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The Proteasome-Associated Deubiquitinase UCHL5/UBH-4 in Proteasome Modulation and As a Prognostic Marker in Gastrointestinal Cancers

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The Proteasome-Associated Deubiquitinase UCHL5/UBH-4 in Proteasome Modulation and As a Prognostic Marker in Gastrointestinal Cancers The Proteasome-Associated Deubiquitinase UCHL5/UBH-4 in Proteasome Modulation and as a Prognostic Marker in Gastrointestinal Cancers Leena Arpalahti Doctoral Programme in Biomedicine (DPBM) Research Programs Unit Translational Cancer Biology Biochemistry and Developmental Biology Medicum Faculty of Medicine University of Helsinki, Finland Academic dissertation To be presented for public examination with the permission of the Faculty of Medicine, University of Helsinki, in Lecture Hall 2, Biomedicum Helsinki 1 (Haartmaninkatu 8, Helsinki), on March 2nd 2018, at 12 noon. Thesis supervisor Docent Carina Holmberg-Still, PhD Research Programs Unit Translational Cancer Biology Program Faculty of Medicine University of Helsinki Finland Reviewers appointed by the Faculty Professor Markus Mäkinen Professor Nico Dantuma Department of Pathology Department of Cell and Molecular Biology Faculty of Medicine Karolinska Institutet University of Oulu Sweden Finland Thesis follow-up committee Professor Dan Lindholm Associate Professor Ville Hietakangas Department of Biochemistry and Faculty of Biological and Developmental Biology Environmental Sciences & Medicum Insitute of Biotechnology Faculty of Medicine University of Helsinki University of Helsinki Finland Finland Opponent appointed by the Faculty Professor Hilde Nilsen Institute of Clinical Medicine Faculty of Medicine University of Oslo Norway ISBN 978-951-51-4016-6 (print) ISBN 978-951-51-4017-3 (PDF) ISSN 2342-3161 (print) ISSN 2342-317X (online) http://ethesis.helsinki.fi Cover layout by Anita Tienhaara Hansaprint, Vantaa, 2018 2 “Many nematodes died to bring us this information.” - “A Scientist is Always Fine.” -Joseph Fink and Jeffrey Cranor 3 CONTENTS CONTENTS .............................................................................................................. 4 LIST OF PUBLICATIONS ...................................................................................... 7 ABBREVIATIONS ................................................................................................... 8 TIIVISTELMÄ ....................................................................................................... 13 ABSTRACT ............................................................................................................ 15 INTRODUCTION................................................................................................... 17 LITERATURE REVIEW ....................................................................................... 18 1. The ubiquitin-proteasome system ................................................................... 18 1.1. Proteasome structure and function .............................................................. 19 1.1.1. 20S core particle ................................................................................. 20 1.1.2. 19S/PA700 regulatory particle ............................................................ 21 1.1.3. Alternate proteasome activators .......................................................... 22 1.1.4. Tissue-specific proteasomes ................................................................ 23 1.2. Polyubiquitinating enzymes ....................................................................... 24 1.3. Deubiquitinating enzymes .......................................................................... 26 1.4. Proteasome-mediated protein degradation .................................................. 27 1.4.1. Ubiquitin-independent protein degradation ......................................... 28 1.4.2. Ubiquitin-dependent protein degradation ............................................ 28 1.5. Proteasome modulation .............................................................................. 29 1.5.1. Transcriptional regulation .................................................................. 30 1.5.2. Proteasome assembly and disassembly ................................................ 30 1.5.3. Post-translational modifications.......................................................... 32 1.5.4. Proteasome-interacting proteins ......................................................... 34 1.5.5. Proteasome-associated deubiquitinating enzymes................................ 35 1.5.5.1. UCHL5/UBH-4 ............................................................................ 36 1.6. The ubiquitin-proteasome system in the regulation of proteostasis in aging. 37 1.7. The ubiquitin-proteasome system in cancer ................................................ 39 1.7.1. Targeting the ubiquitin-proteasome system in cancer therapies ........... 40 2. Gastrointestinal cancers.................................................................................. 42 2.1. Colorectal cancer ....................................................................................... 44 2.2. Gastric cancer ............................................................................................ 48 2.3. Pancreatic ductal adenocarcinoma .............................................................. 50 2.4. An overview of gastrointestinal biomarkers ................................................ 53 3. Caenorhabditis elegans as a model system in biomedical research ................ 57 4 AIMS OF THE STUDY .......................................................................................... 58 PATIENTS, MATERIALS AND METHODS ....................................................... 59 1. In vivo methods used in I................................................................................. 59 1.1. Nematodes ................................................................................................. 59 1.2. In vivo UPS-activity reporters and polyubiquitin reporters .......................... 59 1.3. Lifespan and progeny assays ...................................................................... 60 1.4. Mammalian cell culturing .......................................................................... 60 1.5. Microscopy and image analysis .................................................................. 61 2. Biochemical methods used in I ....................................................................... 61 2.1. Immunofluorescence in C. elegans ............................................................. 61 2.2. RNA interference (RNAi) in C. elegans by feeding .................................... 62 2.3. Immunoprecipitation .................................................................................. 62 2.4. Native proteasome and deubiquitinase activity in-gel assays ....................... 63 2.5. Western blotting......................................................................................... 63 2.6. Quantitative real-time PCR (qPCR) ............................................................ 64 3. Materials and methods used in publications II-IV ......................................... 65 3.1. Patients ...................................................................................................... 65 3.1.1. Patients in publication II ..................................................................... 65 3.1.2. Patients in publication III.................................................................... 65 3.1.3. Patients in publication IV .................................................................... 65 3.2. Preparation of tumor tissue specimens ........................................................ 66 3.3. Antibodies for immunohistochemistry ........................................................ 66 3.4. Immunohistochemistry ............................................................................... 66 3.5. Sample scoring and imaging....................................................................... 66 3.6. Statistical analysis ...................................................................................... 67 RESULTS AND DISCUSSION .............................................................................. 70 1. Proteasome-associated deubiquitinase UCHL5/UBH-4 is a modulator of proteasome activity in C. elegans and human cancer cells (I) ........................... 70 1.1. Insulin/IGF-1 signaling regulates proteasome activity in a tissue-specific manner through DAF-16/FOXO in C. elegans .................................................. 70 1.2. The proteasome-associated deubiquitinase UBH-4 is a DAF-16 target gene 72 1.3. UBH-4 modulates proteasome activity and life history traits in C. elegans .. 73 1.4. Knockdown of uchl5 promotes degradation in mammalian cell lines .......... 75 2. UCHL5 is a prognostic marker in three gastrointestinal cancers (II-IV) ..... 76 2.1. UCHL5 tumor expression pattern varies depending on tissue of origin ....... 76 2.2. UCHL5 tumor expression correlates with cancer-specific survival in colorectal cancer, gastric cancer and pancreatic ductal adenocarcinoma ............ 78 5 2.2.1. UCHL5 tumor expression association with cancer stage ..................... 78 2.2.2. UCHL5 tumor expression association with patient age ........................ 80 3. The potential roles of UCHL5 in association with its binding partners and a summary of the results........................................................................................ 80 CONCLUSIONS AND FUTURE PROSPECTS .................................................... 83 ACKNOWLEDGEMENTS .................................................................................... 85 APPENDIXES ........................................................................................................
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