DOCSLIB.ORG

KRAS/NF-Kb/YY1/Mir-489 Signaling Axis Controls Pancreatic Cancer

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
KRAS/NF-Kb/YY1/Mir-489 Signaling Axis Controls Pancreatic Cancer Published OnlineFirst October 28, 2016; DOI: 10.1158/0008-5472.CAN-16-1898 Cancer Molecular and Cellular Pathobiology Research KRAS/NF-kB/YY1/miR-489 Signaling Axis Controls Pancreatic Cancer Metastasis Peng Yuan1,2, Xiao-Hong He1,2, Ye-Fei Rong3, Jing Cao4, Yong Li5, Yun-Ping Hu6, Yingbin Liu6, Dangsheng Li7, Wenhui Lou3, and Mo-Fang Liu1,2,4 Abstract KRAS activation occurring in more than 90% of pancreatic inhibited migration and metastasis by targeting the extracellular ductal adenocarcinomas (PDAC) drives progression and metas- matrix factors ADAM9 and MMP7. miR-489 downregulation tasis, but the underlying mechanisms involved in these processes elevated levels of ADAM9 and MMP7, thereby enhancing are still poorly understood. Here, we show how KRAS acts through the migration and metastasis of PDAC cells. Together, our inflammatory NF-kB signaling to activate the transcription factor results establish a pivotal mechanism of PDAC metastasis and YY1, which represses expression of the tumor suppressor gene suggest miR-489 as a candidate therapeutic target for their attack. miR-489. In PDAC cells, repression of miR-489 by KRAS signaling Cancer Res; 77(1); 100–11. Ó2016 AACR. KRAS in pancreatic tumors, the most common of which is Introduction G12D KRAS (4). Mounting evidence indicates that such onco- Pancreatic cancer (PDAC) is one of the most lethal malignant genic mutations play critical roles in both the initiation and the tumors, with a 5-year survival rate less than 8% from 2005 to 2011 progression of pancreatic cancer via persistent activation of in United States (1). To date, lack of effective screening tool to KRAS signaling pathways (5). Sustained KRAS signaling leads detect asymptomatic premalignant or early-stage cancer results in to the activation of inflammatory signaling pathways that play the diagnosis of majority patients at their advanced stages. More critical roles in regulating the initiation of pancreatic intrae- than 90% of the patients with PDAC show distal metastasis at pithelial neoplasia (PanIN) and the progression of PDAC advanced stage, which is the major cause of mortality (2). Thus, (6, 7). Of note, NF-kB signaling, a major pathway that connects effective therapeutic interventions to stop PDAC metastasis are inflammation with cancers, is activated by KRAS signaling and urgently needed. However, our ability to design effective thera- has been shown to promote pancreatic cancer progression in peutic interventions aiming to stop PDAC metastasis is limited animal models (8–10). However, the downstream targets of because of our poor understanding of the molecular mechanisms NF-kB signaling that are directly involved in pancreatic cancer underlying pancreatic cancer metastasis (3). progression and metastasis still need to be defined. One prominent feature of PDAC is the high frequency microRNAs (miRNA) are a class of small, noncoding RNAs that (>90%) of KRAS mutations that generate oncogenic forms of negatively regulate protein-coding genes at the posttranscription- 1Center for RNA Research, State Key Laboratory of Molecular Biology–University al level and are involved in virtually all types of carcinogenesis of Chinese Academy of Sciences, CAS Center for Excellence in Molecular Cell (11). In particular, a number of miRNAs have been found to be Science, Shanghai, China. 2Shanghai Key Laboratory of Molecular Andrology, dysregulated in PDAC and involved in PDAC carcinogenesis (12). Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Nevertheless, how these miRNAs are dysregulated in PDAC and Sciences, Chinese Academy of Sciences, Shanghai, China. 