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Developing Strategies to Re-Activate Epigenetically Silenced Tumor Suppressor Genes in Acute Myeloid Leukemia

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Developing Strategies to Re-Activate Epigenetically Silenced Tumor Suppressor Genes in Acute Myeloid Leukemia DEVELOPING STRATEGIES TO RE-ACTIVATE EPIGENETICALLY SILENCED TUMOR SUPPRESSOR GENES IN ACUTE MYELOID LEUKEMIA A Thesis Submitted to the College of Graduate Studies and Research In Partial Fulfillment of the Requirements For the Degree of Masters of Science In the Department of Biochemistry University of Saskatchewan Saskatoon By Carolina Gonzalez Zuluaga © Copyright Carolina Gonzalez Zuluaga, December 2010. All rights reserved Permission to Use In presenting this thesis in partial fulfilment of the requirements for a Postgraduate degree from the University of Saskatchewan, I agree that the Libraries of this University may make it freely available for inspection. I further agree that permission for copying of this thesis in any manner, in whole or in part, for scholarly purposes may be granted by the professor or professors who supervised my thesis work or, in their absence, by the Head of the Department or the Dean of the College in which my thesis work was done. It is understood that any copying or publication or use of this thesis or parts thereof for financial gain shall not be allowed without my written permission. It is also understood that due recognition shall be given to me and to the University of Saskatchewan in any scholarly use which may be made of any material in my thesis. Requests for permission to copy or to make other use of material in this thesis in whole or part should be addressed to: Head of the Department of Biochemistry University of Saskatchewan Saskatoon, Saskatchewan S7N 5E5 ABSTRACT Epigenetic mechanisms are essential for normal cell development. Alteration in those normal processes leads to malignant cell transformation and with this to cancer development. Use of inhibitors that alter the epigenetics of DNA methylation and histone post translational modifications has lead to the exploration of the epigenetic mechanism involved in silencing of tumor suppressor genes in cancer, including acute myeloid leukemia (AML). Moreover, combinations of inhibitors that target various epigenetic enzymes have being recognized to be more effective in the re-activation of tumor suppressor genes than individual drug treatments. Here, we reported that p15, p21 and E-cadherin genes are more effectively re-expressed using a combination of DNA methyltransferase and histone methyltransferase inhibitors in AML cell lines. Re-expression of hypermethylated p15 and E-cadherin genes required reduced levels of promoter histone 3 lysine 9 (H3K9) methylation rather than inhibition of DNA methylation itself. Moreover, induction of p21 expression was associated with changes in promoter histone 3 lysine 9 methylation (H3K9Me) by achieving inhibition of the histone methyltransferase, SUV39H1, activity. Altogether, our results highlight the potential of combining epigenetic drugs in the re-activation of epigenetically silenced tumor suppressor genes and the need for evaluating histone methyltransferases as therapeutic targets for treatment of acute myeloid malignancies. i ACKNOWLEDGEMENTS I want to give many thanks to my supervisor Dr. Ron Geyer, without his patience, guidance and directions the achievement of this project could not be finished. Acknowledgements, to Dr. Roesler for giving me continued encouragement and guidance. To my entire committee member Dr. Khandelwal, Dr. Wilson and Dr. Roesler for the guidance and continue feedback in this research project. To Margaret Ross for her infinite help and patience in assisting me with everything related to the graduate program. I would like to especially thank Asha and Erika for their continued help and guidance in many of my experiments. Also, I want to thank all the members of Dr. Geyer Lab, Wendy Bernhard, Khris Barreto, Landon, Wayne Hill and specially to Alberto Aparicio, Theodora Zlateva and Bharathi Vellalore for their friendship and support during my graduate studies. I also wish to thank Jennifer Nyarko for being a friend and support during this time as well as Family Gomez and all my friends in Saskatoon. Special thanks to my Family and my fiancé and friend Juan for their encouragement, support and love throughout these years. Finally, I want to dedicate this achievement to the memory of my mother and Elaine, two great women whose encouragement taught me that for more difficult that a situation would be you always need to keep your head high and have the strength to continue in life. Thank you all. ii TABLE OF CONTENTS ABSTRACT ................................................................................................................................... i ACKNOWLEDGEMENTS .......................................................................................................... ii LIST OF TABLES ...................................................................................................................... vii LIST OF FIGURES ................................................................................................................... viii LIST OF ABBREVIATIONS ...................................................................................................... xi 1. INTRODUCTION ..................................................................................................................... 1 2. REVIEW OF THE LITERATURE ........................................................................................... 2 2.1. Molecular basis of cancer ................................................................................................... 2 2.1.1. Multistep molecular carcinogenesis ............................................................................. 2 2.2. Chromatin organization and regulation .............................................................................. 3 2.2.1. Chromatin structure ...................................................................................................... 3 2.3. Epigenetics .......................................................................................................................... 4 2.3.1. DNA methylation ......................................................................................................... 4 2.3.1.1. CpG island hypermethylation ................................................................................ 6 2.3.1.2. DNA methyltransferases ........................................................................................ 6 2.3.1.3. DNA methyltransferases inhibitors ........................................................................ 7 2.3.1.4. 5-Aza-2-deoxycytidine (DAC) .............................................................................. 9 2.3.2. Histone methylation ................................................................................................... 11 2.3.2.1. Histone 3 lysine 9 methylation (H3K9Me) .......................................................... 13 2.3.2.2. Histone methyltransferase SUV39H1 .................................................................. 13 2.3.2.3. Histone methyltransferase G9a ............................................................................ 14 2.3.3. Histone methyltransferase inhibitors .......................................................................... 15 2.3.3.1. Chaetocin.............................................................................................................. 15 2.3.3.2. BIX-01294 ........................................................................................................... 16 2.3.4. Regulation of epigenetic events in cancer .................................................................. 17 2.4. Acute myeloid leukemia ................................................................................................... 19 2.5. Tumor suppressor genes in acute myeloid leukemia ........................................................ 21 iii 2.5.1. p15 (INKb) gene ............................................................................................................. 21 2.5.2. p21 (WAF1/CIP1) gene ...................................................................................................... 23 2.5.3. E-cadherin gene .......................................................................................................... 24 3. EXPERIMENTAL OBJECTIVES .......................................................................................... 26 4. MATERIALS AND METHODS ............................................................................................ 27 4.1. Reagents and suppliers ..................................................................................................... 27 4.2. Oligonucleotides ............................................................................................................... 28 4.3. Antibodies ......................................................................................................................... 30 4.4. Cell lines and culture conditions ....................................................................................... 30 4.5. Drug treatments ................................................................................................................ 31 4.6. Molecular techniques ....................................................................................................... 31 4.6.1. DNA extraction from AML cells ............................................................................... 31 4.6.2. RNA extraction from AML cells ................................................................................ 31 4.6.3. Reverse transcriptase
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