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Cyclin B1 Mediates the Effect of UCHL1 in Promoting Cell Cycle Progression in Uterine Papillary Serous Carcinoma

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Cyclin B1 Mediates the Effect of UCHL1 in Promoting Cell Cycle Progression in Uterine Papillary Serous Carcinoma The Texas Medical Center Library DigitalCommons@TMC The University of Texas MD Anderson Cancer Center UTHealth Graduate School of The University of Texas MD Anderson Cancer Biomedical Sciences Dissertations and Theses Center UTHealth Graduate School of (Open Access) Biomedical Sciences 5-2017 Cyclin B1 mediates the effect of UCHL1 in promoting cell cycle progression in uterine papillary serous carcinoma Suet Ying Kwan Follow this and additional works at: https://digitalcommons.library.tmc.edu/utgsbs_dissertations Part of the Cancer Biology Commons, Oncology Commons, and the Translational Medical Research Commons Recommended Citation Kwan, Suet Ying, "Cyclin B1 mediates the effect of UCHL1 in promoting cell cycle progression in uterine papillary serous carcinoma" (2017). The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access). 737. https://digitalcommons.library.tmc.edu/utgsbs_dissertations/737 This Dissertation (PhD) is brought to you for free and open access by the The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences at DigitalCommons@TMC. It has been accepted for inclusion in The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access) by an authorized administrator of DigitalCommons@TMC. For more information, please contact [email protected]. CYCLIN B1 MEDIATES THE EFFECT OF UCHL1 IN PROMOTING CELL CYCLE PROGRESSION IN UTERINE PAPILLARY SEROUS CARCINOMA by Suet Ying Kwan, BSc APPROVED: ______________________________ Karen H. Lu, M.D. Advisory Professor ______________________________ Russell R. Broaddus, M.D., Ph.D. ______________________________ Wenliang Li, Ph.D. ______________________________ Samuel C. Mok, Ph.D. ______________________________ Kwong-Kwok Wong, Ph.D. APPROVED: ____________________________ Dean, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences i CYCLIN B1 MEDIATES THE EFFECT OF UCHL1 IN PROMOTING CELL CYCLE PROGRESSION IN UTERINE PAPILLARY SEROUS CARCINOMA A DISSERTATION Presented to the Faculty of The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY by Suet Ying Kwan, BSc Houston, Texas May 2017 ii DEDICATION This thesis is dedicated to my family: mum, dad, Suet Yan, Rita Urlanda and Benjy; and to Christopher Nguyen, Lorraine Fung, Kenneth Hui and Daniel Man for their unconditional friendship and support. In loving memory of my grandparents. iii ACKNOWLEDGEMENTS I would like to express my sincere gratitude to my advisor Dr. Karen Lu for her expert advice and encouragement, and for reminding me to always look at the bigger picture. I would also like to thank the rest of my thesis committee, Dr. Samuel Mok, Dr. Russell Broaddus, Dr. Wenliang Li and Dr. Kwong Kwok Wong, for providing me with their precious insight. In particular, I am grateful to Dr. Samuel Mok for his guidance, which has been crucial for helping me navigate the intricacies of a dissertation; Dr. Russell Broaddus for asking the difficult yet imperative questions; Dr. Wenliang Li for allowing me to rotate in his laboratory in my first year in graduate school when I still had a lot to learn; and Dr. Kwong Kwok Wong for sparking my interest in the use of bioinformatics to answer important clinical questions. I am thankful to Dr. Rosemarie Schmandt and Dr. Melinda Yates for their helpful feedback on the project. I would also like to thank the past and present members of my research group and neighboring labs, Joseph Celestino, Tri Nguyen, Dr. Qian Zhang, Dr. Connie Teodoro, Dr. YunYun Jiang, Dr. Suet Yan Kwan, Dr. Daisy Izaguirre, Dr. Yvonne Tsang, Dr. Chilam Au-Yeung, Dr. Tsz- Lun Yeung, and Dr. Jessica Bowser, for their expertise and endless support. My gratitude also goes to Stacie Gallardo, Lydia Soto, and Heetae Kim, who have allowed my research to progress smoothly; and Carol Johnston, the North Campus Flow Cytometry Core Facility and the shRNA and ORFeome Core for their services. Lastly, I would like to thank the staff members of GSBS for providing assistance, emotional support and free caffeine. iv CYCLIN B1 MEDIATES THE EFFECT OF UCHL1 IN PROMOTING CELL CYCLE PROGRESSION IN UTERINE PAPILLARY SEROUS CARCINOMA Suet Ying Kwan, BSc Advisory Professor: Karen H. Lu, M.D. Uterine papillary serous carcinoma (UPSC) is an aggressive form of endometrial cancer with poor survival rates and a high risk of recurrence. The rarity of UPSC poses challenges to the discovery of novel targeted therapies. Therefore, the purpose of this dissertation was to identify novel therapeutic targets that could aid in the