3Department of how they interact with key regulatory signaling molecules in Pancreatic Surgery, Zhong Shan Hospital, Shanghai, China. 4School of Life Science and Technology, Shanghai Tech University, Shanghai, China. 5Depart- pancreatic cancer initiation and progression are questions that ment of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, still remain largely unanswered. Most importantly, despite the Ohio. 6Department of General Surgery, Xinhua Hospital Affiliated to Shanghai well-established role of oncogenic KRAS in PDAC, how KRAS Jiao Tong University School of Medicine, Shanghai, China. 7Shanghai Information signaling engages miRNAs to drive pancreatic cancer metastasis Center for Life Sciences, Shanghai Institutes for Biological Sciences, Chinese remains unknown. Academy of Sciences, Shanghai, China. In our attempt to identify important miRNAs involved in Note: Supplementary data for this article are available at Cancer Research pancreatic carcinogenesis, we identified KRAS signaling– Online (http://cancerres.aacrjournals.org/). repressed miR-489 as part of an important mechanism under- Corrected online September 16, 2020. pinning oncogenic KRAS-induced PDAC migration and metasta- P. Yuan, X.-H. He, and Y.-F. Rong contributed equally to this article. sis. Oncogenic KRAS signaling activates NF-kB, leading to Corresponding Authors: Mo-Fang Liu, Institute of Biochemistry and Cell enhanced expression of YY1, the transcription factor that directly MIR489 Biology, Shanghai Institutes for Biological Sciences, the Chinese Academy of suppresses transcription. Our results showed that miR- Sciences, 320 Yueyang Road, Shanghai 200031, China. Phone: 86-21- 489 decreases the migration of PDAC cells in cell cultures and 54921146; Fax: 86-21-54921011; E-mail: mfl[email protected]; and Wenhui Lou, inhibits lung and liver metastatic colonization of PDAC cells in Department of Pancreatic Surgery, Zhong Shan Hospital, 180 Fenglin Road, mice but contributes little to cell proliferation and anchorage- Shanghai 200032, China. Phone: 86-18-616881868; Fax: 86-21-64043947; independent growth. Mechanistically, we identified 2 metallo- E-mail: [email protected] proteinase genes, ADAM9 and MMP7, as novel targets of miR-489 doi: 10.1158/0008-5472.CAN-16-1898 that mediate its antimetastatic effect in these cells. Collectively, Ó2016 American Association for Cancer Research. our findings not only provide new mechanistic insights into how 100 Cancer Res; 77(1) January 1, 2017 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst October 28, 2016; DOI: 10.1158/0008-5472.CAN-16-1898 MIR489 Is a Key Regulator for PDAC Metastasis oncogenic KRAS-induced inflammatory signaling promotes pore size inserts, 3422; Corning) in the Transwell assays according PDAC metastasis but also indicate that miR-489 is a robust to the manufacturer's instructions. The nonmigrating cells were inhibitor of metastasis and a potential therapeutic target for detached, and the migrating cells were stained with 40,6-diamidio- treating PDAC. 2-phenylindole (DAPI) and counted after 24 hours using a fluorescence microscope. All fields were selected in a blind Materials and Methods manner. Cell lines Three-dimensional cell culture assay The human PDAC cell lines BxPC-3 and PANC-1 cells were The 3D cell culture assay was performed as recently described obtained from ATCC (May, 2011) and cultured according to their (17). Transfected and viable cancer cells (1,000) in culture medi- guidelines. All the cell lines were mycoplasma-free and recently um containing 2% Matrigel were seeded on the solidified 100% authenticated by cellular morphology and the STR analysis at Ji- Matrigel-precoated chamber (177402; Nunc). The sphere mor- Ying Inc. (January 2014 and May 2016) according to the guide- phology was observed with a microscope after 19 days. lines from ATCC (13). The 2 