DOCSLIB.ORG

Long Non-Coding RNA CTBP1-AS2 Enhances Cervical Cancer

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Long Non-Coding RNA CTBP1-AS2 Enhances Cervical Cancer Yang et al. Cancer Cell Int (2020) 20:343 https://doi.org/10.1186/s12935-020-01430-5 Cancer Cell International PRIMARY RESEARCH Open Access Long non-coding RNA CTBP1-AS2 enhances cervical cancer progression via up-regulation of ZNF217 through sponging miR-3163 Shanshan Yang1†, Feng Shi2†, Yuting Du1, Zhao Wang1, Yue Feng1, Jiayu Song1, Yunduo Liu3* and Min Xiao4* Abstract Background: Long non-coding RNAs (lncRNAs) play signifcant roles in tumorigenesis and can contribute to identifcation of novel therapeutic targets for cancers. This paper was aimed at exploring the role of CTBP1 divergent transcript (CTBP1-AS2) in cervical cancer (CC) progression. Methods: qRT-PCR and western blot assays were used to detect relevant RNA and protein expressions. In vitro func- tional assays, including CCK8, EdU, TUNEL and transwell assays were applied to explore the functions of CTBP1-AS2 in CC cell proliferation, apoptosis and migration. In vivo animal study was utilized to investigate the role of CTBP1-AS2 in tumor growth. Luciferase reporter, RNA pull down and RIP assays were performed to determine the specifc mechani- cal relationship between CTBP1-AS2, miR-3163 and ZNF217. Results: CTBP1-AS2 was signifcantly overexpressed in CC cell lines. Knockdown of CTBP1-AS2 curbed cell prolifera- tion, migration and invasion, while stimulated cell apoptosis in vitro. CTBP1-AS2 facilitated xenograft tumor growth in vivo. Cytoplasmic CTBP1-AS2 was found to be a miR-3163 sponge in CC cells. MiR-3163 inhibition abolished the anti-tumor efects of CTBP1-AS2 knockdown. Additionally, Zinc fnger protein 217 (ZNF217) was identifed as a direct target of miR-3163. CTBP1-AS2 acted as a miR-3163 sponge to elevate ZNF217 expression. ZNF217 up-regulation abrogated the tumor suppressing efects of CTBP1-AS2 knockdown. Conclusion: CTBP1-AS2 regulates CC progression via sponging miR-3163 to up-regulate ZNF217. Keywords: CTBP1-AS2, miR-3163, ZNF217, Cervical cancer Background approximately 300,000 patients die of cervical cancer Cervical cancer (CC) is the fourth most common diag- worldwide [2]. Human papilloma virus (HPV) is the nosed cancer and the fourth leading cause of cancer- major cause for the high risk of CC. Based on cancer related deaths in females globally [1]. Each year, more statistics in 2019, there were 13,170 estimated new than 500,000 cervical cancer cases are diagnosed and cases and 4250 estimated deaths in the United States [3]. Recently, an increasing trend of morbidity and mortality of CC has been discovered in China [4, 5]. *Correspondence: [email protected]; [email protected] Global strategies for the prevention and screening of † Shanshan Yang and Feng Shi are co-frst authors CC remain to be improved based on various geographic 3 Department of Gynecological Oncology, Harbin Medical University Cancer Hospital, No. 150 Haping Road, Nangang District, Harbin 150081, settings and health systems [6]. Preclinical models have Heilongjiang, China been used for the treatment of CC patients [7]. At pre- 4 Department of Breast Surgery, Harbin Medical University Cancer sent, radiotherapy chemotherapy and surgery remain Hospital, No. 150 Haping Road, Nangang District, Harbin 150081, Heilongjiang, China the main clinical therapeutic methods for patients Full list of author information is available at the end of the article with CC [8–10]. Terefore, it is essential to explore the © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Yang et al. Cancer Cell Int (2020) 20:343 Page 2 of 13 molecular mechanisms behind the initiation and devel- Materials and methods opment of CC. Tissue samples Long non-coding RNAs (lncRNAs) are a class of Tis study was executed between 2014 and 2019, with RNAs longer than 200 nucleotides but lack the pro- the ethical approval from the Ethics Committee of tein-coding potential. Recent fndings indicated that Harbin Medical University Cancer Hospital. Patients lncRNAs play vital roles in gene regulation at the tran- without Human papillomavirus (HPV) infection were scriptional level [11]. Dysregulation of lncRNAs is excluded from this study. All 72 participants had signed associated with a series of biological processes, such the written informed consent. Highly sensitive poly- as cell proliferation, apoptosis, invasion and migration merase chain reaction (PCR) techniques were used to [12–14]. Furthermore, lncRNAs have been identifed detect the HPV. Te number of patients infected with as novel biomarkers of many cancers [15, 16]. To date, HPV-18, HPV-11, HPV-45 and HPV-68 were separately the pathologic roles of most lncRNAs remain unknown, 25, 19, 15, 13. Te 72 CC samples and adjacent normal which indicates the extensive potential of lncRNAs in samples from CC patients were collected and instantly the prediction and treatment of various cancers. maintained in the liquid nitrogen at − 80 °C. In CC, some lncRNAs were discovered to be aber- rantly expressed and exerted important biological func- Cell lines tions. For instance, linc00511 is highly expressed in CC Human cervical cancer cell lines, including SiHa (HPV and knockdown of linc00511 dampens CC cell prolif- positive), HeLa (HPV positive), MS751 (HPV positive) eration and reduces drug resistance to paclitaxel [17]. and C33A (HPV negative) as well as the normal cervi- CTBP1 divergent transcript (CTBP1-AS2), as a newly cal epithelial cells (H8) were purchased from Shanghai identifed lncRNA, was limitedly reported in cancers. Institute of Cell Biology (Shanghai, China), cultured Te only report on the role of CTBP1-AS2 in cancer routinely in RPMI-1640 medium (Invitrogen, Carls- is that CTBP1-AS2 predicts unfavorable prognosis of bad, CA, USA) at 37 °C with 5% CO 2. 10% fetal bovine papillary thyroid cancer [18]. However, the biological serum (FBS; Termo Fisher Scientifc, Waltham, MA, role of CTBP1-AS2 in the carcinogenesis and develop- USA) and antibiotics were applied to supplement the ment of CC has not been studied yet. culture medium. MicroRNAs (miRNAs) are small ncRNAs with a size between 20 and 25 nt. Based on previous studies, miR- Extraction of total RNA and qRT‑PCR NAs can exert various functions in human cancers. Total RNA was extracted from HeLa and SiHa cells For instance, anti-miR-203 suppresses cell growth and using 1 mL of TRIzol (Invitrogen) and reversely tran- stemness in ER-positive breast cancer via targeting scribed into cDNA using PrimeScript RT reagent Kit SOCS3 [19]. MiR-17-5p and miR-20a-5p inhibit hepa- (Takara, Kyoto, Japan) or miRNA reverse transcrip- tocellular carcinoma metastasis [20]. MiR-17 acts as an tion PCR kit (Ribobio; Guangzhou, China). Te relative oncogene in hepatocellular carcinoma through down- gene expression level was measured by SYBR Green regulation of Smad3 [21]. It has been reported that PCR Master Mix (Invitrogen) or SYBR ® PrimeScript® miR-3163 targets ADAM-17 and inhibits the Notch miRNA RT-PCR Kit (Takara), and Step-One Plus Real- pathway to enhance the sensitivity of HCC cells to anti- Time PCR System (Applied Biosystems, Foster City, tumor agents in hepatocellular carcinoma [22]. MiR- CA, USA), and quantifed by the comparative 2−ΔΔCt 3163 promotes colorectal cancer cell growth in vivo method. GAPDH mRNA or U6 snRNA served as the [23]. Tis study was aimed to explore the interaction endogenous control. Te sequences of PCR primers between CTBP1-AS2 and miR-3163. were provided in Additional fle 1: Table S1. Zinc fnger protein 217 (ZNF217) is protein-cod- ing gene contributing to the tumorigenesis of various Cell transfection human cancers. Te coordination between ZNF217 and When the cell density was about 70%, cell transfec- LSD1 facilitates hepatocellular carcinoma progression tion was performed in 24-well plates with CO at 37 °C [24]. ZNF217 is targeted by miR-211-3p and reverses 2 for 48 h utilizing Lipofectamine 2000 (Invitrogen). the efects of miR-211-3p on proliferative and migra- Te duplicate short hairpin RNAs for CTBP1-AS2, tory potentials of non-small cell lung cancer cells [25]. ZNF217 (sh-CTBP1-AS2#1/2, sh-ZNF217#1/2), plas- To summarize, the current study focused on investi- mid pcDNA3.1/ZNF217 were designed by Genepharm gating the role of CTBP1-AS2/miR-3163/ZNF217 axis (Shanghai, China), as well as their relative negative con- in the biological behaviors of HPV-positive cells. trol RNA (sh-Ctrl, pcDNA3.1). MiR-3163 mimics and NC mimics, miR-3163 inhibitor and NC inhibitor were Yang et al. Cancer Cell Int (2020) 20:343 Page 3 of 13 also produced by Genepharm. Relevant sequences were HRP-tagged secondary antibodies (all from Abcam, provided in Additional fle 1: Table S1. Cambridge, MA, USA). GAPDH served as internal con- trol. Samples were analyzed by enhanced chemilumines- Cell counting kit‑8 (CCK‑8) cence reagent (Santa Cruz Biotechnology, Santa Cruz, HeLa or SiHa cells were planted into 96-well plates at CA, USA).
