NAD-dependent protein deacylase sirtuin-6 (SIRT6) (SIRT6)

NAD-dependent protein deacylase sirtuin-6 (SIRT6) is a member of the sirtuin family of NAD+-dependent enzymes, primarily localized in the nucleus where it functions as a critical regulator of genomic stability, metabolism, and longevity [2.1.1, 2.5.1]. It possesses multiple enzymatic activities, including histone deacetylation, long-chain fatty deacylation, and mono-ADP-ribosylation, allowing it to modulate diverse cellular processes such as DNA double-strand break repair, telomere maintenance, and glucose homeostasis [2.1.2, 2.5.2]. SIRT6 acts as a metabolic sensor, suppressing the expression of glycolytic genes and inhibiting the Warburg effect, which contributes to its role as a tumor suppressor in many cancers [2.2.1, 2.5.2]. However, its role in oncology is context-dependent, as it can also promote tumor progression in certain malignancies like chronic lymphocytic leukemia [2.1.4, 2.2.5]. In addition to its role in cancer, SIRT6 is a major player in aging and age-related diseases; its overexpression has been shown to extend lifespan in male mice, while its deficiency leads to a progeroid syndrome and severe metabolic defects like hypoglycemia [2.3.1, 2.4.2]. Therapeutic strategies targeting the SIRT6 pathway focus on the development of small-molecule activators to treat metabolic disorders, neurodegeneration, and inflammatory conditions, as well as inhibitors for specific cancer types [2.2.3, 3.1.3]. Current pharmacological research is exploring both synthetic modulators like MDL-800 and natural products like cyanidin, as well as the repurposing of existing drugs like fluvastatin and SGLT2 inhibitors, to harness the enzyme's protective effects on chromatin and cellular health [3.2.2, 3.3.2].

Other names

SIR2-like protein 6SIR2L6Mono-ADP-ribosyltransferase sirtuin-6Regulatory protein SIR2 homolog 6Sirtuin-6 pathway

Drugs targeting SIRT6 primarily act as allosteric activators or inhibitors of its enzymatic functions. Activators like MDL-800 and UBCS038 bind to the specific acyl-binding channel, enhancing the enzyme's deacetylase and deacylase activities, which leads to suppressed glycolytic gene expression and improved DNA repair. Conversely, inhibitors like OSS-128167 block these activities to potentially arrest cancer cell growth. Some drugs, such as fluvastatin, have been repurposed as SIRT6 activators, while others like SGLT2 inhibitors and GLP-1 agonists are thought to modulate the SIRT6 pathway indirectly to provide cardiovascular and metabolic benefits.