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Regulation of the Oxidative Stress Response by Arid1a

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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 12-2015 REGULATION OF THE OXIDATIVE STRESS RESPONSE BY ARID1A Suet Yan Kwan Follow this and additional works at: https://digitalcommons.library.tmc.edu/utgsbs_dissertations Part of the Oncology Commons Recommended Citation Kwan, Suet Yan, "REGULATION OF THE OXIDATIVE STRESS RESPONSE BY ARID1A" (2015). The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access). 608. https://digitalcommons.library.tmc.edu/utgsbs_dissertations/608 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]. REGULATION OF THE OXIDATIVE STRESS RESPONSE BY ARID1A By Suet Yan Kwan, BSc APPROVED: ______________________________ Kwong-Kwok Wong, Ph.D. Advisory Professor ______________________________ Russell Broaddus, M.D., Ph.D. ______________________________ Joya Chandra, Ph.D. ______________________________ Samuel Mok, Ph.D. ______________________________ Anil Sood, M.D. APPROVED: ____________________________ Dean, The University of Texas Graduate School of Biomedical Sciences at Houston REGULATION OF THE OXIDATIVE STRESS RESPONSE BY ARID1A A DISSERTATION Presented to the Faculty of The University of Texas Health Science Center at Houston and The University of Texas MD Anderson Cancer Center Graduate School of Biomedical Sciences in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY by Suet Yan Kwan, BSc Houston, Texas December, 2015 DEDICATION This thesis is dedicated to my family; mum, dad, Suet Ying, and Rita Urlanda. To Welles Chan, who has remained supportive this whole time. I wouldn’t be able to complete this thesis without him. To my best friend Danny Mak and his family, Mr. and Mrs. Mak, Andy, and Ruby Marasigan, who sadly passed away in 2014. Last but not least, this thesis is also dedicated to my dearest friend Lily Lai. In loving memory of Timothy Chan and Ruby Marasigan. iii ACKNOWLEDGMENTS First of all, I would like to thank Dr. Gershenson and the Molbeck Ovarian Clear Cell Carcinoma Fund for contributing to a part of the funding and made this research possible. I would like to thank Welles Chan. Without him, I would not have been able to complete this thesis. He was always there for me regardless if it was a good or bad day in the lab. He always listened and encouraged me. I would like to thank my advisor Dr. Kwong-Kwok Wong. He accepted me into the GSBS and allowed me to have the freedom to pursue any projects that I came up with. I would like to thank my thesis committee members Dr. Hui-Kuan Lin, Dr. Joya Chandra, Dr. Anil Sood, Dr. Russell Broaddus, and Dr. Samuel Mok for their time and advice in helping to complete this thesis. Dr. Hui-Kuan Lin is truly inspirational and has a huge breath of knowledge. He let me rotate in his lab during my first year, and served in my committee for my whole PhD until his departure from MD Anderson. I would like to thank Dr. Joya Chandra for willing to replace Dr. Hui-Kuan Lin during the final stages of my PhD. She is the expert in studying oxidative stress, and I thank her for giving me advice and her generosity in sharing her lab’s reagents. I would like to thank Dr. Anil Sood for his collaboration on the siRNA screen using ovarian cancer cells and his expertise in studying ovarian cancer. I would like to thank Dr. Russell Broaddus for his advice on how to present the background and results of my research effectively, and having high expectations of me. I would like to thank Dr. Samuel Mok for collaboration with his lab in general and his generosity in sharing his reagents. I would like to thank the current and past members of my lab. Daisy Izaguirre was very supportive both inside and outside of the lab. Yvonne Tsang Lee helped order reagents and maintained the lab. ZhiFei Zu was always friendly and helped generated lentiviruses. In collaborating labs, I would like to thank my sister Suet Ying Kwan for her expertise in analyzing the TCGA data and using the correct statistics. I would like to thank Jean Cheng for her expertise in bioinformatics and analyzing the GDSC database. I would also like to thank Chloe Co for giving me advice and technical support during the early days of my PhD. I would also like to thank members of Mok lab for giving me advice and sharing reagents with me. I would like to thank Leslie Grasse from Dr. Joya Chandra’s lab for teaching me how to do the DCFDA assay. I would also