Redox regulation of estrogen receptor alpha and sodium hydrogen exchanger 1 gene expression by hydrogen peroxide

REDOX REGULATION OF ESTROGEN RECEPTOR ALPHA AND SODIUM HYDROGEN EXCHANGER GENE EXPRESSION BY HYDROGEN PEROXIDE CHUA SUI HUAY BSc (HONOURS) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY NUS GRADUATE SCHOOL FOR INTEGRATIVE SCIENCES AND ENGINEERING NATIONAL UNIVERSITY OF SINGAPORE 2011 ACKNOWLEDGEMENTS I want to express my heartfelt gratitude for my supervisor Associate Professor MarieVeronique Clement, Department of Biochemistry I am thankful that she allowed me to join the lab during my honors year and for continuing my graduate study under her A/P Clement was not just a supervisor, but a mentor who is always willing to listen, to encourage and to share her vast knowledge I would like to thank her for her constant encouragement, patience and faith in my abilities to complete this study I would also like to thank my co-supervisor Dr Alan Kumar for his guidance and support throughout the course of my graduate study in NUS I am grateful for Professor Shazib Pervaiz for being on my thesis advisory committee and for his positive feedback on the direction of my project My warmest thanks to my lab mates in Biochemistry department, for making the long days in lab enjoyable Special thanks to San Min and Jeya who helped me to proofread my thesis I also want to thank Mui Khin for helping me with all the ordering of reagents for my project Thank you NUMI girls for being my great lab mates and friends Thanks for being there to cheer me on and also for being part of my sister gang during my wedding I will certainly miss those days that we out together Finally, my deepest gratitude to my family for their encouragement and support throughout the years, and a special thanks to Zong Hao, who has stood by me through the good and bad times ii SUMMARY There is mounting evidence that implicates reactive oxygen species (ROS) as an important signaling molecule in various physiological processes In contrast to the wealth of information on gene up-regulation by ROS, little attention has been paid to the down-regulation of gene expression by ROS In this thesis, we have studied how two important genes, estrogen receptor alpha (ERα) and sodium hydrogen exchanger (NHE1) were redox-regulated by H2O2 In the first part of the study, the regulation of ERα by oxidative stress induced by the exposure of MCF7 cells to H2O2 was investigated The data supported that ERα protein is down-regulated when exposed to oxidative stress The down-regulation of ERα protein occurs not through proteosomal degradation pathway, but via the decrease in ERα mRNA level We found that Akt, MAPK and caspases were not involved in the down-regulation of ERα by H2O2 Instead, H2O2 inhibition of ERα expression involves an oxidation event that is reversible by the addition of reducing agent, DTT We also demonstrated that 15d-PGJ2 suppressed ERα expression via the production of ROS ERα down-regulation resulted in decreased ERα-responsive gene expression and impaired estrogen signaling These effects could have contributed to the growth arrest observed in H2O2 treated MCF7 cells In the second part of the study, the down-regulation of NHE1 by H2O2 was examined We found that the minimal promoter region required for full transcription activation lies on the 0.15kb of NHE1 promoter This region is also regulated by H2O2 The regulation of NHE1 by H2O2 is similar to the regulation of ERα H2O2 targets NHE1 at the mRNA level in a reversible manner The down-regulation