Sirtuin 1 (SIRT1): the Misunderstood HDAC

The sirtuin family of NAD-dependent histone deacetylases (HDACs) consists of seven mammalian proteins, SIRT1-7. Many of the sirtuin isoforms also deacetylate nonhistone substrates, such as p53 (SIRT1) and α-tubulin (SIRT2). The sirtuin literature focuses on pharmacological activators of SIRT1 (e.g., resveratrol, SRT1720), proposed as therapeutics for diabetes, neurodegeneration, inflammation, and others. However, many of the SIRT1 activator results may have been due to artifacts in the assay methodology (i.e., use of fluorescently tagged substrates). A biological role for SIRT1 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 SIRT1 is indeed a context-specific tumor suppressor. For oncology, SIRT1 inhibitors (dual SIRT1/2) 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 SIRT1 function. While focusing on oncology, it aims to shed light on new concepts of expanding the selectivity spectrum, including other sirtuins such as SIRT2.