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Investigating the Role of HOTTIP, HOXA13 and PSIP1 in Cancer

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Investigating the Role of HOTTIP, HOXA13 and PSIP1 in Cancer Investigating the role of HOTTIP, HOXA13 and PSIP1 in cancer Fionnuala McKenna, B.Sc. (Hons) A thesis submitted for the degree of Doctor of Philosophy. School of Life Sciences University of Essex May 2020 Statement of originality I clarify that the content of this thesis is the result of my own work. All sources and previously published material used are acknowledged accordingly in the text. I further confirm that this work has not been previously used for the award of any degree. ii Acknowledgements Firstly, I would like to thank my family for their continued love and support throughout this PhD journey. To my Mum, Dad, Conor, Eimear and Ciara, thank you for your encouragement and always listening to me going on about my cells! I would like to thank my PhD supervisors, Dr Greg Brooke and Dr Pradeepa Madapura, for all their guidance and support throughout my PhD. I have a learnt a great deal from my time in each of their labs. I would like to thank the members of the Genomics and Computational Biology group for their support and friendship. In particular Dr Mohab Helmy, Dr Patrick Martin and Dr Chris Clarkson for their patience in helping me to dip my toe into the world of bioinformatics! I of course, would like to thank Dr Myles Garstang, for his help and support during the beginning of my PhD. I would also like to thank the members of the Molecular Oncology group in lab 5.20. Working alongside them in the last two years of my PhD has been a pleasure. I have been fortunate to be a part of a large PhD cohort at the University of Essex that has provided a never-ending support system as well as constant fun. To Kirsty, Danni, Amie, Shellie, Jacob and many others, thanks for the coffee, the wine and for always being there. To my non-Essex friends, mainly Leanne and Becky, thanks for always being my cheerleaders in everything I do; I am lucky to have you. Finally, thank you to the University of Essex for funding my PhD and allowing me to carry out this work. I am extremely grateful for the opportunity I have been given to complete this degree and have thoroughly enjoyed my time at Essex. iii Summary Worldwide, colorectal cancer (CRC) is the third most prevalent cancer and prostate cancer (PCa) is the second most prominent cancer in men. Treatments for both CRC and PCa have greatly improved over the last 10-20 years; however, there is still a high mortality rate for both cancers. There is therefore a great need to better understand the factors that drive disease development and progression, and therapy resistance. Long non-coding RNAs (lncRNAs) have gained attention in recent years as potential therapeutic targets for cancer. HOTTIP is one such lncRNA that has previously been implicated in CRC and PCa. HOTTIP is located on the 5’ end of the HOXA locus and regulates nearby HOXA genes including HOXA13 in cis. It has previously been shown that HOTTIP and HOXA genes are regulated by the oncogenic PSIP1 protein. Using both siRNA mediated knockdown and CRISPR-Cas9 mediated genetic knockout approaches, the role of HOTTIP, HOXA13 and PSIP1 were investigated in both CRC and PCa. Through loss of function studies, depletion of HOTTIP, HOXA13 and PSIP1 led to increased sensitivity to chemotherapeutic drugs. This has not previously been observed for HOXA13 in PCa, or HOTTIP, HOXA13 and PSIP1 in CRC. These observations suggest that further study of these genes may help with understanding therapy resistance in CRC and PCa. More in-depth characterisation of how these genes are regulated may identify methods to enhance therapy response or re- sensitise tumours to chemotherapy. iv Abbreviations 5FU = Fluorouracil AR = Androgen receptor Bcl-2 = B-cell lymphoma 2 BMI = Body mass index bp = Base pairs BPH = Benign prostatic hyperplasia C. difficile = Clostridium difficile CASC15 = Cancer susceptibility candidate 15 CD = Crohn's disease cDNA = Complementary DNA CIMP = CpG island methylation CIN = chromosomal instability CR = Charged region CRC = Colorectal cancer CRISPRa = CRISPR activation CRPC = Castrate resistant prostate cancer DOC = Docetaxel DSB = Double strand break EMT = Epithelial-to-mesenchymal transition ESCC = Esophageal squamous cell carcinoma FDA = Food and Drug Administration FOBT = Fecal occult blood test gRNA = Guide RNA h = Hours H3K27me3 = Histone H3 lysine 27 trimethylation H3K4me3 = Histone H3 lysine 4 trimethylation HCC = Hepatocellular carcinoma HIV = Human immunodeficiency virus HNPCC = Hereditary non-polyposis colorectal cancer HOTAIRM1 = HOXA transcript antisense RNA, myeloid-specific 1 HOTTIP = HOXA transcript at the distal tip HOX = HOMEOBOX v IBD = Inflammatory bowel disease IBD = Integrase binding domain IBS = Irritable bowel syndrome KD = Knock down