involves an oxidation mechanism which is reversible by reducing agents DTT and BME The drug 15diii PGJ2 was also shown to down-regulate NHE1 promoter activity via the production of ROS Finally, the data suggested that AP2 is not the transcription factor for NHE1 and is not a target in H2O2 mediated down-regulation of NHE1 iv TABLE OF CONTENTS ACKNOWLEDGEMENTS ………………………………………………… ………II SUMMARY………………………………………………………………………….III TABLE OF CONTENTS…………………… …………………………………… V LIST OF TABLES………………………………………………………………… X LIST OF FIGURES……………………………………………… ……………… XI ABBREVIATIONS…………………………………………………………… …XVI PUBLICATIONS AND PRESENTATIONS…………………………………… XIX CHAPTER 1: INTRODUCTION 1.1 FREE RADICALS, REACTIVE SPECIES AND REDOX BALANCE 1.1.1 Reactive oxygen species 1.1.2 The antioxidant system 1.1.3 Hydrogen peroxide as a signaling molecule 1.2 REDOX REGULATION OF GENE EXPRESSION 10 1.2.1 Transcriptional regulation 10 1.2.2 mRNA stability 13 1.2.3 Direct oxidative modification 14 1.2.4 Regulation of protein turnover 16 1.3 ESTROGEN RECEPTOR 17 1.3.1 Estrogen and estrogen receptors: Introduction 17 1.3.2 Estrogen receptor and genomic signaling 20 1.3.3 Membrane and cytoplasmic ER signaling 21 1.3.4 Regulation of estrogen receptors 23 1.3.5 Estrogen and estrogen receptors in human breast cancer 27 v 1.4 THE SODIUM HYDROGEN EXCHANGER 29 1.4.1 pH regulation in the cells 29 1.4.2 Mammalian Na+/H+ exchanger 30 1.4.3 NHE1: Basic structure 31 1.4.4 Physiological and pathological roles of NHE1 33 1.4.5 Regulation of NHE1 37 1.4.6 Regulation of NHE1 gene transcription 39 1.5 AIM OF STUDY 41 CHAPTER 2: MATERIALS AND METHODS 43 2.1 MATERIALS 43 2.1.1 Chemicals and reagents 43 2.1.2 Antibodies 44 2.1.3 Plasmids 44 2.1.4 Cell lines and cell culture 45 2.2 METHODS 47 2.2.1 Treatment of cells with hydrogen peroxide (H2O2) and other compounds………………………………………………………………………47 2.2.2 Morphology studies 47 2.2.3 Crystal violet assay 47 2.2.4 Plasmid transfection 48 2.2.5 Small interfering RNA (siRNA) transfection 48 2.2.6 Protein concentration determination 49 2.2.7 SDS-PAGE and western blot 50 2.2.8 Caspase assay 51 2.2.9 Single and dual luciferase assay 52 2.2.10 Chloramphenicol acetyl transferase (CAT) assay 53 2.2.11 RNA isolation 54 2.2.12 Reverse transcription (RT) and real-time chain polymerase reaction (PCR)……………………………………………………………………………54 2.2.13 Intracellular ROS measurement by CM-H2DCFDA 55 2.2.14 Nuclear-cytoplasmic fractionation 55 2.2.15 Electromobility shift assay (EMSA) 56 vi 2.2.16 Statistical analysis 57 CHAPTER 3A: RESULTS – REDOX REGULATION OF ERα 58 3A.1 H2O2 AND THE EXPRESSION OF ERα PROTEIN 58 3A.1.1 Morphology and growth of MCF7 cells upon exposure to H2O2 58 3A.1.2 Effect of H2O2 on the expression of ER protein 61 3A.1.3 Effects of estrogen on H2O2 down-regulation of ERα 66 3A.1.4 Time-dependent regulation of ERα protein by H2O2 68 3A.1.5 Chronic ROS leads to continuous suppression of ERα 70 3A.1.6 ROS involved in the down-regulation of ERα expression 71 3A.1.7 Effect of peroxynitrite on the expression of ERα protein 73 3A.2 DOWN-REGULATION OF ERα DOES NOT INVOLVE THE PROTEOSOMAL DEGRADATION PATHWAY 74 3A.3 THE DOWN-REGULATION OF ERα BY H2O2 IS VIA DECREASE IN ERα mRNA LEVEL 78 3A.3.1 Effects of H2O2 on the expression of ERα mRNA level 78 3A.3.2 New protein synthesis is not required for H2O2-induced down-regulation of ERα mRNA 81 3A.4 MECHANISM INVOLVED IN H2O2-INDUCED DOWN-REGULATION OF ERα 82 3A.4.1 Role of Akt activation in H2O2 down-regulation of ERα 82 3A.4.2 Role of MAPK activation in H2O2 down-regulation of ERα 84 3A.4.3 Role of caspases in H2O2 down-regulation of ERα 87 3A.4.4 Oxidation is involved in the down-regulation of ERα by H2O2 89 3A.5 EFFECTS OF ERα DOWN-REGULATION ON ER RESPONSE GENES.