DOCSLIB.ORG

Dysregulation of Spliceosome Gene Expression in Advanced Prostate Cancer by RNA-Binding Protein PSF

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Dysregulation of Spliceosome Gene Expression in Advanced Prostate Cancer by RNA-Binding Protein PSF Dysregulation of spliceosome gene expression in advanced prostate cancer by RNA-binding protein PSF Ken-ichi Takayamaa, Takashi Suzukib, Tetsuya Fujimurac, Yuta Yamadac, Satoru Takahashid, Yukio Hommac, Yutaka Suzukie, and Satoshi Inouea,f,1 aDepartment of Functional Biogerontology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan; bDepartment of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, Miyagi 980-8575, Japan; cDepartment of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; dDepartment of Urology, Nihon University School of Medicine, Tokyo 173-0032, Japan; eDepartment of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8652, Japan; and fDivision of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama 350-1241, Japan Edited by Hsing-Jien Kung, National Health Research Institutes, Miaoli, Taiwan, and accepted by Editorial Board Member Peter K. Vogt July 26, 2017 (received for review April 13, 2017) Developing therapeutic approaches are necessary for treating PSF is a ubiquitous nuclear protein essential for neural de- hormone-refractory prostate cancer. Activation of androgen re- velopment by regulating axon viability (12, 13). PSF has a unique ceptor (AR) and its variants’ expression along with the down- structure possessing both DNA- and RNA-binding domains, stream signals are mostly important for disease progression. implicated in transcription and nuclear RNA processing (14–16). However, the mechanism for marked increases of AR signals and However, the transcriptional and posttranscriptional specific its expression is still unclear. Here, we revealed that various spli- targets and the clinical significance of these proteins in prostate ceosome genes are aberrantly induced by RNA-binding protein cancer progression still remain to be elucidated. Here, we con- PSF, leading to enhancement of the splicing activities for AR ex- ducted global systematic analyses to determine both transcrip- pression. Our high-speed sequence analyses identified global PSF- tional targets and PSF-binding RNAs using CRPC model cells. binding transcripts. PSF was shown to stabilize and activate key Notably, we found that a broad range of spliceosome genes are long noncoding RNAs and AR-regulated gene expressions in pros- primary targets of PSF, and they are induced for activation of tate cancer cells. Interestingly, mRNAs of spliceosome-related splicing and mRNA production in CRPC. Thus, our findings genes are putative primary targets of PSF. Their gene expressions MEDICAL SCIENCES are up-regulated by PSF in hormone-refractory prostate cancer. shed light on the regulatory mechanism of various splicing fac- Moreover, PSF coordinated these spliceosome proteins to form a tors by RNA-binding proteins in prostate cancer progression. complex to promote AR splicing and expression. Thus, targeting Results PSF and its related pathways implicates the therapeutic possibility for hormone-refractory prostate cancer. PSF Promotes Castration-Resistant Prostate Tumor Growth. To in- vestigate the role of PSF in prostate cancer, we analyzed the androgen receptor | RNA-binding protein | PSF | NONO | prostate cancer expression level of PSF. In prostate cancer cell lines, we observed increased expression of PSF in several prostate cancer cells such ndrogen receptor (AR) regulates many genes central to the as DU145, LNCaP, and LNCaP-derived CRPC model cells, Aidentity and behavior of prostate cancer cells (1). AR long-term androgen deprivation (LTAD) cells compared with functions in a ligand-dependent manner in many prostate can- cers, and androgen deprivation therapy is effective in inhibiting Significance tumor growth. However, most of the patients acquire resistance to this therapy and eventually suffer from castration-resistant Elevated downstream signals of androgen receptor (AR) and its prostate cancer (CRPC) (2, 3). Previous studies have discov- variants are important for prostate cancer progression. We ered the importance of enhanced AR downstream signaling (3, show that an RNA-binding transcriptional and splicing factor, 4), expression of AR and its splice variants lacking the ligand