Sirtuin deacetylases and forkhead box class O (FOXO) transcription factors are central regulators of cell survival, cell cycle and cellular resistance to stress in response to signals from hormones, growth factors and oxidative stress. FOXO activity is modulated by the sirtuins, which function in a NAD+-dependent manner. Sirtuin activity, on the other hand is subject to inhibition by a natural compound nicotinamide (NAM).
We found significant changes in gene expression from the NAM treatment at different concentration. Substantial changes in expression profiles were detected for genes involved in a number of unique cellular pathways and functions, including cell cycle arrest, cellular proliferation and differentiation, metabolism, apoptotic signalling, inflammatory regulation and various disease conditions such as cancer. In addition, we also observed that sirtuin activities exhibit complex cell- and context-dependent behaviour in modulating FOXO signalling. Contrasting roles of FOXOs and sirtuins appear to have opposite effects on cellular homeostasis. The coexistence of reciprocal regulations in this cell system suggested several levels of feedback control and illustrated the complexity of an existing fine-tuned regulatory network system between these two proteins.
Future work aims to characterize putative regulators and effectors of sirtuin- and FOXO-related pathways using molecular approaches such and RNA interference knockdown of individual FOXO-isoforms, as well as transcriptional regulation at the level of microRNAs. The inter-connectivity of the pathways will provide invaluable insight into current understanding of cell degeneration diseases such as diabetes, cancers and neurological disorders.
