SIRT1, is it a tumor promoter or tumor suppressor?

Abstract

SIRT1 has been considered as a tumor promoter because of its increased expression in some types of cancers and its role in inactivating proteins that are involved in tumor suppression and DNA damage repair. However, recent studies demonstrated that SIRT1 levels are reduced in some other types of cancers, and that SIRT1 deficiency results in genetic instability and tumorigenesis, while overexpression of SIRT1 attenuates cancer formation in mice heterozygous for tumor suppressor p53 or APC. Here, I review these recent findings and discuss the possibility that activation of SIRT1 both extends lifespan and inhibits cancer formation.

Keywords: DNA damage repair; SIRT1; tumor promoter; tumor suppressor.

Figure 1

Models illustrating possible functions of SIRT1 in tumor promotion or suppression. A. SIRT1 deacetylates and inactivates p53, leading to down regulation of p53-mediated growth arrest and apoptosis. This may result in increased risk of cancer. Transcription and activity of SIRT1 are also negatively regulated by many tumor suppressor genes, including DBC1, HIC1, and p53, which may regulate SIRT1 through HIC1. B. BRCA1 and resveratrol can positively regulate SIRT1 transcription and activity, respectively. Increased SIRT1, in turn, inhibits expression and/or activity of several oncogenes, leading to reduced cell proliferation, increased apoptosis, and tumor suppression. C. In response to DNA damage, SIRT1 dissociates from highly repetitive DNA and relocalizes to DSBs to promote repair and maintain genome integrity. ATM and γH2AX are required for the efficient recruitment of SIRT1 to DSBs. Moreover, SIRT1 deficiency impaired BRCA1, RAD51 and NBS1 foci formation, suggesting direct or indirect interactions of these proteins in the DNA damage foci. SIRT1 overexpression suppresses the age-related transcriptional changes and tumor formation, suggesting a possibility to extend lifespan and inhibit tumor formation through activation of SIRT1.