Load more

Recommended publications
  • A Pathogenic Ctbp1 Missense Mutation Causes Altered Cofactor Binding and Transcriptional Activity
    neurogenetics (2019) 20:129–143 https://doi.org/10.1007/s10048-019-00578-1 ORIGINAL ARTICLE A pathogenic CtBP1 missense mutation causes altered cofactor binding and transcriptional activity David B. Beck1 & T. Subramanian2 & S. Vijayalingam2 & Uthayashankar R. Ezekiel3 & Sandra Donkervoort4 & Michele L. Yang5 & Holly A. Dubbs6 & Xilma R. Ortiz-Gonzalez7 & Shenela Lakhani8 & Devorah Segal9 & Margaret Au10 & John M. Graham Jr10 & Sumit Verma11 & Darrel Waggoner12 & Marwan Shinawi13 & Carsten G. Bönnemann4 & Wendy K. Chung14 & G. Chinnadurai2 Received: 23 October 2018 /Revised: 18 March 2019 /Accepted: 9 April 2019 /Published online: 30 April 2019 # Springer-Verlag GmbH Germany, part of Springer Nature 2019 Abstract We previously reported a pathogenic de novo p.R342W mutation in the transcriptional corepressor CTBP1 in four independent patients with neurodevelopmental disabilities [1]. Here, we report the clinical phenotypes of seven additional individuals with the same recurrent de novo CTBP1 mutation. Within this cohort, we identified consistent CtBP1-related phenotypes of intellectual disability, ataxia, hypotonia, and tooth enamel defects present in most patients. The R342W mutation in CtBP1 is located within a region implicated in a high affinity-binding cleft for CtBP-interacting proteins. Unbiased proteomic analysis demonstrated reduced interaction of several chromatin-modifying factors with the CtBP1 W342 mutant. Genome-wide transcriptome analysis in human glioblastoma cell lines expressing -CtBP1 R342 (wt) or W342 mutation revealed changes in the expression profiles of genes controlling multiple cellular processes. Patient-derived dermal fibroblasts were found to be more sensitive to apoptosis during acute glucose deprivation compared to controls. Glucose deprivation strongly activated the BH3-only pro-apoptotic gene NOXA, suggesting a link between enhanced cell death and NOXA expression in patient fibroblasts.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Cellular and Molecular Signatures in the Disease Tissue of Early
    Cellular and Molecular Signatures in the Disease Tissue of Early Rheumatoid Arthritis Stratify Clinical Response to csDMARD-Therapy and Predict Radiographic Progression Frances Humby1,* Myles Lewis1,* Nandhini Ramamoorthi2, Jason Hackney3, Michael Barnes1, Michele Bombardieri1, Francesca Setiadi2, Stephen Kelly1, Fabiola Bene1, Maria di Cicco1, Sudeh Riahi1, Vidalba Rocher-Ros1, Nora Ng1, Ilias Lazorou1, Rebecca E. Hands1, Desiree van der Heijde4, Robert Landewé5, Annette van der Helm-van Mil4, Alberto Cauli6, Iain B. McInnes7, Christopher D. Buckley8, Ernest Choy9, Peter Taylor10, Michael J. Townsend2 & Costantino Pitzalis1 1Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. Departments of 2Biomarker Discovery OMNI, 3Bioinformatics and Computational Biology, Genentech Research and Early Development, South San Francisco, California 94080 USA 4Department of Rheumatology, Leiden University Medical Center, The Netherlands 5Department of Clinical Immunology & Rheumatology, Amsterdam Rheumatology & Immunology Center, Amsterdam, The Netherlands 6Rheumatology Unit, Department of Medical Sciences, Policlinico of the University of Cagliari, Cagliari, Italy 7Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK 8Rheumatology Research Group, Institute of Inflammation and Ageing (IIA), University of Birmingham, Birmingham B15 2WB, UK 9Institute of
    [Show full text]
  • A Mechanism of COOH–Terminal Binding Protein– Mediated Repression
