Interplay between SIRT proteins and tumour suppressor transcription factors in chemotherapeutic resistance of cancer

Sirtuins, commonly referred to as SIRTs, are a family of seven mammalian NAD(+)-dependent deacetylases implicated in the regulation of critical biological processes, including metabolism, cell division, differentiation, survival, and senescence. These diverse functions reflect the ability of SIRTs to target and modify a broad spectrum of protein substrates, including cytoskeletal proteins, signalling components, transcription factors, and histones. SIRTs are also implicated in tumorigenesis as well as in the response of the tumour to chemotherapy. In particular, SIRT1 has been found to be overexpressed in many drug resistant cancers. Emerging evidence suggests that the role of SIRTs in drug resistance may be foremost related to their ability to target and modulate the activity of tumour suppressors, including p53, p73. E2F1, and FOXO3a. In other words, while SIRT-dependent deacetylation of transcription factors is normally used to fine-tune gene expression, this function is hijacked by cancer cells to evade proliferative arrest and cell death in response to chemotherapy. Consequently, interventions predicated on disrupting the interactions between tumour suppressors and SIRTs may be effective in circumventing or reversing drug resistance in cancer. (C) 2010 Elsevier Ltd. All rights reserved.