cell lines stably expressing luciferase (PANC-1-luc and BxPC-3-luc) were generated from their parental cell lines as previously reported (14). Xenograft assays in mice NOD/SCID mice were purchased from SLAC Corporation and were housed under standard housing conditions at the animal Antibodies and reagents facilities in the Institute of Biochemistry and Cell Biology, Shang- The antibodies used in this study included: anti-KRAS (60309- hai Institutes for Biological Sciences, Chinese Academy of 1; Proteintech), anti-PCNA (#2586; Cell Signaling Technology), Sciences. The lung and liver metastasis assay was performed as anti-YY1 (ab38422; Abcam), anti-ETS-1 (sc-350; Santa Cruz Bio- described previously (14, 18). PANC-1-luc cells (4 Â 104)or technology), anti-p65 (10745-1-AP, Proteintech), anti-ADAM9 BxPC-3-luc cells (1 Â 105) in 100 mL Dulbecco PBS (D-PBS) were (ab186833, Abcam), anti-MMP7 (10374-2-AP, Proteintech), injected into 6- to 8-week NOD/SCID mice through the tail vein (n anti-b-actin (A3854; Sigma-Aldrich), anti-mouse secondary anti- ¼ 5–6), and the luciferase activity in lungs was analyzed 50 days body (A9044, Sigma-Aldrich), and anti-rabbit secondary anti- later. PANC-1-luc cells (1 Â 105) orBxPC-3-luc cells (5 Â 105)in body (A9169, Sigma-Aldrich). These antibodies were diluted 50 mL D-PBS were injected into the spleens of 6- to 8-week-old according to the manufacturers' instructions. The NF-kB signaling NOD/SCID mice (n ¼ 4–5), and the tumor numbers in livers were inhibitor BAY 11-7082 (S2913; Selleck) was first diluted in cancer analyzed 60 days later. For bioluminescence imaging, mice were cell culture medium and then used as in previous studies with given luciferin 5 minutes before imaging and were then anesthe- some modifications (i.e., incubation at 5 mmol/L for 24 hours; tized (3% isoflurane). Luminescence imaging was performed and ref. 15). The sequences of chemically synthesized DNA and RNA analyzed using the Xenogen IVIS
Load more

Recommended publications
  • TGF-Β1 Signaling Targets Metastasis-Associated Protein 1, a New Effector in Epithelial Cells
    Oncogene (2011) 30, 2230–2241 & 2011 Macmillan Publishers Limited All rights reserved 0950-9232/11 www.nature.com/onc ORIGINAL ARTICLE TGF-b1 signaling targets metastasis-associated protein 1, a new effector in epithelial cells SB Pakala1, K Singh1,3, SDN Reddy1, K Ohshiro1, D-Q Li1, L Mishra2 and R Kumar1 1Department of Biochemistry and Molecular Biology and Institute of Coregulator Biology, The George Washington University Medical Center, Washington, DC, USA and 2Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA In spite of a large number of transforming growth factor b1 gene chromatin in response to upstream signals. The (TGF-b1)-regulated genes, the nature of its targets with TGF-b1-signaling is largely mediated by Smad proteins roles in transformation continues to be poorly understood. (Massague et al., 2005) where Smad2 and Smad3 are Here, we discovered that TGF-b1 stimulates transcription phosphorylated by TGF-b1-receptors and associate with of metastasis-associated protein 1 (MTA1), a dual master the common mediator Smad4, which translocates to the coregulator, in epithelial cells, and that MTA1 status is a nucleus to participate in the expression of TGF-b1-target determinant of TGF-b1-induced epithelial-to-mesenchymal genes (Deckers et al., 2006). Previous studies have shown transition (EMT) phenotypes. In addition, we found that that CUTL1, also known as CDP (CCAAT displacement MTA1/polymerase II/activator protein-1 (AP-1) co-activator protein), a target of TGF-b1, is needed for its short-term complex interacts with the FosB-gene chromatin and stimu- effects of TGF-b1 on cell motility involving Smad4- lates its transcription, and FosB in turn, utilizes FosB/histone dependent pathway (Michl et al.,2005).