kDa = Kilodaltons K-M plot = Kaplan Meier plot KO = Knock out L19 = 60S ribosomal protein L19 LEDGF = Lens epithelium-derived growth factor lncRNA = Long non-coding RNA MLL1 = Mixed Lineage Leukaemia 1 MMR = Mismatch repair mRNA = Messenger RNA ncRNA = Non-coding RNA NLS = Nuclear localisation signal nm = Nanometre NTC = Non-targeting control OD = Optical density OX = Oxaliplatin PC4 = Positive Cofactor 4 PCa = Prostate cancer PCA3 = Prostate Cancer Antigen 3 PCDHA-PC = Protocadherin-PC PcG = Polycomb group PCNA = Proliferating cell nuclear antigen PI = Propidium iodide PIA = Proliferative inflammatory atrophy PIN = Prostatic intraepithelial neoplasia PRC1 = Polycomb repressive complex 1 PRC2 = Polycomb repressive complex 2 PRE = Polycomb response elements PSIP1 = PC4- and SF-interacting protein 1 PWWP = Proline Tryptophan Tryptophan Proline RALP = Robot-assisted laparoscopic radical prostatectomy vi RIN = RNA integrity number RNA Pol II = RNA Polymerase II RPKM = Reads per kilobase of transcript per million mapped reads RT-qPCR = Quantitative reverse transcription PCR SDS-PAGE = Sodium dodecyl sulfate-polyacrylamide gel electrophoresis siRNA = Short interfering RNA SMA = Superior mesenteric artery SP-RALP = Single port robot-assisted laparoscopic radical prostatectomy TFs = Transcription factors Trx = Trithorax TS = Thymidylate synthase TSS = Transcriptional start site TUG1 = Taurine UpRegulated 1 UC = Ulcerative colitis WDR5 = WD repeat-containing protein 5 vii Table of contents Statement of originality ................................................................................................. ii Acknowledgements ...................................................................................................... iii Summary ....................................................................................................................... iv Abbreviations ................................................................................................................. v Table of contents ........................................................................................................ viii List of figures ............................................................................................................... xiv List of Tables .............................................................................................................. xvii 1. General Introduction .................................................................................................1 1.1 Colorectal cancer ............................................................................................1 1.1.1 Diseases of the bowel and colon .............................................................1 1.1.2 Colorectal cancer statistics ......................................................................1 1.1.2.1 Epidemiology of colorectal cancer ................................................................ 2 1.1.2.2 Symptoms and diagnosis of colorectal cancer .............................................. 3 1.1.2.3 Histology and grading of colorectal cancer ................................................... 4 1.1.2.4 Colorectal cancer risk factors ........................................................................ 7 1.1.2.5 Screening and treating colorectal cancer ...................................................... 9 1.2 Prostate Cancer .............................................................................................11 1.2.1 The prostate gland .................................................................................11 1.2.2 Prostate cancer ......................................................................................12 1.2.2.1 Symptoms and diagnosis of prostate cancer .............................................. 13 1.2.2.2 Histology and grading of prostate cancer ................................................... 14 1.2.2.3 Prostate cancer risk factors ......................................................................... 17 1.2.2.4 Screening and treating prostate cancer ...................................................... 18 1.3 Long non-coding RNAs ..................................................................................22 1.3.1 LncRNAs and gene regulation ................................................................24 1.3.2 LncRNAs in disease ................................................................................24 1.3.2.1 LncRNAs in cancer ....................................................................................... 25 1.4 HOX genes .....................................................................................................26 1.4.1 HOX genes in cancer ..............................................................................30 1.4.1.1 HOXA13 in colorectal cancer ......................................................................
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