recent years, mounting evidence suggests that FBP1 acts as an RNA-binding protein and regulates mRNA translation or stability of genes, such as GAP43, p27 Kip and nucleophosmin. During retroviral infection, FBP1 binds to and mediates replication of RNA from Hepatitis C and Enterovirus 71. As a nuclear protein, FBP1 may translocate to the cytoplasm in apoptotic cells. The interaction of FBP1 with p38/ JTV-1 results in FBP1 ubiquitination and degradation by the proteasomes. Transcriptional and post-transcriptional regulations by FBP1 contribute to cell proliferation, migration or cell death. FBP1 association with carcinogenesis has been reported in c-Myc dependent or independent manner. This review summarizes biochemical features of FBP1, its mechanism of action, FBP family members and the involvement of FBP1 in carcinogenesis. Oncogene (2013) 32, 2907–2916; doi:10.1038/onc.2012.350; published online 27 August 2012 Keywords: FBP1; FUSE; cancer INTRODUCTION IDENTIFICATION OF FBP1 The far upstream element binding protein 1 (FBP1) was first FBP1 was first cloned from a cDNA library generated from the discovered as a transcriptional regulator of the proto-oncogene undifferentiated human monoblastic line U937.6 Such an c-Myc.
    [Show full text]
  • A MAFG-Lncrna Axis Links Systemic Nutrient Abundance to Hepatic Glucose Metabolism
    ARTICLE https://doi.org/10.1038/s41467-020-14323-y OPEN A MAFG-lncRNA axis links systemic nutrient abundance to hepatic glucose metabolism Marta Pradas-Juni et al.# Obesity and type 2 diabetes mellitus are global emergencies and long noncoding RNAs (lncRNAs) are regulatory transcripts with elusive functions in metabolism. Here we show that a high fraction of lncRNAs, but not protein-coding mRNAs, are repressed during diet-induced 1234567890():,; obesity (DIO) and refeeding, whilst nutrient deprivation induced lncRNAs in mouse liver. Similarly, lncRNAs are lost in diabetic humans. LncRNA promoter analyses, global cistrome and gain-of-function analyses confirm that increased MAFG signaling during DIO curbs lncRNA expression. Silencing Mafg in mouse hepatocytes and obese mice elicits a fasting-like gene expression profile, improves glucose metabolism, de-represses lncRNAs and impairs mammalian target of rapamycin (mTOR) activation. We find that obesity-repressed LincIRS2 is controlled by MAFG and observe that genetic and RNAi-mediated LincIRS2 loss causes elevated blood glucose, insulin resistance and aberrant glucose output in lean mice. Taken together, we identify a MAFG-lncRNA axis controlling hepatic glucose metabolism in health and metabolic disease. #A full list of authors and their affiliations appears at the end of the paper. NATURE COMMUNICATIONS | (2020) 11:644 | https://doi.org/10.1038/s41467-020-14323-y | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-14323-y ellular and organism-level energy homeostasis and nutri- by MAFG and CRISPR–Cas9-mediated knockout, or antisense- Cent partitioning are instrumental for survival. In higher mediated RNA interference of LincIRS2 causes hyperglycemia, organisms, multi-organ systems evolved to react to shifts insulin resistance, likely caused by alterations in glucogenic in energy supply by storing (anabolic) or metabolizing (catabolic) gene expression in lean mice.
