Sirtuin 1 (SIRT1): The Misunderstood HDAC

The sirtuin family of NAD-dependent histone deacetylases (HDACs) consists of seven mammalian proteins, SIRT 1-7. Many of the sirtuin isoforms also deacetylate nonhistone substrates, such as p53 (SIRT 1) and alpha-tubulin (SIRT 2). The sirtuin literature focuses on pharmacological activators of SIRT 1 (e. g., resveratrol, SRT 1720), proposed as therapeutics for diabetes, neurodegeneration, inflammation, and others. However, many of the SIRT 1 activator results may have been due to artifacts in the assay methodology (i.e., use of fluorescently tagged substrates). A biological role for SIRT 1 in cancer has been given less scrutiny but is no less equivocal. Although proposed initially as an oncogene, we present herein compelling data suggesting that SIRT 1 is indeed a context-specific tumor suppressor. For oncology, SIRT 1 inhibitors (dual SIRT 1/2) are indicated as potential therapeutics. A number of sirtuin inhibitors have been developed but with mixed results in cellular systems and animal models. It is unclear whether this has been due to poorly understood model systems, signalling redundancy, and/or inadequately potent and selective tool compounds. This review provides an overview of recent developments in the field of SIRT 1 function. While focusing on oncology, it aims to shed light on new concepts of expanding the selectivity spectrum, including other sirtuins such as SIRT 2. (Journal of Biomolecular Screening 2011: 1153-1169)