    A Mechanism of COOH–Terminal Binding Protein– Mediated Repression Alison R. Meloni,1 Chun-Hsiang Lai,2 Tso-Pang Yao,2 and Joseph R. Nevins1,3 Departments of 1Molecular Genetics and Microbiology and 2Pharmacology and Cancer Biology and 3Duke Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, North Carolina Abstract repression involves the recruitment of histone deacetylase The E2F4 and E2F5 proteins specifically associate with (HDAC) to E2F site–containing promoters, presumably the Rb-related p130 protein in quiescent cells to repress resulting in an alteration of chromatin conformation that transcription of various genes encoding proteins hinders transcription (7-9). important for cell growth. A series of reports has Several observations suggest that additional events, inde- provided evidence that Rb-mediated repression involves pendent of HDAC recruitment, may contribute to the both histone deacetylase (HDAC)–dependent and repression. For example, many genes subject to E2F/Rb- HDAC-independent events. Our previous results mediated repression are not derepressed by treatment with the suggest that one such mechanism for Rb-mediated HDAC inhibitor trichostatin A (7). Moreover, Rb mutants that repression, independent of recruitment of HDAC, can no longer interact with HDAC are still capable of repressing involves the recruitment of the COOH-terminal binding transcription (10, 11). Based on these observations, it would protein (CtBP) corepressor, a protein now recognized to seem that HDAC-independent mechanisms of transcriptional play a widespread role in transcriptional repression. We repression contribute to the Rb control of transcription. Indeed, now find that CtBP can interact with the histone several Rb-interacting proteins, such as the chromatin remodel- acetyltransferase, cyclic AMP–responsive element– ing complex proteins BRG1 and human BRM, the methyl- binding protein (CREB) binding protein, and inhibit its transferase protein SUV39H1, and RBP1, have been shown to ability to acetylate histone.
    [Show full text]
  • Supp Table 6.Pdf
    Supplementary Table 6. Processes associated to the 2037 SCL candidate target genes ID Symbol Entrez Gene Name Process NM_178114 AMIGO2 adhesion molecule with Ig-like domain 2 adhesion NM_033474 ARVCF armadillo repeat gene deletes in velocardiofacial syndrome adhesion NM_027060 BTBD9 BTB (POZ) domain containing 9 adhesion NM_001039149 CD226 CD226 molecule adhesion NM_010581 CD47 CD47 molecule adhesion NM_023370 CDH23 cadherin-like 23 adhesion NM_207298 CERCAM cerebral endothelial cell adhesion molecule adhesion NM_021719 CLDN15 claudin 15 adhesion NM_009902 CLDN3 claudin 3 adhesion NM_008779 CNTN3 contactin 3 (plasmacytoma associated) adhesion NM_015734 COL5A1 collagen, type V, alpha 1 adhesion NM_007803 CTTN cortactin adhesion NM_009142 CX3CL1 chemokine (C-X3-C motif) ligand 1 adhesion NM_031174 DSCAM Down syndrome cell adhesion molecule adhesion NM_145158 EMILIN2 elastin microfibril interfacer 2 adhesion NM_001081286 FAT1 FAT tumor suppressor homolog 1 (Drosophila) adhesion NM_001080814 FAT3 FAT tumor suppressor homolog 3 (Drosophila) adhesion NM_153795 FERMT3 fermitin family homolog 3 (Drosophila) adhesion NM_010494 ICAM2 intercellular adhesion molecule 2 adhesion NM_023892 ICAM4 (includes EG:3386) intercellular adhesion molecule 4 (Landsteiner-Wiener blood group)adhesion NM_001001979 MEGF10 multiple EGF-like-domains 10 adhesion NM_172522 MEGF11 multiple EGF-like-domains 11 adhesion NM_010739 MUC13 mucin 13, cell surface associated adhesion NM_013610 NINJ1 ninjurin 1 adhesion NM_016718 NINJ2 ninjurin 2 adhesion NM_172932 NLGN3 neuroligin
    [Show full text]
  • The Leukemia-Associated Transcription Repressor AML1/MDS1/EVI1 Requires Ctbp to Induce Abnormal Growth and Di€Erentiation of Mu