splicing factor proline and glutamine-rich (PSF/SFPQ), predicts binding domain (ARVs) in CRPC (5, 6). The variant AR-V7 was worse prognosis of prostate cancer patients. Inhibition of PSF shown to regulate distinct and androgen-independent activation expression repressed treatment-resistant prostate tumor growth of its downstream signals, which contributes to the development in our animal model. Our global analysis of PSF-binding RNAs of CRPC (7). Thus, targeting AR, AR-V7, and its downstream revealed that PSF enhances AR-regulated genes and noncoding RNAs associated with prostate cancer progression. Interestingly, signals could have efficacy in treating CRPC. various splicing factors, which are primary targets of PSF, are Long noncoding (lnc) RNAs function through interaction with upregulated in metastatic prostate tumors. These enhanced fac- epigenetic factors in cancer (8–11). Previous reports highlighted tors form complexes with PSF to promote AR expression and the lncRNA-mediated association of RNA-binding proteins or splicing. Our findings suggest a role of RNA-binding protein for transcription factors with specific genomic regions for prostate AR activation for prostate cancer progression. cancer progression (10, 11). We have reported that androgen- induced lncRNA (named CTBP1-AS) in the antisense region Author contributions: K.T. and S.I. designed research; K.T., T.S., and Y.S. performed re- of carboxyl terminal binding protein 1 (CTBP1) promotes search; T.F., Y.Y., S.T., and Y.H. contributed new reagents/analytic tools; K.T., T.S., and S.I. castration-resistant tumor growth. CTBP1-AS interacts with an analyzed data; and K.T. and S.I. wrote the paper. RNA-binding transcriptional and splicing factor, splicing factor The authors declare no conflict of interest. proline and glutamine-rich (PSF/SFPQ), and represses cell cycle This article is a PNAS Direct Submission. H.-J.K. is a guest editor invited by the regulators by epigenetic mechanism (11). We also found that Editorial Board. PSF and its interacting factor, non–POU-domain–containing Data deposition: Sequences have been deposited in the Gene Expression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession nos. GSE94577, GSE94028, octamer-binding protein (NONO), have an important role in GSE94243, and GSE100239). prostate cancer cell proliferation, suggesting the possibility that 1To whom correspondence should be addressed. Email: [email protected]. these RNA-binding proteins are also implicated in the disease This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. progression (11). 1073/pnas.1706076114/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1706076114 PNAS | September 26, 2017 | vol. 114 | no. 39 | 10461–10466 Downloaded by guest on September 24, 2021 normal prostate epithelial cells (PrEC) (SI Appendix,Fig.S1A). We reduced the growth of tumors derived from 22Rv1 cells (Fig. 1D). evaluated the PSF protein expression in clinical tumor samples by In tumors with reduced PSF expression, induced cell cycle regula- immunohistochemical (IHC) analysis (Fig. 1A) using anti-PSF tors such as p53 and p21 proteins were also observed, suggesting specific antibody (SI Appendix,Fig.S1B). Low PSF staining was that PSF could be a potential target for the treatment of CRPC observed in benign prostate tissues, whereas high PSF staining was (Fig. 1E). These data highlight a potential role of increased PSF in observed in a subset of tumor samples, and higher expression of the CRPC tumor growth. (Additional results are shown in SI PSF correlated with the patients’ cancer-specific survival after Appendix, Text S1 and Figs. S3–S5.) surgery and the PSA-free survival after hormone therapy (Fig. 1B and SI Appendix,Fig.S1C). According to public databases of ex- Global Mapping of PSF-Binding Transcripts Revealed That AR-Regulated pression profiles in prostate cancer clinical samples (such as Genes and Prostate Cancer-Associated lncRNAs Are Specific Targets of Oncomine) (17–19), PSF mRNA expression is significantly ele- PSF. To explore other functions of PSF in prostate cancer, we next vatedinmetastaticoradvancedprostatecancersamples,suggest- analyzed RNAs bound with PSF using deep-sequence analysis (Fig. ing that PSF expression is associated with prostate cancer 2A). First, we performed RNA immunoprecipitation coupled with progression (Fig. 1C and SI Appendix,Fig.S1D–F). deep