UBCS039 is a specificSirtuin 6 activator which showed robust activating effects on Sirt6-dependent H3K18ac deacetylation of both full-length histone proteins and complete HeLa nucleosomes.
Sirtuin 6 (SIRT6) is a member of the NAD+-dependent class III deacetylase sirtuin family, which plays a key role in cancer by controlling transcription, genome stability, telomere integrity, DNA repair, and autophagy[1]. UBCS039 is the first synthetic SIRT6 activator with EC50 of 38 μM, which can induce time-dependent activation of autophagy in various human tumor cell lines[2]. UBCS039 (75 μM) induced a time-dependent deacetylation of histone H3K9 in H1299 non-small cell lung cancer. UBCS039 also triggered deacetylation of histone H3K56 in HT1080 cells. Moreover, knockdown of SIRT6, by increasing in a time dependent manner H3K9 acetylation levels, exerted opposite effects compared to UBCS039 treatment. Collectively, these results demonstrated that UBCS039 is a specific activator of SIRT6 in several human tumor models. UBCS039 (75 μM) enhanced, in a time-dependent manner, LC3B conversion from LC3B form I (18 kDa) to an autophagosome-associating form, LC3 form II (16 kDa) in both human H1299 and HeLa cell lines. UBCS039-induced autophagosome accumulation was also observed in HT1080 fibrosarcoma cells stably transfected with EGFP-LC3B fusion protein, thus indicating ageneral effect on autophagy upon activation of SIRT6. Notably, UBCS039 treatment increased AMP-activated protein kinase (AMPK) phosphorylation in H1299 cells, indicating UBCS039 induced autophagy via AMPK signaling pathway activation[1].
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