    [Show full text]
  • Long Noncoding RNA DANCR Regulates Proliferation and Migration by Epigenetically Silencing FBP1 in Tumorigenesis of Cholangiocar
    Wang et al. Cell Death and Disease (2019) 10:585 https://doi.org/10.1038/s41419-019-1810-z Cell Death & Disease ARTICLE Open Access Long noncoding RNA DANCR regulates proliferation and migration by epigenetically silencing FBP1 in tumorigenesis of cholangiocarcinoma Ni Wang1, Chongguo Zhang2, Wulin Wang3,JieLiu4,YangYu1,YouLi5, Mingjiong Zhang6,XianxiuGe1, Quanpeng Li1 and Lin Miao 1 Abstract Recently, long noncoding RNAs (lncRNAs) have been shown to play significant regulatory roles in human tumorigenesis. However, the biological function of lncRNAs in cholangiocarcinoma (CCA) remains largely unknown. In this study, DANCR was shown to be significantly upregulated in CCA. DANCR regulated the proliferation and migration of CCA cells in vitro. Moreover, downregulation of DANCR suppressed CCA cells proliferation in vivo. RNA-seq revealed that DANCR knockdown preferentially affected genes linked with cell proliferation and cell differentiation. Furthermore, mechanistic investigation validated that DANCR could bind EZH2 and modulate the histone methylation of promoter of FBP1, thereby regulating CCA cells growth and migration. Taken together, these results demonstrated the significant roles of DANCR in CCA and may provide a theoretical basis for clinical diagnosis and treatment of CCA. 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Introduction Long noncoding RNAs (lncRNAs), the RNA transcripts Cholangiocarcinoma (CCA), an extremely malignant longer than 200 nucleotides with little or no protein- tumor that arises from cholangiocytes, has been a major coding potential4,5, have been shown to exhibit critical health burden worldwide for decades1. Given the lack of function in tumorigenesis, including CCA6,7. In addition, sensitive indicators, the diagnosis of the majority of CCA as a regulator in the process of epigenetics, lncRNAs cases typically occurs at a late stage, resulting that patients could regulate gene expression in chromatin modification, with unresectable tumors only have a median overall transcription and posttranscription process8.
    [Show full text]
  • MAGE-TRIM28 Complex Promotes the Warburg Effect and Hepatocellular Carcinoma Progression by Targeting FBP1 for Degradation
    OPEN Citation: Oncogenesis (2017) 6, e312; doi:10.1038/oncsis.2017.21 www.nature.com/oncsis ORIGINAL ARTICLE MAGE-TRIM28 complex promotes the Warburg effect and hepatocellular carcinoma progression by targeting FBP1 for degradation X Jin1,2,YPan2, L Wang3, L Zhang4, R Ravichandran5, PR Potts5, J Jiang6,HWu7 and H Huang2,8,9 Hepatocellular carcinoma (HCC) is one of the leading cause of cancer death in the world. Fructose-1,6-biphosphatase (FBP1), a rate-limiting enzyme in gluconeogenesis, has been identified recently as a tumor suppressor in HCC and other cancer types. In this study, we demonstrated that the tripartite motif-containing protein 28 (TRIM28) binds directly to and promotes FBP1 for ubiquitination and degradation. MAGE-A3 and MAGE-C2, which are known to be overexpressed in HCC, can enhance TRIM28-dependent degradation of FBP1 by forming ubiquitin ligase complexes with TRIM28. We further showed that expression of TRIM28 increased glucose consumption and lactate production by promoting FBP1 degradation in HCC cells and that FBP1 is a key mediator of TRIM28-induced HCC growth in culture and in mice. Moreover, we demonstrated that FBP1 and TRIM28 protein levels inversely correlated in HCC patient specimens. Finally, we showed that the proteasome inhibitor bortezomib mitigated the Warburg effect by inhibiting FBP1 degradation in HCC. Collectively, our findings not only identify oncogenic MAGE-TRIM28 complex-mediated proteasome degradation of FBP1 as a key mechanism underlying downregulation of FBP1 proteins in HCC, but also reveal that MAGE-TRIM28-regulated reprogramming of cancer cell metabolism and HCC tumorigenesis is mediated, at least in part, through FBP1 degradation.