sequencing (RIP-seq) in LNCaP cells treated with vehicle or We previously reported that PSF-inhibited cell cycle-associated DHT. By mapping sequence tags to RefSeq, GENCODE, and gene such as p53 and SMAD3 expression by transcriptional NONCODE, we identified putative PSF target genes (Fold > 2, P < −5 mechanism in AR-dependent prostate cancer cell lines (LNCaP, 10 ) including lncRNAs (Fig. 2B and SI Appendix,Fig.S6A–C). VCaP) and their CRPC models, LTAD cells (11). In this study, by We further performed RIP-seq in CRPC model cells (LTAD and using short-interference (si) RNAs targeting PSF, we efficiently 22Rv1) (Fig. 2C). In LTAD and 22Rv1 cells, we found more depleted the expression of PSF in other hormone-refractory pros- binding genes, which significantly overlapped with those of LNCaP tate cancer cells such as DU145
Load more

Recommended publications
  • Chromatin State Signatures Associated with Tissue-Specific Gene Expression and Enhancer Activity in the Embryonic Limb. Justin C
    Downloaded from genome.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Chromatin state signatures associated with tissue-specific gene expression and enhancer activity in the embryonic limb. Justin Cotney1, Jing Leng2, Sunghee Oh1+, Laura E. DeMare1, Steven K. Reilly1, Mark B. Gerstein2,3,4 and James P. Noonan1,2,5* 1. Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA 2. Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA. 3. Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA. 4. Department of Computer Science, Yale University, New Haven, CT 06511, USA. 5. Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USA + Current address: Division of Human Genetics, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229 *Corresponding author Running title: Chromatin states identify developmental enhancers Keywords: chromatin, enhancers, development, limb, ChIP-seq Downloaded from genome.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Abstract The regulatory elements that direct tissue-specific gene expression in the developing mammalian embryo remain largely unknown. Although chromatin profiling has proven to be a powerful method for mapping regulatory sequences in cultured cells, chromatin states characteristic of active developmental enhancers have not been directly identified in embryonic tissues. Here we use whole transcriptome analysis coupled with genome-wide profiling of H3K27ac and H3K27me3 to map chromatin states and enhancers in mouse embryonic forelimb and hindlimb. We show that gene expression differences between forelimb and hindlimb, and between limb and other embryonic cell types, are correlated with tissue-specific H3K27ac signatures at promoters and distal sites.
    [Show full text]
  • Aneuploidy: Using Genetic Instability to Preserve a Haploid Genome?
    Health Science Campus FINAL APPROVAL OF DISSERTATION Doctor of Philosophy in Biomedical Science (Cancer Biology) Aneuploidy: Using genetic instability to preserve a haploid genome? Submitted by: Ramona Ramdath In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Science Examination Committee Signature/Date Major Advisor: David Allison, M.D., Ph.D. Academic James Trempe, Ph.D. Advisory Committee: David Giovanucci, Ph.D. Randall Ruch, Ph.D. Ronald Mellgren, Ph.D. Senior Associate Dean College of Graduate Studies Michael S. Bisesi, Ph.D. Date of Defense: April 10, 2009 Aneuploidy: Using genetic instability to preserve a haploid genome? Ramona Ramdath University of Toledo, Health Science Campus 2009 Dedication I dedicate this dissertation to my grandfather who died of lung cancer two years ago, but who always instilled in us the value and importance of education. And to my mom and sister, both of whom have been pillars of support and stimulating conversations. To my sister, Rehanna, especially- I hope this inspires you to achieve all that you want to in life, academically and otherwise. ii Acknowledgements As we go through these academic journeys, there are so many along the way that make an impact not only on our work, but on our lives as well, and I would like to say a heartfelt thank you to all of those people: My Committee members- Dr. James Trempe, Dr. David Giovanucchi, Dr. Ronald Mellgren and Dr. Randall Ruch for their guidance, suggestions, support and confidence in me. My major advisor- Dr. David Allison, for his constructive criticism and positive reinforcement.