    Oncogene (2002) 21, 3232 ± 3240 ã 2002 Nature Publishing Group All rights reserved 0950 ± 9232/02 $25.00 www.nature.com/onc The leukemia-associated transcription repressor AML1/MDS1/EVI1 requires CtBP to induce abnormal growth and dierentiation of murine hematopoietic cells Vitalyi Senyuk1, Soumen Chakraborty1, Fady M Mikhail1,2, Rui Zhao1, Yiqing Chi1 and Giuseppina Nucifora*,1 1Department of Pathology and The Cancer Center, University of Illinois at Chicago, Chicago, Illinois, USA; 2Clinical Pathology Department, Faculty of Medicine, University of Alexandria, Alexandria, Egypt The leukemia-associated fusion gene AML1/MDS1/ (ME) genes, is a product of the (3;21)(q26;q22) EVI1 (AME) encodes a chimeric transcription factor translocation that is associated with de novo and that results from the (3;21)(q26;q22) translocation. This therapy-related myelodysplastic syndrome/acute mye- translocation is observed in patients with therapy-related loid leukemia (t-MDS/AML) patients, and to a lesser myelodysplastic syndrome (MDS), with chronic myelo- extent with chronic myelogenous leukemia (CML) genous leukemia during the blast crisis (CML-BC), and patients during the blast crisis of their disease (Rubin with de novo or therapy-related acute myeloid leukemia et al., 1990; Nucifora et al., 1993). The AML1 gene (AML). AME is obtained by in-frame fusion of the (also known as CBFA2, PEBP2 or RUNX1) encodes AML1 and MDS1/EVI1 genes. We have previously the DNA-binding subunit of the core-binding tran- shown that AME is a transcriptional repressor that scription factor (CBF). AML1 interacts with the other induces leukemia in mice. In order to elucidate the role subunit of CBF, CBFb, which has no DNA-binding of AME in leukemic transformation, we investigated the domain.
    [Show full text]
  • Transcriptional and Epigenetic Control of Brown and Beige Adipose Cell Fate and Function
    REVIEWS Transcriptional and epigenetic control of brown and beige adipose cell fate and function Takeshi Inagaki1,2, Juro Sakai1,2 and Shingo Kajimura3 Abstract | White adipocytes store excess energy in the form of triglycerides, whereas brown and beige adipocytes dissipate energy in the form of heat. This thermogenic function relies on the activation of brown and beige adipocyte-specific gene programmes that are coordinately regulated by adipose-selective chromatin architectures and by a set of unique transcriptional and epigenetic regulators. A number of transcriptional and epigenetic regulators are also required for promoting beige adipocyte biogenesis in response to various environmental stimuli. A better understanding of the molecular mechanisms governing the generation and function of brown and beige adipocytes is necessary to allow us to control adipose cell fate and stimulate thermogenesis. This may provide a therapeutic approach for the treatment of obesity and obesity-associated diseases, such as type 2 diabetes. Interscapular BAT Adipose tissue has a central role in whole-body energy subjects who had previously lacked detectable BAT Brown adipose tissue (BAT) is a homeostasis. White adipose tissue (WAT) is the major depots before cold exposure, presumably owing to the specialized organ that adipose organ in mammals. It represents 10% or more emergence of new thermogenic adipocytes. This, then, produces heat. BAT is localized of the body weight of healthy adult humans and is leads to an increase in non-shivering thermogenesis in the interscapular and 6–9 perirenal regions of rodents specialized for the storage of excess energy. Humans and/or an improvement in insulin sensitivity . These and infants.
