Oxford Prostate Cancer Biology Group
Areas of research
Glycosylation and OGlcNAc transferase
The unfolded protein response and metabolic dysregulation support tumorigenesis by enhancing metabolic capacity whilst mitigating proteotoxic stress. In addition, post-translational modifications including OGlcNAcylation can also sustain tumorigenesis by affecting the turnover of oncogenes and tumour suppressors and the stability and recruitment of transcriptional and DNA repair complexes to sites across the genome. Our particular focus here is on OGlcNAc transferase (OGT) the sole enzyme that catalyses the conjugation of an amino-sugar adduct (O-linked N-acetylglucosamine or OGlcNAc) to the side-chains of serine and threonine amino acids of intracellular proteins. This work is led by Dr Reema Singh and Dr Ninu Poulose. Substrates include c-Myc and Tp53. In many cases, the modification sites are also phosphorylation sites and OGlcNAcylation is therefore a competitive modification that alter intracellular signalling. In addition, OGT can sustain cell proliferation through other activities, including a protease activity. Our work has previously shown that OGT can maintain c-Myc overexpression and restrict the induction of p53 expression in wild-type cancer cells under conditions of oncogenic stress (REF). The latter effect is mediated by VprBP/DCAF1 (REF). Working in collaboration with Dr. Harri Itkonen (a former PhD student, postdoc and now a PI in Helsinki) we have shown that targeting OGT synergises with inhibitors of a sub-set of cyclin-dependent kinases that regulate RNA polymerase II function – for example CDK9 but also CDK7 and CDK12 (REF). Our current work is aimed at further characterising the effects of OGT on transcription and metabolism and in defining the molecular basis for the regulation of p53 activity by VprBP/DCAF1.