Trichostatin A inhibits deacetylation of histone H3 and p53 by SIRT6

Abstract

SIRT6 is an epigenetic modification enzyme that regulates gene transcription through its deacetylase activity. In addition to histone protein, SIRT6 also modify other proteins and enzymes, some of which are central players in metabolic reprogramming and aging process. Therefore, SIRT6 has emerged as a therapeutic target for the treatment of metabolic disorder and age-related diseases. Here, we report that SIRT6 deacetylates lysine 382 of p53 in short synthetic peptide sequence and in full length p53. Further studies showed that the deacetylation of H3K9Ac and p53K382Ac are insensitive to nicotinamide inhibition, but are sensitive to trichostatin A (TSA) inhibition. Detailed kinetic analysis revealed that TSA competes with the peptide substrate for inhibition, and this inhibition is unique to SIRT6 in the sirtuin family. Taken together, this study not only suggests potential roles of SIRT6 in regulating apoptosis and stress resistance via direct deacetylation of p53, but also provides lead compound for the development of potent and selective SIRT6 inhibitors.

Nuclear transport of nicotinamide phosphoribosyltransferase is cell cycle–dependent in mammalian cells, and its inhibition slows cell growth

“…We further tested effect of SIRT6 and PARP inhibition on NAMPT localization. Trichostatin A (TSA) is an inhibitor of SIRT6 and class I and class II histone deacetylases (13). TSA at 0.75 nmol⅐liter Ϫ1 , which did not affect cell viability, increased the number of cells with cytoplasmic NAMPT localization ( Fig.…”

High-Throughput Functional Annotation of Natural Products by Integrated Activity Profiling

“…Subsequent chromatographic optimization, purification and NMR analysis from SW218953 (Figure 4D) identified this product as the known bacterial metabolite trichostatin A (Figure 4E). Trichostatin A has been extensively studied for its activity as an HDAC inhibitor 28,29 . Notably, Cluster 49 also contained pure trichostatin A from the Selleck library (cluster members are listed in Supplementary Table 3).…”

p53 cooperates with SIRT6 to regulate cardiolipin de novo biosynthesis

“…In addition, p53 restores SIRT6 levels after Aβ42-induced DNA damage, suggesting a mechanism of p53-dependent SIRT6 DNA damage protection in this context 33 . Furthermore, two recent studies showed that SIRT6 deacetylates p53 at lysine 382 34 and lysine 381 31 . The former modification is sensitive to trichostatin A (TSA) inhibition 34 and the latter negatively regulates p53 stability and activity and affects the aging process in mice 31 .…”

“…Furthermore, two recent studies showed that SIRT6 deacetylates p53 at lysine 382 34 and lysine 381 31 . The former modification is sensitive to trichostatin A (TSA) inhibition 34 and the latter negatively regulates p53 stability and activity and affects the aging process in mice 31 . Consistent with these studies, we show here a link between p53 and SIRT6 in the regulation of lipid metabolism.…”