Nuclear-localized SIRT1 inhibits apoptosis via deacetylating p53

• Published in: The international journal of biochemistry & cell biology Vol. 187; p. 106841
• Main Authors: Cheng, Lin, Wu, Ge, Yao, Wei, Deng, Kangrong, Zhang, Chunsun, Chen, Tongsheng
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.10.2025
• Subjects: Acetylation - drug effects; apoptosis; Apoptosis - drug effects; Cell Line, Tumor; Cell Nucleus - metabolism; cytoplasm-localized SIRT1; Humans; nuclear-localized SIRT1; p53; Sirtuin 1 - genetics; Sirtuin 1 - metabolism; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Rr; ShRNAs; Eto; TSA; NSCLC; IP; apoptosis; PARP; nuclear-localized SIRT1; DOX; SIRT1; p53; NAD; RC; STS; NLS; cytoplasm-localized SIRT1; FRET; WT; ED
• ISSN: 1357-2725; 1878-5875; 1878-5875
• DOI: 10.1016/j.biocel.2025.106841

The function of silencing information regulator 1 (SIRT1) in promoting or inhibiting apoptosis remains a subject of debate. Here, we aim to evaluate the roles of nuclear-localized SIRT1 in STS/DOX-induced apoptosis. Silencing nuclear-localized SIRT1 significantly enhanced STS/DOX-induced apoptosis, while overexpression of nuclear-localized SIRT1 markedly inhibited STS/DOX-induced process, demonstrating the anti-apoptotic ability of the nuclear-localized SIRT1. Critically, silencing p53 compromised the anti-apoptotic function of nuclear-localized SIRT1, thereby underscoring the essential role of p53 in mediating SIRT1's anti-apoptotic capability. Western blot analysis further revealed that wild-type SIRT1 robustly downregulated Ac-p53 expression to inhibit apoptosis, whereas a deacetylase-defective mutant of SIRT1 (SIRT1H363Y) markedly upregulated Ac-p53 to promote apoptosis. Fluorescence resonance energy transfer (FRET) analyses for the cells co-expressing nuclear-localized SIRT1-CFP and p53-YFP showed that STS enhanced the direct interaction between SIRT1 and p53 in nucleus, suggesting that the nuclear-localized SIRT1 directly interacts with p53 to deacetylate p53, thus inhibiting apoptosis. On the contrary，overexpression of cytoplasm-localized SIRT1 markedly promoted STS/DOX-induced apoptosis, firmly demonstrating the pro-apoptotic ability of the cytoplasm-localized SIRT1. These results firmly demonstrate a notion that nuclear-localized SIRT1 inhibits apoptosis via deacetylating p53.