like to thank the North Campus Flow Cytometry Core Facility for their help in doing flow cytometry analyses, especially Duncan Mak who was patient in helping me whenever problems or questions came up. Finally, I would like to thank Dr. Bill Mattox from the GSBS for his advice on how to proceed successfully during the final stages of my PhD. iv ABSTRACT Regulation of the oxidative stress response by ARID1A Suet Yan Kwan, BSc Advisory Professor: Kwong-Kwok Wong, Ph.D. SWI/SNF is mutated in about 20% of all human cancers; in particular ARID1A is the most frequently mutated SWI/SNF subunit. ARID1A is a tumor suppressor gene, inactivating mutations in ARID1A are most frequently found in ovarian and endometrial cancers, specifically uterine corpus endometrioid carcinomas (UCEC), ovarian clear cell carcinomas (OCCC) and ovarian endometrioid carcinomas (OEC). The functional roles of ARID1A are not completely understood and there are limited therapeutic strategies that specifically target ARID1A-mutant cancers. Given that ARID1A expression is lost in cancer, ARID1A mutations cannot be targeted directly and novel therapeutic strategies are required to target ARID1A-mutant cancers. In this study, drug responses between ARID1A-wildtype and ARID1A-mutant cell lines were compared using the ‘Genomics of Drug Sensitivities in Cancer’ database. From this analysis, I found that ARID1A-mutant cell lines are more sensitive to elesclomol, which is a reactive oxygen species (ROS)-inducing agent. This finding was validated using a panel of ovarian and endometrial cancer cell lines, where ARID1A-mutant cell lines exhibited lower IC50 values and higher apoptotic rates when treated with elesclomol. Knockdown and re-expression of ARID1A in ovarian cancer cells showed that ARID1A is required to protect cancer cells from v oxidative stress. In the absence of ARID1A, intracellular ROS levels were increased, and this increase was required for increased cell growth upon ARID1A depletion. Next, I investigated the relationship between ARID1A and NRF2, the major regulator of the antioxidant response in the cell. I found that ARID1A negatively regulates the expression of NRF2. Knockdown of NRF2 in ovarian cancer cell lines revealed that NRF2 expression may be preferentially required for protection from oxidative stress and cell proliferation in ARID1A- mutant cells. Analysis using The Cancer Genome Atlas (TCGA) UCEC dataset revealed that ARID1A-mutant tumor samples have higher expression of NRF2 and NRF2-target genes. In summary, this study revealed novel roles of ARID1A in protecting ovarian cancer cells against oxidative stress. In the absence of ARID1A, NRF2 is up-regulated and may be required to compensate for ARID1A deficiency. These findings suggest that ROS-inducing agents and NRF2 inhibitors may be used as therapeutic strategies in targeting ARID1A-mutant ovarian cancer cells. vi TABLE OF CONTENTS DEDICATION............................................................................................................................. iii ACKNOWLEDGMENTS .......................................................................................................... iv ABSTRACT .................................................................................................................................. v TABLE OF CONTENTS .......................................................................................................... vii LIST OF FIGURES .................................................................................................................... xi LIST OF TABLES .................................................................................................................... xiii CHAPTER 1: INTRODUCTION ............................................................................................... 1 1.1 Ovarian cancer ...................................................................................................................... 1 1.2 Endometriosis-associated ovarian cancers ....................................................................... 2 1.2 The chromatin remodeler SWI/SNF..................................................................................... 3 1.2.1 Chromatin remodeling-independent functions of SWI/SNF ......................................... 4 1.2.2 Alterations of the SWI/SNF complex in cancer ............................................................ 5 1.3 Tumor suppressive
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