    [Show full text]
  • Conditional Deletion of HIF-1Α Provides New Insight
    bioRxiv preprint doi: https://doi.org/10.1101/2021.01.16.426940; this version posted January 16, 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. Conditional deletion of HIF-1 provides new insight regarding the murine response to gastrointestinal infection with Salmonella Typhimurium Laura Robrahn *, Aline Dupont †, Sandra Jumpertz *, Kaiyi Zhang †, Christian H. Holland ‡ §, Joël Guillaume ¶1, Sabrina Rappold *, Vuk Cerovic ¶, Julio Saez-Rodriguez ‡ §, Mathias W. Hornef † || #, and Thorsten Cramer * ** †† ‡‡ * Department of General, Visceral and Transplantation Surgery, RWTH University Hospital, Pauwelsstraße 30, 52074 Aachen, Germany; † Institute of Medical Microbiology, RWTH University Hospital, Pauwelsstraße 30, 52074 Aachen, Germany; ‡ Institute for Computational Biomedicine, Faculty of Medicine, Heidelberg University, and Heidelberg University Hospital, Bioquant, Heidelberg, Germany; § Joint Research Center for Computational Biomedicine, RWTH Aachen University Hospital, Aachen, Germany; ¶ Institute of Molecular Medicine, RWTH University Hospital, Aachen, Germany; ** ESCAM – European Surgery Center Aachen Maastricht, Germany and The Netherlands; †† Department of Surgery, Maastricht University Medical Center, Maastricht, The Netherlands; ‡‡ NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht,
    [Show full text]
  • Rbpj-Dependent and -Independent Notch2 Signaling Regulates
    RBPJ-DEPENDENT AND -INDEPENDENT NOTCH2 SIGNALING REGULATES CILIARY BODY DEVELOPMENT IN THE MOUSE EYE By Yi Zhou B.S., Tsinghua University, 2010 Submitted to the graduate degree program in Anatomy and Cell Biology and the Graduate Faculty of the University of Kansas in partial fulfillment of the requirements for the degree of Doctor of Philosophy. ________________________________ Ting Xie, Ph.D., Co-Chair ________________________________ William Kinsey, Ph.D., Co-Chair ________________________________ Dale Abrahamson, Ph.D. ________________________________ Peter Smith, Ph.D. ________________________________ Jerry Workman, Ph.D. Date Defended: Jan 6th, 2016 The Dissertation Committee for Yi Zhou certifies that this is the approved version of the following dissertation: RBPJ-DEPENDENT AND -INDEPENDENT NOTCH2 SIGNALING REGULATES CILIARY BODY DEVELOPMENT IN THE MOUSE EYE ________________________________ Ting Xie, Ph.D., Co-Chair ________________________________ William Kinsey, Ph.D., Co-Chair Date Approved: Jan 15th, 2016 ii ABSTRACT The ciliary body (CB) is a two-layered structure in the anterior eye, which is composed of the pigmented outer ciliary epithelium (OCE) and the non-pigmented inner ciliary epithelium (ICE). It is responsible for aqueous humor secretion and lens accommodation. Despite the important roles in maintaining normal eye functions, its development still remains poorly understood. The Notch signaling pathway is an evolutionarily conserved pathway that has diverse functions during tissue development and homeostasis. Canonical Notch signaling is mediated through the recombination signal binding protein for immunoglobulin kappa J region (RBPJ)-dependent transcription activation and repression. In this study, I have demonstrated that Notch2 and RBPJ are important regulators of CB development by conditionally deleting them in the developing CB.
    [Show full text]
  • Estradiol Inhibits ER Stress-Induced Apoptosis Through
    Laboratory Investigation (2014) 94, 906–916 & 2014 USCAP, Inc All rights reserved 0023-6837/14 17b-Estradiol inhibits ER stress-induced apoptosis through promotion of TFII-I-dependent Grp78 induction in osteoblasts Yun-Shan Guo1,2,5, Zhen Sun1,5, Jie Ma3,5, Wei Cui4,5, Bo Gao1, Hong-Yang Zhang1, Yue-Hu Han1, Hui-Min Hu1, Long Wang1, Jing Fan1, Liu Yang1, Juan Tang2 and Zhuo-Jing Luo1 Although many studies have suggested that estrogen prevents postmenopausal bone loss partially due to its anti-apoptosis effects in osteoblasts, the underlying mechanism has not been fully elucidated. In the present study, we found that 17b-estradiol (17b-E2), one of the primary estrogens, inhibited endoplasmic reticulum (ER) stress-induced apoptosis in MC3T3-E1 cells and primary osteoblasts. Interestingly, 17b-E2-promoted Grp78 induction, but not CHOP induction in response to ER stress. We further confirmed that Grp78-specific siRNA reversed the inhibition of 17b-E2 on ER stress-induced apoptosis by activating caspase-12 and caspase-3. Moreover, we found that 17b-E2 markedly increased the phosphorylated TFII-I levels and nuclear localization of TFII-I in ER stress conditions. 17b-E2 stimulated Grp78 promoter activity in a dose-dependent manner in the presence of TFII-I and enhanced the binding of TFII-I to the Grp78 promoter. In addition, 17b-E2 notably increased phosphorylated ERK1/2 levels and Ras kinase activity in MC3T3-E1 cells. The ERK1/2 activity-specific inhibitor U0126 remarkably blocked 17b-E2-induced TFII-I phosphorylation and Grp78 expression in response to ER stress. Together, 17b-E2 protected MC3T3-E1 cells against ER stress-induced apoptosis by promoting Ras-ERK1/2-TFII-I signaling pathway-dependent Grp78 induction.