    [Show full text]
  • Overview of Research on Fusion Genes in Prostate Cancer
    2011 Review Article Overview of research on fusion genes in prostate cancer Chunjiao Song1,2, Huan Chen3 1Medical Research Center, Shaoxing People’s Hospital, Shaoxing University School of Medicine, Shaoxing 312000, China; 2Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing 312000, China; 3Key Laboratory of Microorganism Technology and Bioinformatics Research of Zhejiang Province, Zhejiang Institute of Microbiology, Hangzhou 310000, China Contributions: (I) Conception and design: C Song; (II) Administrative support: Shaoxing Municipal Health and Family Planning Science and Technology Innovation Project (2017CX004) and Shaoxing Public Welfare Applied Research Project (2018C30058); (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: C Song; (V) Data analysis and interpretation: H Chen; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Chunjiao Song. No. 568 Zhongxing Bei Road, Shaoxing 312000, China. Email: [email protected]. Abstract: Fusion genes are known to drive and promote carcinogenesis and cancer progression. In recent years, the rapid development of biotechnologies has led to the discovery of a large number of fusion genes in prostate cancer specimens. To further investigate them, we summarized the fusion genes. We searched related articles in PubMed, CNKI (Chinese National Knowledge Infrastructure) and other databases, and the data of 92 literatures were summarized after preliminary screening. In this review, we summarized approximated 400 fusion genes since the first specific fusion TMPRSS2-ERG was discovered in prostate cancer in 2005. Some of these are prostate cancer specific, some are high-frequency in the prostate cancer of a certain ethnic group. This is a summary of scientific research in related fields and suggests that some fusion genes may become biomarkers or the targets for individualized therapies.
    [Show full text]
  • Novel Mechanisms of Transcriptional Regulation by Leukemia Fusion Proteins
    Novel mechanisms of transcriptional regulation by leukemia fusion proteins A dissertation submitted to the Graduate School of the University of Cincinnati in partial fulfillment of the requirement for the degree of Doctor of Philosophy in the Department of Cancer and Cell Biology of the College of Medicine by Chien-Hung Gow M.S. Columbia University, New York M.D. Our Lady of Fatima University B.S. National Yang Ming University Dissertation Committee: Jinsong Zhang, Ph.D. Robert Brackenbury, Ph.D. Sohaib Khan, Ph.D. (Chair) Peter Stambrook, Ph.D. Song-Tao Liu, Ph.D. ABSTRACT Transcription factors and chromatin structure are master regulators of homeostasis during hematopoiesis. Regulatory genes for each stage of hematopoiesis are activated or silenced in a precise, finely tuned manner. Many leukemia fusion proteins are produced by chromosomal translocations that interrupt important transcription factors and disrupt these regulatory processes. Leukemia fusion proteins E2A-Pbx1 and AML1-ETO involve normal function transcription factor E2A, resulting in two distinct types of leukemia: E2A-Pbx1 t(1;19) acute lymphoblastic leukemia (ALL) and AML1-ETO t(8;21) acute myeloid leukemia (AML). E2A, a member of the E-protein family of transcription factors, is a key regulator in hematopoiesis that recruits coactivators or corepressors in a mutually exclusive fashion to regulate its direct target genes. In t(1;19) ALL, the E2A portion of E2A-Pbx1 mediates a robust transcriptional activation; however, the transcriptional activity of wild-type E2A is silenced by high levels of corepressors, such as the AML1-ETO fusion protein in t(8;21) AML and ETO-2 in hematopoietic cells.