    [Show full text]
  • Externalized Glycolytic Enzymes Are Novel, Conserved, and Early Biomarkers of Apoptosis*DS
    Supplemental Material can be found at: http://www.jbc.org/content/suppl/2012/01/18/M111.314971.DC1.html THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 287, NO. 13, pp. 10325–10343, March 23, 2012 © 2012 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A. Externalized Glycolytic Enzymes Are Novel, Conserved, and Early Biomarkers of Apoptosis*□S Received for publication, October 19, 2011, and in revised form, December 23, 2011 Published, JBC Papers in Press, January 18, 2012, DOI 10.1074/jbc.M111.314971 David S. Ucker‡1, Mohit Raja Jain§¶, Goutham Pattabiraman‡, Karol Palasiewicz‡, Raymond B. Birge¶, and Hong Li§¶2 From the ‡Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, Illinois 60612 and the §Center for Advanced Proteomics Research and ¶Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School Cancer Center, Newark, New Jersey 07214 Background: Apoptotic cell recognition triggers profound immunosuppressive responses; relevant recognition determi- nants are uncharacterized. Results: Surface exposure of glycolytic enzymes is a common early apoptotic event. Conclusion: Externalized glycolytic enzyme molecules are novel apoptotic biomarkers and candidate immunomodulatory/ recognition determinants. Significance: Apoptotic glycolytic enzyme externalization explicates plasminogen binding to mammalian cells and potential Downloaded from mechanisms of immune privilege by commensal bacteria and pathogens. The intriguing cell biology of apoptotic
    [Show full text]
  • Alternative Splicing Is Frequent During Early Embryonic Development in Mouse BMC Genomics 2010, 11:399
    Revil et al. BMC Genomics 2010, 11:399 http://www.biomedcentral.com/1471-2164/11/399 RESEARCH ARTICLE Open Access AlternativeResearch article splicing is frequent during early embryonic development in mouse Timothée Revil*1, Daniel Gaffney*1, Christel Dias1,2, Jacek Majewski1,2 and Loydie A Jerome-Majewska†1,3 Abstract Background: Alternative splicing is known to increase the complexity of mammalian transcriptomes since nearly all mammalian genes express multiple pre-mRNA isoforms. However, our knowledge of the extent and function of alternative splicing in early embryonic development is based mainly on a few isolated examples. High throughput technologies now allow us to study genome-wide alternative splicing during mouse development. Results: A genome-wide analysis of alternative isoform expression in embryonic day 8.5, 9.5 and 11.5 mouse embryos and placenta was carried out using a splicing-sensitive exon microarray. We show that alternative splicing and isoform expression is frequent across developmental stages and tissues, and is comparable in frequency to the variation in whole-transcript expression. The genes that are alternatively spliced across our samples are disproportionately involved in important developmental processes. Finally, we find that a number of RNA binding proteins, including putative splicing factors, are differentially expressed and spliced across our samples suggesting that such proteins may be involved in regulating tissue and temporal variation in isoform expression. Using an example of a well characterized splicing factor, Fox2, we demonstrate that changes in Fox2 expression levels can be used to predict changes in inclusion levels of alternative exons that are flanked by Fox2 binding sites.
    [Show full text]
  • Genome-Wide Transcript and Protein Analysis Reveals Distinct Features of Aging in the Mouse Heart
    bioRxiv preprint doi: https://doi.org/10.1101/2020.08.28.272260; this version posted April 21, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Genome-wide transcript and protein analysis reveals distinct features of aging in the mouse heart Isabela Gerdes Gyuricza1, Joel M. Chick2, Gregory R. Keele1, Andrew G. Deighan1, Steven C. Munger1, Ron Korstanje1, Steven P. Gygi3, Gary A. Churchill1 1The Jackson Laboratory, Bar Harbor, Maine 04609 USA; 2Vividion Therapeutics, San Diego, California 92121, USA; 3Harvard Medical School, Boston, Massachusetts 02115, USA Corresponding author: [email protected] Key words for online indexing: Heart Aging Transcriptomics Proteomics eQTL pQTL Stoichiometry ABSTRACT Investigation of the molecular mechanisms of aging in the human heart is challenging due to confounding factors, such as diet and medications, as well limited access to tissues. The laboratory mouse provides an ideal model to study aging in healthy individuals in a controlled environment. However, previous mouse studies have examined only a narrow range of the genetic variation that shapes individual differences during aging. Here, we analyzed transcriptome and proteome data from hearts of genetically diverse mice at ages 6, 12 and 18 months to characterize molecular changes that occur in the aging heart. Transcripts and proteins reveal distinct biological processes that are altered through the course of natural aging. Transcriptome analysis reveals a scenario of cardiac hypertrophy, fibrosis, and reemergence of fetal gene expression patterns.