    [Show full text]
  • In Vitro Targeting of Transcription Factors to Control the Cytokine Release Syndrome in 2 COVID-19 3
    bioRxiv preprint doi: https://doi.org/10.1101/2020.12.29.424728; this version posted December 30, 2020. 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 4.0 International license. 1 In vitro Targeting of Transcription Factors to Control the Cytokine Release Syndrome in 2 COVID-19 3 4 Clarissa S. Santoso1, Zhaorong Li2, Jaice T. Rottenberg1, Xing Liu1, Vivian X. Shen1, Juan I. 5 Fuxman Bass1,2 6 7 1Department of Biology, Boston University, Boston, MA 02215, USA; 2Bioinformatics Program, 8 Boston University, Boston, MA 02215, USA 9 10 Corresponding author: 11 Juan I. Fuxman Bass 12 Boston University 13 5 Cummington Mall 14 Boston, MA 02215 15 Email: [email protected] 16 Phone: 617-353-2448 17 18 Classification: Biological Sciences 19 20 Keywords: COVID-19, cytokine release syndrome, cytokine storm, drug repurposing, 21 transcriptional regulators 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.12.29.424728; this version posted December 30, 2020. 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 4.0 International license. 22 Abstract 23 Treatment of the cytokine release syndrome (CRS) has become an important part of rescuing 24 hospitalized COVID-19 patients. Here, we systematically explored the transcriptional regulators 25 of inflammatory cytokines involved in the COVID-19 CRS to identify candidate transcription 26 factors (TFs) for therapeutic targeting using approved drugs.
    [Show full text]
  • Enhancer, Hs3 Igh ′ Activator of the Murine 3 Yin Yang 1 Is A
    Yin Yang 1 Is a Lipopolysaccharide-Inducible Activator of the Murine 3 ′ Igh Enhancer, hs3 This information is current as Steven J. Gordon, Shireen Saleque and Barbara K. Birshtein of September 23, 2021. J Immunol 2003; 170:5549-5557; ; doi: 10.4049/jimmunol.170.11.5549 http://www.jimmunol.org/content/170/11/5549 Downloaded from References This article cites 66 articles, 40 of which you can access for free at: http://www.jimmunol.org/content/170/11/5549.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 23, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2003 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Yin Yang 1 Is a Lipopolysaccharide-Inducible Activator of the Murine 3؅ Igh Enhancer, hs31 Steven J. Gordon, Shireen Saleque,2 and Barbara K. Birshtein3 The 3؅ Igh enhancers, DNase I hypersensitive site (hs) 3B and/or hs4, are required for germline transcription, and hence, class switch recombination for multiple isotypes.
    [Show full text]
  • Endothelial Specific YY1 Deletion Restricts Tumor Angiogenesis And
    www.nature.com/scientificreports OPEN Endothelial specifc YY1 deletion restricts tumor angiogenesis and tumor growth Huan Liu1,2, Yikai Qiu1, Xiuying Pei1, Ramamurthy Chitteti2, Rebbeca Steiner2, Shuya Zhang1,2* & Zheng Gen Jin2* Angiogenesis is a physiological process for the formation of new blood vessels from the pre-existing vessels and it has a vital role in the survival and growth of neoplasms. During tumor angiogenesis, the activation of the gene transcriptions in vascular endothelial cells (ECs) plays an essential role in the promotion of EC proliferation, migration, and vascular network development. However, the molecular mechanisms underlying transcriptional regulation of EC and tumor angiogenesis remains to be fully elucidated. Here we report that the transcription factor Yin Yang 1 (YY1) in ECs is critically involved in tumor angiogenesis. First, we utilized a tamoxifen-inducible EC-specifc YY1 defcient mouse model and showed that YY1 deletion in ECs inhibited the tumor growth and tumor angiogenesis. Using the in vivo matrigel plug assay, we then found that EC-specifc YY1 ablation inhibited growth factor-induced angiogenesis. Furthermore, vascular endothelial growth factor (VEGF)-induced EC migration was diminished in YY1-depleted human umbilical vein endothelial cells (HUVECs). Finally, a rescue experiment revealed that YY1-regulated BMP6 expression in ECs was involved in EC migration. Collectively, our results demonstrate that endothelial YY1 has a crucial role in tumor angiogenesis and suggest that targeting endothelial
    [Show full text]
  • The YY1 Transcription Factor Is a Component of Ribonucleoprotein Complexes In