    [Show full text]
  • Identification of Genomic Targets of Krüppel-Like Factor 9 in Mouse Hippocampal
    Identification of Genomic Targets of Krüppel-like Factor 9 in Mouse Hippocampal Neurons: Evidence for a role in modulating peripheral circadian clocks by Joseph R. Knoedler A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Neuroscience) in the University of Michigan 2016 Doctoral Committee: Professor Robert J. Denver, Chair Professor Daniel Goldman Professor Diane Robins Professor Audrey Seasholtz Associate Professor Bing Ye ©Joseph R. Knoedler All Rights Reserved 2016 To my parents, who never once questioned my decision to become the other kind of doctor, And to Lucy, who has pushed me to be a better person from day one. ii Acknowledgements I have a huge number of people to thank for having made it to this point, so in no particular order: -I would like to thank my adviser, Dr. Robert J. Denver, for his guidance, encouragement, and patience over the last seven years; his mentorship has been indispensable for my growth as a scientist -I would also like to thank my committee members, Drs. Audrey Seasholtz, Dan Goldman, Diane Robins and Bing Ye, for their constructive feedback and their willingness to meet in a frequently cold, windowless room across campus from where they work -I am hugely indebted to Pia Bagamasbad and Yasuhiro Kyono for teaching me almost everything I know about molecular biology and bioinformatics, and to Arasakumar Subramani for his tireless work during the home stretch to my dissertation -I am grateful for the Neuroscience Program leadership and staff, in particular
    [Show full text]
  • Ctbp1/2 Differentially Regulate Genomic Stability and DNA Repair
    Oncogenesis www.nature.com/oncsis ARTICLE OPEN CtBP1/2 differentially regulate genomic stability and DNA repair pathway in high-grade serous ovarian cancer cell ✉ YingYing He 1, Zhicheng He 2,3, Jian Lin 2,3, Cheng Chen2,3, Yuanzhi Chen 2,3 and Shubai Liu 2,3 © The Author(s) 2021 The C-terminal binding proteins (CtBPs), CtBP1 and CtBP2, are transcriptional co-repressor that interacts with multiple transcriptional factors to modulate the stability of chromatin. CtBP proteins were identified with overexpression in the high-grade serous ovarian carcinoma (HGSOC). However, little is known about CtBP proteins’ regulatory roles in genomic stability and DNA repair in HGSOC. In this study, we combined whole-transcriptome analysis with multiple research methods to investigate the role of CtBP1/2 in genomic stability. Several key functional pathways were significantly enriched through whole transcription profile analysis of CtBP1/2 knockdown SKOV3 cells, including DNA damage repair, apoptosis, and cell cycle. CtBP1/2 knockdown induced cancer cell apoptosis, increased genetic instability, and enhanced the sensitivity to DNA damage agents, such as γ-irradiation and chemotherapy drug (Carboplatin and etoposide). The results of DNA fiber assay revealed that CtBP1/2 contribute differentially to the integrity of DNA replication track and stability of DNA replication recovery. CtBP1 protects the integrity of stalled forks under metabolic stress condition during prolonged periods of replication, whereas CtBP2 acts a dominant role in stability of DNA replication recovery. Furthermore, CtBP1/2 knockdown shifted the DSBs repair pathway from homologous recombination (HR) to non-homologous end joining (NHEJ) and activated DNA-PK in SKOV3 cells.
    [Show full text]
  • A Role for Mediator Complex Subunit MED13L in Rb&Sol;E2F-Induced
    Oncogene (2012) 31, 4709 --4717 & 2012 Macmillan Publishers Limited All rights reserved 0950-9232/12 www.nature.com/onc ORIGINAL ARTICLE A role for Mediator complex subunit MED13L in Rb/E2F-induced growth arrest SP Angus and JR Nevins The Rb/E2F pathway is deregulated in virtually all human tumors. It is clear that, in addition to Rb itself, essential cofactors required for transcriptional repression and silencing of E2F target genes are mutated or lost in cancer. To identify novel cofactors required for Rb/E2F-mediated inhibition of cell proliferation, we performed a genome-wide short hairpin RNA screen. In addition to several known Rb cofactors, the screen identified components of the Mediator complex, a large multiprotein coactivator required for RNA polymerase II transcription. We show that the Mediator complex subunit MED13L is required for Rb/E2F control of cell growth, the complete repression of cell cycle target genes, and cell cycle inhibition. Oncogene (2012) 31, 4709--4717; doi:10.1038/onc.2011.622; published online 16 January 2012 Keywords: tumor suppressor; cell cycle; senescence INTRODUCTION Typically, the levels of CDKN2A are greatly increased, leading to The retinoblastoma tumor suppressor (Rb) is a critical negative the accumulation of active, hypophosphorylated Rb. Senescent regulator of cellular proliferation that is frequently inactivated in cells characteristically exhibit flat-cell morphology and are positive 20 human cancer.1,2 In its active form, Rb binds to the members of for senescence-associated beta-galactosidase (SA-b-gal) activity. 21 the E2F family of transcription factors and either suppresses their Additionally, Narita et al. described the formation of senescence- transactivation function or assembles an active repressor com- associated heterochromatic foci at E2F promoters during V12 plex.3 E2F family members are essential regulators of genes Ras -induced senescence.
    [Show full text]