    [Show full text]
  • Glucose Starvation to Rapid Death of Nrf1, but Not Nrf2, Deficient Hepatoma Cells from Its Fatal Defects in the Redox Metabolism Reprogramming
    bioRxiv preprint doi: https://doi.org/10.1101/2019.12.13.875369; this version posted December 13, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Glucose starvation to rapid death of Nrf1, but not Nrf2, deficient hepatoma cells from its fatal defects in the redox metabolism reprogramming Yu-ping Zhu1, Ze Zheng1, Yuancai Xiang2, and Yiguo Zhang1* 1The Laboratory of Cell Biochemistry and Topogenetic Regulation, College of Bioengineering and Faculty of Medical Sciences, Chongqing University, No. 174 Shazheng Street, Shapingba District, Chongqing 400044, China. 2Department of Biochemistry and Molecular Biology, Collage of Basic Medical Sciences, Southwest Medical University, Sichuan, 646000, China. *Correspondence should be addressed to Yiguo Zhang (Email: [email protected], or [email protected]) Abstract Metabolic reprogramming exists in a variety of cancer cells, with the most relevance to glucose as a source of energy and carbon for survival and proliferation. Of note, Nrf1 was shown to be essential for regulating glycolysis pathway, but it is unknown whether it plays a role in cancer metabolic reprogramming, particularly in response to glucose starvation. Herein, we discover that Nrf1α/-derived hepatoma cells are sensitive to rapid death induced by glucose deprivation, such cell death appears to be rescued by Nrf2 interference, but Nrf1/2/ or Nrf2/-derived cells are roughly unaffected by glucose starvation. Further evidence revealed that Nrf1α/ cell death is resulted from severe oxidative stress arising from abberrant redox metabolism. Strikingly, altered gluconeogenesis pathway was aggravated by glucose starvation of Nrf1α/ cells, as also accompanied by weakened pentose phosphate pathway, dysfunction of serine-to-glutathione synthesis, and accumulation of reactive oxygen species (ROS) and damages, such that the intracellular GSH and NADPH were exhausted.
    [Show full text]
  • Table S1. 103 Ferroptosis-Related Genes Retrieved from the Genecards
    Table S1. 103 ferroptosis-related genes retrieved from the GeneCards. Gene Symbol Description Category GPX4 Glutathione Peroxidase 4 Protein Coding AIFM2 Apoptosis Inducing Factor Mitochondria Associated 2 Protein Coding TP53 Tumor Protein P53 Protein Coding ACSL4 Acyl-CoA Synthetase Long Chain Family Member 4 Protein Coding SLC7A11 Solute Carrier Family 7 Member 11 Protein Coding VDAC2 Voltage Dependent Anion Channel 2 Protein Coding VDAC3 Voltage Dependent Anion Channel 3 Protein Coding ATG5 Autophagy Related 5 Protein Coding ATG7 Autophagy Related 7 Protein Coding NCOA4 Nuclear Receptor Coactivator 4 Protein Coding HMOX1 Heme Oxygenase 1 Protein Coding SLC3A2 Solute Carrier Family 3 Member 2 Protein Coding ALOX15 Arachidonate 15-Lipoxygenase Protein Coding BECN1 Beclin 1 Protein Coding PRKAA1 Protein Kinase AMP-Activated Catalytic Subunit Alpha 1 Protein Coding SAT1 Spermidine/Spermine N1-Acetyltransferase 1 Protein Coding NF2 Neurofibromin 2 Protein Coding YAP1 Yes1 Associated Transcriptional Regulator Protein Coding FTH1 Ferritin Heavy Chain 1 Protein Coding TF Transferrin Protein Coding TFRC Transferrin Receptor Protein Coding FTL Ferritin Light Chain Protein Coding CYBB Cytochrome B-245 Beta Chain Protein Coding GSS Glutathione Synthetase Protein Coding CP Ceruloplasmin Protein Coding PRNP Prion Protein Protein Coding SLC11A2 Solute Carrier Family 11 Member 2 Protein Coding SLC40A1 Solute Carrier Family 40 Member 1 Protein Coding STEAP3 STEAP3 Metalloreductase Protein Coding ACSL1 Acyl-CoA Synthetase Long Chain Family Member 1 Protein
    [Show full text]