    [Show full text]
  • ATP Is Required for Interactions Between UAP56 and Two Conserved Mrna Export Proteins, Aly and CIP29, to Assemble the TREX Complex
    ATP is required for interactions between UAP56 and two conserved mRNA export proteins, Aly and CIP29, to assemble the TREX complex Kobina Dufu,1 Michaela J. Livingstone,2 Jan Seebacher,1 Steven P. Gygi,1 Stuart A. Wilson,2 and Robin Reed1,3 1Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA; 2Department of Molecular Biology and Biotechnology, University of Sheffield, Western Bank, Sheffield S10 2TN, United Kingdom The conserved TREX mRNA export complex is known to contain UAP56, Aly, Tex1, and the THO complex. Here, we carried out proteomic analysis of immunopurified human TREX complex and identified the protein CIP29 as the only new component with a clear yeast relative (known as Tho1). Tho1 is known to function in mRNA export, and we provide evidence that CIP29 likewise functions in this process. Like the known TREX components, a portion of CIP29 localizes in nuclear speckle domains, and its efficient recruitment to mRNA is both splicing- and cap-dependent. We show that UAP56 mediates an ATP-dependent interaction between the THO complex and both CIP29 and Aly, indicating that TREX assembly is ATP-dependent. Using recombinant proteins expressed in Escherichia coli, we show that UAP56, Aly, and CIP29 form an ATP-dependent trimeric complex, and UAP56 bridges the interaction between CIP29 and Aly. We conclude that the interaction of two conserved export proteins, CIP29 and Aly, with UAP56 is strictly regulated by ATP during assembly of the TREX complex. [Keywords: CIP29; Aly; UAP56; TREX complex; Tho1; helicase] Supplemental material is available at http://www.genesdev.org. Received December 20, 2009; revised version accepted July 30, 2010.
    [Show full text]
  • Primepcr™Assay Validation Report
    PrimePCR™Assay Validation Report Gene Information Gene Name DEAD (Asp-Glu-Ala-Asp) box polypeptide 39 Gene Symbol Ddx39 Organism Mouse Gene Summary Description Not Available Gene Aliases 2610307C23Rik, BAT1, DDXL, Ddx39a, URH49 RefSeq Accession No. NC_000074.6, NT_078575.7 UniGene ID Mm.28222 Ensembl Gene ID ENSMUSG00000005481 Entrez Gene ID 68278 Assay Information Unique Assay ID qMmuCED0044888 Assay Type SYBR® Green Detected Coding Transcript(s) ENSMUST00000019576, ENSMUST00000109810, ENSMUST00000172396 Amplicon Context Sequence GGAAAATGAACTTTTGGATTATGATGAAGATGAAGAGCCCCAGGCACCCCAGGA GAGCACTCCAGCTCCCCCGAAGAAAGATGTCAAAGGATCTTATGTCTCCAT Amplicon Length (bp) 75 Chromosome Location 8:83719408-83719512 Assay Design Exonic Purification Desalted Validation Results Efficiency (%) 99 R2 0.9996 cDNA Cq 20.53 cDNA Tm (Celsius) 82.5 gDNA Cq 24.83 Specificity (%) 100 Information to assist with data interpretation is provided at the end of this report. Page 1/4 PrimePCR™Assay Validation Report Ddx39, Mouse Amplification Plot Amplification of cDNA generated from 25 ng of universal reference RNA Melt Peak Melt curve analysis of above amplification Standard Curve Standard curve generated using 20 million copies of template diluted 10-fold to 20 copies Page 2/4 PrimePCR™Assay Validation Report Products used to generate validation data Real-Time PCR Instrument CFX384 Real-Time PCR Detection System Reverse Transcription Reagent iScript™ Advanced cDNA Synthesis Kit for RT-qPCR Real-Time PCR Supermix SsoAdvanced™ SYBR® Green Supermix Experimental Sample qPCR Mouse Reference Total RNA Data Interpretation Unique Assay ID This is a unique identifier that can be used to identify the assay in the literature and online. Detected Coding Transcript(s) This is a list of the Ensembl transcript ID(s) that this assay will detect.
