A small molecule Inauhzin inhibits SIRT1 activity and suppresses tumour growth through activation of p53.
Bottom Line: Here, we report a novel small molecule Inauhzin (INZ) that effectively reactivates p53 by inhibiting SIRT1 activity, promotes p53-dependent apoptosis of human cancer cells without causing apparently genotoxic stress.Moreover, INZ stabilizes p53 by increasing p53 acetylation and preventing MDM2-mediated ubiquitylation of p53 in cells, though not directly in vitro.Hence, our study unearths INZ as a novel anti-cancer therapeutic candidate that inhibits SIRT1 activity and activates p53.
Affiliation: Department of Biochemistry & Molecular Biology and Cancer Center, Tulane University School of Medicine, Louisiana, LA, USA.Show MeSH
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Mentions: Previous studies have demonstrated that p53 is also modulated by reversible acetylation, which is inverse to ubiquitylation (Li et al, 2002) because the two post-translational modifications occur at similar lysine residues within p53. Hence, we tested whether INZ would influence p53 acetylation in cells. Indeed, at 2 µM it induced p53 acetylation at lysine 382 as detected by anti-acetylated K382 antibodies, which correlated well with the increment of p53 levels (Fig 5A) and more markedly than did Etoposide at 10 µM (Fig 5B and C). Interestingly, INZ induced acetylation of p53 in H460 cells, but not tubulin in constrast with trichostatin A (TSA), which induced acetylation of tubulin (Fig 5D) by inhibiting the activity of the HDAC family, such as HDAC1 and HDAC2 (Finnin et al, 1999).
Affiliation: Department of Biochemistry & Molecular Biology and Cancer Center, Tulane University School of Medicine, Louisiana, LA, USA.