RESUMO
SIRT6 is a NAD(+)-dependent histone deacetylase and has been implicated in the regulation of genomic stability, DNA repair, metabolic homeostasis and several diseases. The effect of SIRT6 in cerebral ischemia and oxygen/glucose deprivation (OGD) has been reported, however the role of SIRT6 in oxidative stress damage remains unclear. Here we used SH-SY5Y neuronal cells and found that overexpression of SIRT6 led to decreased cell viability and increased necrotic cell death and reactive oxygen species (ROS) production under oxidative stress. Mechanistic study revealed that SIRT6 induced autophagy via attenuation of AKT signaling and treatment with autophagy inhibitor 3-MA or knockdown of autophagy-related protein Atg5 rescued H2O2-induced neuronal injury. Conversely, SIRT6 inhibition suppressed autophagy and reduced oxidative stress-induced neuronal damage. These results suggest that SIRT6 might be a potential therapeutic target for neuroprotection.
Assuntos
Humanos , Adenina , Toxicidade , Autofagia , Proteína 5 Relacionada à Autofagia , Genética , Metabolismo , Western Blotting , Linhagem Celular Tumoral , Peróxido de Hidrogênio , Toxicidade , Proteínas Associadas aos Microtúbulos , Metabolismo , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-akt , Metabolismo , Interferência de RNA , RNA Mensageiro , Metabolismo , RNA Interferente Pequeno , Metabolismo , Espécies Reativas de Oxigênio , Metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais , Sirtuínas , Genética , Metabolismo , TransfecçãoRESUMO
SIRT6 is an important histone modifying protein that regulates DNA repair, telomere maintenance, energy metabolism, and target gene expression. Recently SIRT6 has been identified as a tumor suppressor and is down-regulated in certain cancer types, but not in other cancers. From deposited gene profiling studies we found that SIRT6 was overexpressed in prostate tumors, compared with normal or paratumor prostate tissues. Tissue micro-array studies confirmed the higher levels of SIRT6 in both prostate tumor tissues and prostate cancer cells than in their normal counterparts. Knockdown of SIRT6 in human prostate cancer cells led to sub-G1 phase arrest of cell cycle, increased apoptosis, elevated DNA damage level and decrease in BCL2 gene expression. Moreover, SIRT6-deficiency reduced cell viability and enhanced chemotherapeutics sensitivity. Taken together, this study provides the first evidence of SIRT6 overexpression in human prostate cancer, and SIRT6 regulation could be exploited for prostate cancer therapy.