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The Role of ING5 in Maintaining Stemness of Brain Tumor Initiating Cells

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The Role of ING5 in Maintaining Stemness of Brain Tumor Initiating Cells University of Calgary PRISM: University of Calgary's Digital Repository Graduate Studies The Vault: Electronic Theses and Dissertations 2016 The Role of ING5 in Maintaining Stemness of Brain Tumor Initiating Cells Wang, Fangwu Jr Wang, F. J. (2016). The Role of ING5 in Maintaining Stemness of Brain Tumor Initiating Cells (Unpublished master's thesis). University of Calgary, Calgary, AB. doi:10.11575/PRISM/28327 http://hdl.handle.net/11023/3233 master thesis University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission. Downloaded from PRISM: https://prism.ucalgary.ca UNIVERSITY OF CALGARY The Role of ING5 in Maintaining Stemness of Brain Tumor Initiating Cells by Fangwu Wang A THESIS SUBMITTED TO THE FACULTY OF GRADUATE STUDIES IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE GRADUATE PROGRAM IN BIOCHEMISTRY AND MOLECULAR BIOLOGY CALGARY, ALBERTA AUGUST, 2016 © Fangwu Wang 2016 Abstract Brain tumor initiating cells (BTICs) are believed to account for the recurrence of glioblastomas following treatment. Recent studies have shown that the stemness of BTICs and intratumoral differentiation hierarchy are determined largely on the epigenetic level. The ING family of epigenetic regulators function in diverse growth regulatory, metastasis and chemoresistance pathways, through targeting different histone acetyltransferase (HAT) and histone deacetylase (HDAC) complexes to the H3K4me3 mark to alter histone acetylation. ING5, a stoichiometric unit of three HAT complexes, has been directly implicated in the maintenance of epidermal stem cells. Here we found that ING5 was highly expressed in BTICs and rapidly downregulated upon in vitro differentiation. Ectopic expression of ING5 promoted self-renewal, prevented lineage differentiation and increased the stem cell pool in the BTIC population, accompanied by an elevated expression of stem cell core transcription factors OCT4, OLIG2 and Nestin. ING5 enhanced the activity of the PI3K/AKT and MEK/ERK pathways in the absence of growth factors to sustain self-renewal of BTICs over serial sphere passage. Transcriptome analysis indicated ING5 was an inducer of the intracellular calcium signaling and follicle stimulating hormone pathways, which were confirmed to co-operatively enhance the self-renewal of BTICs. This study identifies ING5 as a positive regulator of BTIC stem cell character, whose expression negatively correlates with patient prognosis, especially in the Proneural subtype and tumors with low SOX2 expression, therefore suggesting that altering histone acetylation status and the signaling pathways induced by ING5 may provide useful clinical targets to reduce recurrence in glioblastoma. ii Acknowledgements First, I would like to express my gratitude to my supervisor, Dr. Karl Riabowol, for his continuous guidance, encouragement and support during my Master’s study and research. Second, I would like to thank the members of my supervisory committee, Dr. Jennifer Cobb and Dr. Derrick Rancourt, for their very helpful advice and support. And I would like to thank the members in our lab, Mr. Arash Nabbi, Dr. Subhash Thalappilly, Dr. Yang Yang, Ms. Nancy Adam, and the previous student Dr. Uma Rajarajacholan, for their unconditional help and precious advice throughout the two years. I would also like to thank Dr. Alice Wang, Dr. Artee Luchman and Mr. Charles Chesnelong for their valuable inputs and technical supports about our research system. Finally, I would like to thank my dear parents and families for their understanding and kind encouragement during my Master’s study. iii Table of Contents Abstract ............................................................................................................................... ii Acknowledgements ............................................................................................................ iii Table of Contents ............................................................................................................... iv List of Tables ..................................................................................................................... vi List of Figures and Illustrations ........................................................................................ vii List of Symbols, Abbreviations and Nomenclature ........................................................... ix CHAPTER I: INTRODUCTION .........................................................................................1 1.1 Brain tumor epidemiology .......................................................................................1 1.2 Molecular subtypes of Glioblastoma .......................................................................4 1.2.1 Driver mutations in GBM ..................................................................................4 1.2.2 Molecular subtypes of GBM .............................................................................5 1.2.3 Epigenetic subtypes ...........................................................................................5 1.3 Tumor initiating cells in GBM .................................................................................7 1.3.1 The cancer stem cell model ................................................................................7 1.3.2 Isolation and characterization of BTICs ..........................................................14 1.3.3 Cell markers for CNS lineages and BTIC differentiation ...............................16 1.3.4 The cellular origin of BTICs and GBM ..........................................................18 1.4 Mechanisms of BTIC stemness ...............................................................................20 1.4.1 Pluripotency factors in BTIC regulation .........................................................20 1.4.2 Neurodevelopmental factors in BTIC regulation ............................................21 1.4.3 Mitogenic pathways and tumor suppressors in BTIC regulation ....................22 1.4.4 Epigenetic regulation of BTICs .......................................................................24 1.5 The INhibitor of Growth (ING) family of epigenetic regulators .............................28 1.5.1 Major functions of ING1 in growth regulation and cancer biology ................28 1.5.2 Structural features of the ING proteins ...........................................................30 1.5.3 Epigenetic functions of ING proteins ..............................................................31 1.5.4 Functions of ING5 in cancer ...........................................................................32 1.5.5 ING5 in stem cell maintenance .......................................................................33 1.6 Objectives ................................................................................................................38 CHAPTER TWO: MATERIALS AND METHODS ........................................................39 2.1 BTIC cultures and sphere formation assays ............................................................39 2.2 Sphere cell differentiation and immunofluorescence ..............................................39 2.3 pCI plasmid transfection ..........................................................................................40 2.4 PiggyBac stable cell lines ........................................................................................42 2.5 siRNA transfection ..................................................................................................43 2.6 lentiviral-based shRNA system ...............................................................................44 2.7 Quantitative Real-Time PCR ...................................................................................45 2.8 Gene expression microarray and data analysis ........................................................45 2.9 Western blotting .......................................................................................................45 2.10 Flow cytometry ......................................................................................................46 2.11 Cell division symmetry analysis ............................................................................46 2.12 Live cell calcium imaging ......................................................................................47 2.13 Chemicals ...............................................................................................................47 iv 2.14 Statistics .................................................................................................................47 CHAPTER THREE: RESULTS ........................................................................................48 3.1 Determining the expression of ING5 during BTIC differentiation .........................48 3.2 Determining the function of ING5 in BTIC self-renewal ........................................52 3.3 The effects of ING5 on BTIC differentiation ..........................................................64 3.4 Examining the function of ING5 in BTIC self-renewal in the absence of growth factors ................................................................................................................................64 3.5 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