    The YY1 Transcription Factor is a Component of Ribonucleoprotein Complexes in Xenopus laevis Oocytes and Embryos. A Thesis Submitted to the College of Graduate Studies and Research In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy In the Department of Anatomy and Cell Biology University of Saskatchewan Saskatoon Saskatchewan By Andrew Douglas Ficzycz Spring 2003 © Copyright Andrew Do uglas Ficzyc z, 2003. All rights reserv ed. Permission to use P ERMIS SION TO US E I n presenting this thesis in partial f ulfilment of the r equirements for a P ostgraduate degree f rom the University of S askatchew an, I agree that the Libraries of this U nivers ity may make it f reely available f or inspection. I f urther agree that permission f or copying of this thesis in any manner, in w hole or in part, for s cholarly purpos es may be granted by the professor or profess ors w ho supervis ed my thesis w ork or , in their absence, by the Head of the D epartment or the D ean of the College in w hich my thesis work was done. I t is unders tood that any copying or publication or use of this thesis or parts thereof f or financial gain s hall not be allowed without my w ritten permis sion. It is also understood that due r ecognition shall be given to me and to the Univer s ity of Saskatchew an in any scholarly use w hich may be made of any material in my thesis.
    [Show full text]
  • Relief of YY1 Transcriptional Repression by Adenovirus E1A Is Mediated by E1A-Associated Protein P300
    Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Relief of YY1 transcriptional repression by adenovirus E1A is mediated by E1A-associated protein p300 Jeng-Shin Lee, 1"2 Katherine M. Galvin, l's Raymond H. See, l's Richard Eckner, 3 David Livingston, 3 Elizabeth Moran, 4 and Yang Shi 1'2'6 ~Department of Pathology, 2Committee on Virology, Harvard Medical School, Boston, Massachusetts 02115 USA; aDivision of Cellular and Molecular Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115 USA; 4The Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140 USA YY1 represses transcription when bound upstream of transcriptional initiation sites. This repression can be relieved by adenovirus E1A. Here, we present genetic evidence that the ability of E1A to relieve YY1 repression was impaired by mutations that affect EIA binding to its associated protein p300. This suggests that E1A may modulate the repressor activity of YY1 by binding to p300, which may be physically complexed with YY1. A YY1/p300 protein complex in vivo was demonstrated by several independent approaches, and the YYl-interacting domain was mapped to the carboxy-terminal region of p300, distinct from the E1A-binding site. Unlike E2F/RB, the YY1/p300 complex is not disrupted by E1A. Functional studies using recombinant p300 demonstrated unequivocally that p300 is capable of mediating E1A-induced transcriptional activation through YY1. Taken together, these results reveal, for the first time, a YY1/p300 complex that is targeted by EIA and demonstrate a function for p300 in mediating interactions between YY1 and E1A.
    [Show full text]
  • PDF-Document
    Supplementary Material Investigating the role of microRNA and Transcription Factor co-regulatory networks in Multiple Sclerosis pathogenesis Nicoletta Nuzziello1, Laura Vilardo2, Paride Pelucchi2, Arianna Consiglio1, Sabino Liuni1, Maria Trojano3 and Maria Liguori1* 1National Research Council, Institute of Biomedical Technologies, Bari Unit, Bari, Italy 2National Research Council, Institute of Biomedical Technologies, Segrate Unit, Milan, Italy 3Department of Basic Sciences, Neurosciences and Sense Organs, University of Bari, Bari, Italy Supplementary Figure S1 Frequencies of GO terms and canonical pathways. (a) Histogram illustrates the GO terms associated to assembled sub-networks. (b) Histogram illustrates the canonical pathways associated to assembled sub-network. a b Legends for Supplementary Tables Supplementary Table S1 List of feedback (FBL) and feed-forward (FFL) loops in miRNA-TF co-regulatory network. Supplementary Table S2 List of significantly (adj p-value < 0.05) GO-term involved in MS. The first column (from the left) listed the GO-term (biological processes) involved in MS. For each functional class, the main attributes (gene count, p-value, adjusted p-value of the enriched terms for multiple testing using the Benjamini correction) have been detailed. In the last column (on the right), we summarized the target genes involved in each enriched GO-term. Supplementary Table S3 List of significantly (adj p-value < 0.05) enriched pathway involved in MS. The first column (from the left) listed the enriched pathway involved in MS. For each pathway, the main attributes (gene count, p-value, adjusted p-value of the enriched terms for multiple testing using the Benjamini correction) have been detailed. In the last column (on the right), we summarized the target genes involved in each enriched pathway.