……………………………………………………………………………94 3A.5.1 Down-regulation of ERα by H2O2 inhibits estrogen response element (ERE) activity 94 3A.5.2 H2O2 down-regulates ERα response genes 96 vii 3A.6 15-DEOXY-DELTA-12,14-PROSTAGLANDIN J2 (15D-PGJ2) DOWNREGULATION OF ERα IS VIA ROS 99 3A.6.1 Morphology and growth of MCF7 cells exposed to 15d-PGJ2 99 3A.6.2 15d-PGJ2 down-regulates ERα at the protein and mRNA level 101 3A.6.3 15d-PGJ2 produces ROS in MCF7 cells 103 3A.6.4 Scavenging of ROS by NAC restores cell growth and ERα expression … ……………………………………………………………… 107 CHAPTER 3B: RESULTS – REDOX REGULATION OF NHE1…………… …110 3B.1 DOWN-REGULATION OF NHE1 BY H2O2 110 3B.1.1 Identification of crucial region in the promoter of NHE1 110 3B.1.2 H2O2 down-regulates 0.15kb proximal NHE1 promoter activity 114 3B.1.3 Oxidation is involved in the down-regulation of 0.15kb proximal NHE1 promoter activity and endogenous mRNA level by H2O2 118 3B.1.4 Peroxynitrite down-regulates 0.15kb NHE1 promoter activity 124 3B.1.5 Role of caspases in H2O2-mediated down-regulation of 0.15kb NHE1 proximal promoter activity 125 3B.1.6 15d-PGJ2 down-regulates 0.15kb NHE1 promoter activity and NHE1 mRNA level via ROS production 129 3B.1.7 H2O2 down-regulates NHE1 expression in MCF7 breast cancer cells ……………………………………………………………………………135 3B.2 TRANSCRIPTION FACTOR INVOLVED IN H2O2 DOWN-REGULATION OF NHE1 EXPRESSION 141 3B.2.1 Analysis of the region between 0.15kb and 0.12kb of NHE1 promoter …………………………………………………………………… 141 3B.2.2 Transcription factor AP2, SP1 and COUP 145 3B.2.3 Investigation of AP2 as transcription factor for NHE1 148 CHAPTER 4: DISCUSSION……………………………………………………….162 4.1 REDOX REGULATION OF ERα 162 4.1.1 Regulation of ERα expression and function by oxidative stress 163 4.1.2 Oxidation as the mechanism mediating H2O2-induced down-regulation of ERα…………………………………………………………………………170 4.1.3 Significances of ERα as a redox regulated gene 172 4.1.4 ROS-induced suppression of ERα gene expression: Possible development of ERα-negative breast cancer phenotype 178 viii 4.2 REDOX REGULATION OF NHE1 181 4.2.1 H2O2 regulates an important region of NHE1 promoter 181 4.2.2 Targeting NHE1 expression through ROS-producing agents ……….184 4.2.3 AP2 is a transcription factor of NHE1: True or false? 186 4.3 ERα AND NHE1: TWO IMPORTANT MEDIATORS OF CANCER CELL SURVIVAL 189 4.3.1 H2O2 regulates ERα and NHE1 in similar ways 189 4.3.2 Relevance of ERα and NHE1 expression as prognosis markers in breast cancer………………………………………………………………………… 191 4.4 FUTURE WORK 192 4.4.1 To determine if H2O2 affect the stability of ERα mRNA 192 4.4.2 To investigate the mechanism of ROS-producing compounds in suppression of ERα expression …193 4.4.3 To identify the transcription factor that regulates NHE1 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REGULATION OF NHE1…………… ? ?11 0 3B .1 DOWN -REGULATION OF NHE1 BY H2O2 11 0 3B .1. 1 Identification of crucial region in the promoter of NHE1 11 0 3B .1. 2 H2O2 down-regulates 0 .15 kb proximal NHE1 promoter... signaling 21 1.3.4 Regulation of estrogen receptors 23 1. 3.5 Estrogen and estrogen receptors in human breast cancer 27 v 1. 4 THE SODIUM HYDROGEN EXCHANGER 29 1. 4 .1 pH regulation. .. turnover 16 1. 3 ESTROGEN RECEPTOR 17 1. 3 .1 Estrogen and estrogen receptors: Introduction 17 1. 3.2 Estrogen receptor and genomic signaling 20 1. 3.3 Membrane and cytoplasmic