Regulation of SIRT1 protein in cancer metabolism and ribosome biogenesis

The deacetylase signalling enzyme SIRT1 has been subject of much research interest, in part due to its ability to promote the survival of cancer cells, and redundancy in non-cancer cell viability. The deacetylation and downregulation of p53 and the FOXO family of tumour suppressors has been identified among the downstream effects of SIRT1 in cancer. Importantly, the regulation of cancer cell survival upstream of SIRT1 has not been well characterised, creating the possibility of targeting SIRT1 via its endogenous regulatory mechanisms for anti-cancer therapeutic gain. This Thesis validates two putative anti-cancer targets that promote SIRT1 activity and have also been implicated in essential processes that are commonly aberrant in cancer: cellular metabolism and translational control.
SIRT1 is a sirtuin, which are unique deacetylases due to their requirement for the redox metabolite NAD+ as a co-enzyme. The potential to promote SIRT1 activity via provision of NAD+ is analysed here by targeting the metabolic enzyme lactate dehydrogenase A (LDH-A). LDH-A catalyses NAD+ production and promotes aberrant cancer metabolism by perpetuating the Anaerobic Glycolysis cycle. A link is found between cancer metabolism and SIRT1 activity, with LDH-A observed to suppress cancer cell apoptosis via a mechanism consistent with SIRT1 activation.
SIRT1 is also subject to regulation by direct interaction with the protein AROS (Active Regulator Of SIRT1). AROS associates with and promotes SIRT1 pro-survival function in cancer cells. Here, AROS is found to specifically promote cancer cell survival, via a mechanism appearing to involve SIRT1 and downstream substrates. However, AROS regulation of SIRT1 is not as simple as originally thought, varying by cell context and substrate. Further to its role in directing SIRT1 activity, AROS also forms a binding interaction with the ribosomal protein RPS19. The effect of AROS upon RPS19 protein and function is analysed for the first time, revealing a role for AROS in 40S ribosomal subunit biogenesis. Beyond this, AROS is discussed as a regulator of translation, and the functional interplay between RPS19, AROS and SIRT1 is described. This provides a link between cancer associated anti-apoptotic signalling and ribosome biogenesis centred on regulation of SIRT1 activity, which could be exploited by anti-cancer therapeutics.