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The Innate Immune Kinase Ikkε As a Novel Regulator of PSAT1 and Serine Metabolism

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The Innate Immune Kinase Ikkε As a Novel Regulator of PSAT1 and Serine Metabolism The innate immune kinase IKKε as a novel regulator of PSAT1 and serine metabolism William Edward Jones A PhD thesis submitted in partial fulfilment of the requirements of the Degree of Doctor of Philosophy Principal Supervisor: Dr Katiuscia Bianchi Secondary Supervisor: Dr Tyson Sharp Barts Cancer Institute Barts and the London School of Medicine and Dentistry Queen Mary University of London May 02, 2018 Statement of Originality I, William Edward Jones, confirm that the research included within this thesis is my own work and that where it has been carried out in collaboration with, or supported by others, that this is duly acknowledged below, and my contribution indicated. Previously published material is also acknowledged below. I attest that I have exercised reasonable care to ensure that the work is original and does not, to the best of my knowledge, break any UK law, infringe any third party’s copyright or other Intellectual Property Right, or contain any confidential material. I accept that the College has the right to use plagiarism detection software to check the electronic version of the thesis. I confirm that this thesis has not been previously submitted for the award of a degree by this or any other university. The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author. Signature: Date: 2nd May 2018 Details of collaboration and publications: • The work presented throughout this thesis is currently under peer review at The EMBO Journal in advance of publication. • Work presented in this thesis was selected for presentation in poster form at Cell Symposia: Hallmarks of Cancer 2016 in Ghent, Belgium i Contents • Collaborations: • Labelled metabolite analysis was performed in collaboration with Dr Ruoyan Xu (Barts Cancer Institute, London, UK) who prepared the samples, and Dr Christian Frezza and Dr Sofia De Costa (MRC Cancer Unit, Cambridge, UK) who performed mass spectrometry analysis and provided the heat-maps of significantly modified results presented in Figures 3.5 and 3.6. This author contributed to the subsequent analysis of these results. • Phosphoproteomic analysis was performed in collaboration with Dr Ewa Wilcz- Villega (Barts Cancer Institute, London, UK) who prepared the samples, and Dr Pedro Cutillas and Dr Vinothini Rajeeve (Barts Cancer Institute, London, UK) who performed mass spectrometry analysis and the KEGGs pathway analysis of the results. This author contributed to the subsequent analysis of these results. • The in vitro kinase assay was performed in collaboration with Dr Pedro Cutillas and Dr Vinothini Rajeeve. This author prepared the samples, and Dr Cutillas and Dr Rajeeve performed the mass spectrometry analysis. • The promoter analysis investigating the presence of transcription factor binding sites in the promoter regions of PHGDH, PSAT1 and PSPH genes was performed in collaboration with Professor Claude Chelala and Dr Ai Nagano of the bioinformatics team at Barts Cancer Institute, London, UK. This author contributed to the analysis of these results. • The investigations into the effect of siRNA-mediated suppression of ATF4 in breast cancer cell lines were performed with the support of Miss Sheila Olendo Barasa, a masters degree student under this authors supervision in the lab. Miss Barasa performed two replica for the experiments presented in Figure 5.8. • The data describing analysis of oxygen consumption rate was kindly provided by Dr Ruoyan Xu. • Analysis of mitochondrial membrane potential by TMRM staining was performed in collaboration with Professor Gyorgy Szabadkai (University College London, London, UK) who imaged mitochondrial staining following preparation of cells by Dr Ruoyan Xu and this author. ii Acknowledgements My first and foremost thanks must go to my supervisor, Katiuscia, who made what I can only assume was a significant gamble and took on a relatively unproven young student, giving him the opportunity to learn and thrive amongst a fantastic group of people. Thank you for your patience with all the failed westerns, for helping me to become a capable and confident scientist, for offering me the freedom to drive my own project and work in a dynamic and exciting field, but ultimately, for taking a chance on a nervous young undergraduate student who wore a tie for his preliminary Skype interview. My thanks also go to both Ruoyan and Ewa. The Bianchi lab membership has fluctuated over 3 and a half years, as masters and undergraduate students have come and gone, but our core group of 3 has remained. Thank you both for your perpetual willingness to help. Your endless endurance against my steady flow of questions and