management of UPSC. To do so, we began with the relatively large cohort of UPSC cases in the TCGA data set, which was used to identify differentially expressed genes between UPSC and low-grade endometrioid endometrial carcinoma (EEC) and normal tissue. We identified Ubiquitin Carboxyl-Terminal Hydrolase L1 (UCHL1) to be a gene of interest, as it was significantly upregulated in UPSC and correlated with poorer overall survival. These findings were validated through immunohistochemical analysis of an independent cohort of tumor samples. Due to its role as a deubiquitinating enzyme, we hypothesized that UCHL1 contributes to UPSC tumor progression by modulating the protein stability of target genes. To test this hypothesis, we first examined the functional role of UCHL1 in UPSC progression. Subsequently, we found that UCHL1 silencing reduced cell proliferation in vitro and in vivo. The treatment of UPSC-bearing mice with the UCHL1-specific inhibitor LDN-57444 via intraperitoneal injection also reduced tumor growth and increased overall survival times. Next, we found that the effect of UCHL1 on increased cell proliferation was due to its ability to stabilize cyclin B1 protein, an essential protein in mitotic progression. Specifically, we demonstrated that UCHL1 and cyclin B1 interact with each other in both the cytoplasm and nuclear space prior to mitosis. UCHL1 silencing increased the deubiquitination of cyclin B1, suggesting that UCHL1 counteracts the ubiquitination of cyclin B1 by the anaphase-promoting complex. v Accordingly, UCHL1 silencing slowed the progression of cells into mitosis. Taken together, our findings indicate that UCHL1 impairs the degradation of cyclin B1, leading to uncontrolled cell cycle progression. In summary, we have identified UCHL1 as a prognostic marker for UPSC and a viable therapeutic target. vi TABLE OF CONTENTS Approval sheet ....................................................................................................................................... i Title page ............................................................................................................................................... ii Dedication............................................................................................................................................. iii Acknowledgements .............................................................................................................................. iv Abstract ................................................................................................................................................. v Table of contents ................................................................................................................................. vii List of figures ....................................................................................................................................... xi List of tables ....................................................................................................................................... xiii CHAPTER 1: INTRODUCTION ...................................................................................................... 1 ENDOMETRIAL CANCER .............................................................................................................. 2 Histopathological classification of endometrial cancer .................................................................. 2 Pathogenesis of endometrial cancer ............................................................................................... 3 Molecular classification of endometrial cancer .............................................................................. 5 UPSC patterns of spread ................................................................................................................. 6 Current treatment strategies for endometrial cancer ....................................................................... 7 Development of targeted therapeutic strategies for UPSC ............................................................. 8 THE UBIQUITIN-PROTEASOME SYSTEM ................................................................................ 10 UCHL1 ......................................................................................................................................... 11 Dysregulation of UCHL1 in cancer .............................................................................................. 12 Mechanisms of action of UCHL1 ................................................................................................. 13 CELL CYCLE PROGRESSION .....................................................................................................
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