    [Show full text]
  • DEAH)/RNA Helicase a Helicases Sense Microbial DNA in Human Plasmacytoid Dendritic Cells
    Aspartate-glutamate-alanine-histidine box motif (DEAH)/RNA helicase A helicases sense microbial DNA in human plasmacytoid dendritic cells Taeil Kima, Shwetha Pazhoora, Musheng Baoa, Zhiqiang Zhanga, Shino Hanabuchia, Valeria Facchinettia, Laura Bovera, Joel Plumasb, Laurence Chaperotb, Jun Qinc, and Yong-Jun Liua,1 aDepartment of Immunology, Center for Cancer Immunology Research, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030; bDepartment of Research and Development, Etablissement Français du Sang Rhône-Alpes Grenoble, 38701 La Tronche, France; and cDepartment of Biochemistry, Baylor College of Medicine, Houston, TX 77030 Edited by Ralph M. Steinman, The Rockefeller University, New York, NY, and approved July 14, 2010 (received for review May 10, 2010) Toll-like receptor 9 (TLR9) senses microbial DNA and triggers type I Microbial nucleic acids, including their genomic DNA/RNA IFN responses in plasmacytoid dendritic cells (pDCs). Previous and replicating intermediates, work as strong PAMPs (13), so studies suggest the presence of myeloid differentiation primary finding PRR-sensing pathogenic nucleic acids and investigating response gene 88 (MyD88)-dependent DNA sensors other than their signaling pathway is of general interest. Cytosolic RNA is TLR9 in pDCs. Using MS, we investigated C-phosphate-G (CpG)- recognized by RLRs, including RIG-I, melanoma differentiation- binding proteins from human pDCs, pDC-cell lines, and interferon associated gene 5 (MDA5), and laboratory of genetics and physi- regulatory factor 7 (IRF7)-expressing B-cell lines. CpG-A selectively ology 2 (LGP2). RIG-I senses 5′-triphosphate dsRNA and ssRNA bound the aspartate-glutamate-any amino acid-aspartate/histi- or short dsRNA with blunt ends.
    [Show full text]
  • The DEAD Box RNA Helicase Ddx39a Is Essential for Myocyte and Lens
    bioRxiv preprint doi: https://doi.org/10.1101/209650; this version posted October 26, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. The DEAD box RNA helicase Ddx39a is essential for myocyte and lens development in zebrafish Linlin Zhang1, Beibei Li1, Yuxi Yang1, Ian C. Scott2, 3 and Xin Lou1 1Model Animal Research Center, Nanjing University, China. 2Program in Developmental and Stem Cell Biology, The Hospital for Sick Children; 3Department of Molecular Genetics, University of Toronto, Canada. * Correspondence should be addressed to Xin Lou, Model Animal Research Center, Nanjing University Address: Rm 403B, 12 Xuefu Road, Nanjing, Jiangsu, China Phone: +86-2558641547. e-mail: [email protected] Running title: Function of ddx39a in embryogenesis Keywords: RNA helicase, myocyte, lens, RNA splicing, zebrafish 1 bioRxiv preprint doi: https://doi.org/10.1101/209650; this version posted October 26, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Abstract RNA helicases from the DEAD-box family are found in almost all organisms and have important roles in RNA metabolism including RNA synthesis, processing and degradation. The function and mechanism of action of most of these helicases in animal development and human disease are largely unexplored.
    [Show full text]
  • Integrated Analysis of DEAD-Box Helicase 56: a Potential Oncogene in Osteosarcoma
    ORIGINAL RESEARCH published: 26 June 2020 doi: 10.3389/fbioe.2020.00588 Integrated Analysis of DEAD-Box Helicase 56: A Potential Oncogene in Osteosarcoma Chen Zhu 1†, Xianzuo Zhang 1*†, Nikolaos Kourkoumelis 2, Yong Shen 3,4* and Wei Huang 1 1 Division of Life Sciences and Medicine, Department of Orthopedics, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China, 2 Department of Medical Physics, School of Health Sciences, University of Ioannina, Ioannina, Greece, 3 Institute on Aging and Brain Disorders, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China, 4 Division of Life Sciences and Medicine, Neurodegenerative Disorder Research Center, University of Science and Technology of China, Hefei, China Background: Osteosarcoma is a solid tumor common in the musculoskeletal system. The DEAD-box helicase (DDX) families play an important role in tumor genesis and proliferation. Objective: To screen potential molecular targets in osteosarcoma and elucidate its Edited by: Bing Wang, relationship with DDX56. Anhui University of Technology, China Methods: We employed the Gene Expression Omnibus and The Cancer Genome Reviewed by: Atlas datasets for preliminary screening. DDX56 expression was measured by RT-qPCR Chun Hoi Yan, The University of Hong Kong, in three osteosarcoma cell lines. Biological roles of DDX56 were explored by Gene Hong Kong ontology, Kyoto Encyclopedia of Genes and Genomes and Ingenuity Pathway Analysis. Tao Cheng, TM Shanghai Jiao Tong University, China Cell proliferation, cycle, and apoptosis assays were performed using Lentivirus *Correspondence: knockdown technique. Xianzuo Zhang Results: It was found that DDX56 expression was regularly upregulated in osteosarcoma [email protected] Yong Shen tissue and cell lines, while DDX56 knockdown inhibited cell proliferation and promoted [email protected] cell apoptosis.
