PhD Graduate: Shi Chi LEOW
under the A*STAR-Imperial College London Partnership Programme (AIP)
Thesis Title: Novel Functions of NF-κB in Cancer
Cell proliferation involves an active reprogramming of cellular bioenergetic pathways towards glucose metabolism in order to meet the metabolic demands of anabolic growth. NF-κB family of transcription factors coordinate many of the signals that drive proliferation during immunity, inflammation and oncogenesis, but whether NF-κB plays a role in regulating the metabolic reprogramming necessary for cell division during these processes is unknown. In the first study, NF-κB was found to function as a central regulator of energy homeostasis by managing the balance between the utilization of glycolysis and mitochondrial respiration. NF-κB inhibition causes cellular reprogramming to aerobic glycolysis under basal conditions and induces necrosis on glucose deprivation. The metabolic rearrangement that results from NF-κB inhibition bypasses the requirement for tumour suppressor mutation in oncogenic transformation and hinders metabolic adaptation in cancer in vivo. A mechanism through which NF-κB regulates metabolism was also identified and the physiological significance of the role of NF-κB in metabolic adaptation in normal and cancerous cells was demonstrated. Additional functions of NF-κB in oncogenesis mediated via the regulation of telomerase, a tumourigenic factor and downstream target of NF-κB, were also investigated. Telomerase is a ribonucleoprotein enzyme complex that elongates the telomeres of chromosomes to compensate for normal telomeric erosion which occurs at all chromosomes. In recent years, a growing body of evidence has suggested telomere-independent roles of telomerase. In the second study, findings demonstrated a previously unanticipated role for the catalytic subunit of telomerase, TERT, in regulating the Myc-dependent signalling program which provides one explanation for the role of sustained telomerase activity in human cancer. Given that in cancer, Myc is often a passive conduit for upstream oncogenic flux including that of aberrant NF-κB activity, and global inhibition of both Myc and NF-κB could lead to undesirable toxicities, our data might lead to the development of novel combinatorial cancer treatment modalities.