requests for assistance has not gone unappreciated and it has been a genuine pleasure working alongside you both. I would also like to thank both Tyson, my secondary supervisor and our centre lead, for his support and guidance and, of course, all the collaborators on this project, who have provided crucial assistance at key points in the work presented within. Thank you to Christian Frezza and Sofia De Costa for the labelled metabolite analysis, to Pedro Cutillas and Vinothini Rajeeve for the various mass spectrometry work, to Claude Chelala and Ai Nagano for the promoter analysis, to Gyorgy Szabadkai for the TMRM staining and to Tencho Tenev for unparalleled assistance with cloning. My gratitude must also go to the Medical Research Council for their funding, without which I could not have performed this work in the first place. To the members of the KiSS group, both past and present, thank you for making the Barts Cancer Institute 3rd floor sauna a thoroughly enjoyable place to work. I hope you will continue to cope without mum around. Particular thanks must go to the members of the McClelland lab, of whom I am absolutely, definitely not a member. Nadeem, Naoka, Alice and Tineke, you all saved me from the eternal threat of solitary lunches and provided much-needed social distractions whenever it was most required. I hope the newest members of your lab Laura and Sarah will enjoy their time with you as much as I did, and I sincerely hope that our paths will continue to cross in the future. For their consistent love and care I must thank my family, particularly Mum and Dad. Your invaluable wisdom on work, life, the universe and everything have seen me through the ups and downs of my first quarter century and a seemingly eternal education. I certainly cannot express the full extent of my gratitude with so few words. I love you both. Lastly, but most importantly, my thanks go to my fiancée Charlotte. This thesis, which I am sure you will find long, dull and tedious, exists because of the love you have given me. To put it simply, I would not have achieved everything I have without your support and I owe you everything. As the end of this journey draws near, I am excited that our true adventure can finally begin. iii Abstract Induced and activated as part of the innate immune response, the first line of defence against bacterial or viral infections, Inhibitor of Kappa-B Kinase ε (IKKε) triggers NF-κB and IFNβ signalling. Whilst not expressed at basal levels in healthy cells and tissue, the kinase is overexpressed in roughly 30% of human breast cancer cases, driving oncogenesis through aberrant activation of NF-κB. The impracticality of therapeutic targeting of NF-κB for cancer treatment has led to a requirement for greater understanding of IKKε’s oncogenic potential to treat tumours driven by the kinase. Considering that IKKε alters cellular metabolism in dendritic cells, promoting aerobic glycolysis akin to the metabolic phenotype observed in cancer, it was hypothesised that the kinase would play a similar role in breast cancer. Using a Flp-In 293 model of IKKε induction and suppressing IKKε expression in a panel of breast cancer cell lines using siRNA, IKKε-dependent changes in cellular metabolism were characterised using labelled metabolite analysis. IKKε was found to induce serine biosynthesis, an important pathway in breast cancer development that supports glutamine-fuelling of the TCA cycle and contributes to one carbon metabolism to maintain redox balance. Promotion of serine biosynthesis occurred via a dual mechanism. Firstly, PSAT1, the second enzyme of the pathway, was found to be phosphorylated in an IKKε-dependent manner, promoting protein stabilisation. Secondly, an IKKε-dependent transcriptional upregulation of all three serine biosynthesis enzymes, PHGDH, PSAT1 and PSPH, was observed, induced by the inhibition of mitochondrial activity and the subsequent induction of ATF4-mediated mitochondria-to-nucleus retrograde signalling. These data demonstrate a previously uncharacterised mechanism of metabolic regulation by IKKε and highlight new potential therapeutic targets for the treatment of IKKε-driven breast cancer in the form of the enzymes of the serine biosynthesis pathway. iv Contents Statement of Originality ......................................................................................................................... i Acknowledgements ............................................................................................................................... iii Abstract ................................................................................................................................................ iv List of Figures .......................................................................................................................................
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