    [Show full text]
  • Mrna Export: Threading the Needle
    MINI REVIEW ARTICLE published: 22 March 2013 doi: 10.3389/fpls.2013.00059 mRNA export: threading the needle Ouassila Gaouar and Hugo Germain* Groupe de Recherche en Biologie Végétale, Département de Chimie et Physique, Université du Québec à Trois-Rivières,Trois-Rivières, QC, Canada Edited by: After mRNA biogenesis, several proteins interact with the messenger to ensure its Susana Rivas, Laboratoire des proper export to the cytoplasm. Some of these proteins will bind RNA early on, at the Interactions Plantes-Microorganismes; Centre onset of transcription by RNA polymerase II holoenzyme, while others will join later National de la Recherche Scientifique, for downstream processing steps, such as poly-adenylation or splicing, or may direct France mRNA ribonucleoprotein particle migration to the nucleopore. We recently discovered Reviewed by: that Arabidopsis plant knockout for the protein MOS11 (MODIFIER OFSNC1, 11) Kemal Kazan, Commonwealth partially suppresses autoimmune responses observed in the TNL-type [TIR/NBS/LRR Scientific and Industrial Research Organization, Australia (Toll-interleukin-like receptor/nucleotide-binding site/C-terminal leucine-rich repeat)] R gene Steven H. Spoel, University of gain-of-function variant snc1 (suppressor of npr1-1, constitutive 1). This suppression of Edinburgh, UK resistance to pathogens appears to be caused by a decrease in nuclear mRNA export Xin Li, University of British Columbia, in mos11-1 snc1 plants. In humans, the putative ortholog of MOS11, CIP29 (29-kDa Canada cytokine-induced protein), interacts with three proteins that are also involved in mRNA *Correspondence: Hugo Germain, Groupe de Recherche export: DDX39 (DEAD-box RNA helicase),TAF15 of the FUS family (FUSED IN SARCOMA), en Biologie Végétale, Département de and ALY (ALWAYS EARLY), a protein implicated in mRNA export in mammalian systems.
    [Show full text]
  • DDX39 As a Predictor of Clinical Prognosis and Immune Checkpoint
    DDX39 as a predictor of clinical prognosis and immune checkpoint therapy efficacy in patients with clear cell renal cell carcinoma Yewei Bao1†, Aimin Jiang1†, Kai Dong1†, Xinxin Gan2, Wenliang Gong1, Zhenjie Wu2, Bing Liu2 , Yi Bao2, Jie Wang1,2＊, Linhui Wang1＊ 1.Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China, 2.Department of Urology, Changzheng Hospital, Naval Medical University (Second Military Medical University), Shanghai, China. ＊ Correspondence: Jie Wang [email protected] , Linhui Wang [email protected] † These authors have contributed equally to this work and share first authorship Abstract: DEAD-box protein 39 (DDX39) has been demonstrated to be a tumorigenic gene in multiple tumor types, but its role in the progression and immune microenvironment of clear cell renal cell cancer (ccRCC) remains unclear. The aim of the present study was to investigate the role of DDX39 in the ccRCC tumor progression, immune microenvironment and efficacy of immune checkpoint therapy. The DDX39 expression level was first detected in tumors in the public data and then verified in ccRCC samples from Changzheng Hospital. The prognostic value of DDX39 expression was assessed in the Cancer Genome Atlas (TCGA) and ccRCC patients from Changhai Hospital. The role of DDX39 in promoting ccRCC was analyzed by bioinformatic analysis and in vitro experiments. The association between DDX39 expression and immune cell infiltration and immune inhibitory markers was analyzed, and its value in predicting the immune checkpoint therapy efficacy in ccRCC were evaluated in the public database. DDX39 expression was elevated in Oncomine, GEO and TCGA ccRCC databases, as well as in Changzheng ccRCC samples.
    [Show full text]