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Role of Heat Shock Transcription Factor 1 in Ovarian Cancer

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Role of Heat Shock Transcription Factor 1 in Ovarian Cancer University of South Florida Scholar Commons Graduate Theses and Dissertations Graduate School November 2017 Role of Heat Shock Transcription Factor 1 in Ovarian Cancer Epithelial-Mesenchymal Transition and Drug Sensitivity Chase David Powell University of South Florida, [email protected] Follow this and additional works at: http://scholarcommons.usf.edu/etd Part of the Cell Biology Commons, Molecular Biology Commons, and the Oncology Commons Scholar Commons Citation Powell, Chase David, "Role of Heat Shock Transcription Factor 1 in Ovarian Cancer Epithelial-Mesenchymal Transition and Drug Sensitivity" (2017). Graduate Theses and Dissertations. http://scholarcommons.usf.edu/etd/7079 This Dissertation is brought to you for free and open access by the Graduate School at Scholar Commons. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Scholar Commons. For more information, please contact [email protected]. Role of Heat Shock Transcription Factor 1 in Ovarian Cancer Epithelial-Mesenchymal Transition and Drug Sensitivity by Chase David Powell A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Department of cell Biology, Microbiology, and Molecular Biology College of Arts and Sciences University of South Florida Major Professor: Sandy D. Westerheide, Ph.D. Brant R. Burkhardt, Ph.D. Younghoon Kee, Ph.D Meera Nanjundan, Ph.D Date of Approval: November 3, 2017 Keywords: Heat Shock Factor 1, Ovarian Cancer, Epithelial to Mesenchymal Transition, Transforming Growth Factor β, HSP90 Inhibitors, Spheroid Culture, Intrinsic Disorder Copyright © 2017, Chase D. Powell DEDICATION I would like to dedicate this work to my wife, Anne T Powell, for all of her support, patience, and love. To my children Elise, Madeleine, Aidan, and Ethan for the encouragement and inspiration they have provided me. To my parents Christina and Chris Simcox for their continued belief in me. And lastly, to my mentor Sandy D. Westerheide for allowing me the opportunity to learn. ACKNOWLEDGMENTS I would like to acknowledge my committee members, Brant Burkhardt, Ph.D., Younghoon Kee, Ph.D., and Meera Nanjundan Ph.D. for their guidance and understanding. I would most especially like to acknowledge my major professor, Sandy D. Westerheide, Ph.D., for her infinite patience. TABLE OF CONTENTS List of Tables…………………………………………………………………………………………… .. iv List of Figures…………………………………………………………………………………………….. v Abstract………………………………………………………………………………………………… .. vii Chapter One: Introduction………… ............................................................................................. 1 Discovery of the Heat Shock Response ........................................................................... 1 Regulation of the Heat Shock Response by HSF1 .......................................................... 2 Overview of Heat Shock Response Regulation by HSF1 ..................................... 2 Activation of the HSR ........................................................................................... 3 Repression of the HSR ........................................................................................ 5 HSF1 Regulated Response……………. .......................................................................... 7 Heat Shock Proteins………… .............................................................................. 7 HSP27 ..................................................................................................... 7 HSP40 ..................................................................................................... 8 HSP70 ..................................................................................................... 8 HSP90 ..................................................................................................... 8 HSP110 .................................................................................................... 8 Other Cytoprotective Functions……………. ......................................................... 9 Role of HSF1 in Cancer………… ................................................................................... 11 Ovarian Cancer……………. ........................................................................................... 12 Ovarian Cancer Types…………………… ........................................................... 12 Treatments….. ................................................................................................... 13 Epithelial to Mesenchymal Transition……………. .............................................. 13 Spheroid Model .................................................................................................. 15 Transforming Growth Factor β…… .................................................................... 15 Studies………………………. ......................................................................................... 16 Chapter Two: Intrinsic Disorder in the HSF Transcription Factor Family and Molecular Chaperones……………………………….. .............................................................................. 19 Abstract………………….. .............................................................................................. 19 Intrinsically Disordered Proteins: General Overview ...................................................... 20 Intrinsic Disorder and Transcription Regulation ............................................................. 22 An Overview of Intrinsic Disorder in Chaperones .......................................................... 25 The Heat Shock Response ........................................................................................... 28 HSF1- The Master Heat Shock Response Regulator ..................................................... 29 Domains of HSF1……………......................................................................................... 29 DNA Binding Domain ......................................................................................... 30 Trimerization Domain ......................................................................................... 31 Transactivation Domain ..................................................................................... 31 Regulatory Domain ............................................................................................ 32 i Conservation of HSF Across Different Species ............................................................. 32 Alternative Splicing of HSF1 .......................................................................................... 33 Post-Translational Modifications Regulate HSF1 Transcriptional Activity ....................... 33 Phosphorylation ................................................................................................. 33 Sumoylation…………….. ................................................................................... 35 Acetylation……………… .................................................................................... 35 A Correlation between Intrinsic Disorder and Post Translational Modifications .............. 36 HSF1 as an Interaction Hub .......................................................................................... 38 Other Heat Shock Transcription Family Members ......................................................... 40 HSF2………………… ......................................................................................... 40 HSF4…………………... ...................................................................................... 41 HSF3, 5, X and Y ............................................................................................... 42 Chapter Three: The Heat Shock Transcription Factor HSF1 Induces Ovarian Cancer Epithelial-Mesenchymal Transition in a 3D Spheroid Growth Model ......................... 53 Abstract…………………………….. ................................................................................ 53 Introduction……………………… .................................................................................... 54 Materials and Methods .................................................................................................. 56 HSF1 Copy Number, Expression Determination and Survival Analysis .............. 56 Cell Culture and Treatments .......................................................................... 56 Lentiviral Creation and Infection for Stable, Inducible shRNA-Mediated HSF1 Knockdown .......................................................................................... 57 Protein isolation, SDS-PAGE, and Western analysis ......................................... 57 Cell Viability Assay ............................................................................................. 58 Clonogenic Assay .............................................................................................. 58 Wound Healing Assay ........................................................................................ 59 Cell Migration ................................................................................................... 59 Spheroid Formation ........................................................................................... 59 Quantitative RT-PCR ......................................................................................... 60 Results……………………….. ........................................................................................ 60 HSF1 is Overexpressed in Ovarian Cancer ........................................................ 60 Establishment of SKOV3
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