    [Show full text]
  • YY1 Suppresses FEN1 Over-Expression and Drug
    Wang et al. BMC Cancer (2015) 15:50 DOI 10.1186/s12885-015-1043-1 RESEARCH ARTICLE Open Access YY1 suppresses FEN1 over-expression and drug resistance in breast cancer Jianwei Wang1, Lina Zhou1,2, Zhi Li3, Ting Zhang1, Wenpeng Liu1, Zheng Liu2, Yate-Ching Yuan2, Fan Su2,LuXu3, Yan Wang3, Xiaotong Zhou3, Hong Xu4, Yuejin Hua4, Ying-Jie Wang5, Li Zheng2, Yue-E Teng3* and Binghui Shen2* Abstract Background: Drug resistance is a major challenge in cancer therapeutics. Abundant evidence indicates that DNA repair systems are enhanced after repetitive chemotherapeutic treatments, rendering cancers cells drug-resistant. Flap endonuclease 1 (FEN1) plays critical roles in DNA replication and repair and in counteracting replication stress, which is a key mechanism for many chemotherapeutic drugs to kill cancer cells. FEN1 was previously shown to be upregulated in response to DNA damaging agents. However, it is unclear about the transcription factors that regulate FEN1 expression in human cancer. More importantly, it is unknown whether up-regulation of FEN1 has an adverse impact on the prognosis of chemotherapeutic treatments of human cancers. Methods: To reveal regulation mechanism of FEN1 expression, we search and identify FEN1 transcription factors or repressors and investigate their function on FEN1 expression by using a combination of biochemical, molecular, and cellular approaches. Furthermore, to gain insights into the impact of FEN1 levels on the response of human cancer to therapeutic treatments, we determine FEN1 levels in human breast cancer specimens and correlate them to the response to treatments and the survivorship of corresponding breast cancer patients. Results: We observe that FEN1 is significantly up-regulated upon treatment of chemotherapeutic drugs such as mitomycin C (MMC) and Taxol in breast cancer cells.
    [Show full text]
  • The Emerging Role of Estrogen Related Receptorα in Complications of Non‑Small Cell Lung Cancers (Review)
    ONCOLOGY LETTERS 21: 258, 2021 The emerging role of estrogen related receptorα in complications of non‑small cell lung cancers (Review) TAPAN K. MUKHERJEE1‑3, PARTH MALIK4 and JOHN R. HOIDAL1‑3 1Division of Respiratory, Critical Care and Occupational Pulmonary Medicine and 2Department of Internal Medicine, University of Utah; 3George E. Wahlen Department of Veterans Affairs Medical Centre, Salt Lake City, UT 84132, USA; 4School of Chemical Sciences, Central University of Gujarat, Gandhinagar, Gujarat 382030, India Received July 6, 2020; Accepted November 18, 2020 DOI: 10.3892/ol.2021.12519 Abstract. Approximately 85% of lung cancer cases are recog‑ cause of NSCLC complications, its consequences are distinctly nized as non‑small cell lung cancer (NSCLC) with a perilous manifest with respect to sex bias, due to differential gene and (13‑17%) 5‑year survival in Europe and the USA. Although sex hormone expression. Estrogen related receptor α (ERRα), tobacco smoking has consistently emerged as the leading a member of the nuclear orphan receptor superfamily is normally expressed in the lungs, and activates various nuclear genes without binding to the ligands, such as estrogens. In NSCLC ERRα expression is significantly higher compared Correspondence to: Dr Tapan K. Mukherjee, Division with healthy individuals. It is well established ERα and ERβ‚ of Respiratory, Critical Care and Occupational Pulmonary have 93% and 60% identity in the DNA and ligand binding Medicine, Wintrobe Building, University of Utah, Salt Lake City, domains, respectively. ERα and ERRα have 69% (70% with UT 84132, USA ERRα‑1) and 34% (35% with ERRα‑1) identity, respectively; E‑mail: [email protected] ERRα and ERRβ‚ have 92 and 61% identity, respectively.
    [Show full text]