SIRT7 activates p53 by enhancing PCAF-mediated MDM2 degradation to arrest the cell cycle

Abstract

Sirtuin 7 (SIRT7), an NAD +-dependent deacetylase, plays vital roles in energy sensing, but the underlying mechanisms of action remain less clear. Here, we report that SIRT7 is required for p53-dependent cell-cycle arrest during glucose deprivation. We show that SIRT7 directly interacts with p300/CBP-associated factor (PCAF) and the affinity for this interaction increases during glucose deprivation. Upon binding, SIRT7 deacetylates PCAF at lysine 720 (K720), which augments PCAF binding to murine double minute (MDM2), the p53 E3 ubiquitin ligase, leading to accelerated MDM2 degradation. This effect results in upregulated expression of the cell-cycle inhibitor, p21 Waf1/Cip1 , which further leads to cellcycle arrest and decreased cell viability. These data highlight the importance of the SIRT7-PCAF interaction in regulating p53 activity and cell-cycle progression during conditions of glucose deprivation. This axis may represent a new avenue to design effective therapeutics based on tumor starvation.

SIRT7 Deacetylates STRAP to Regulate p53 Activity and Stability

“…However, other reports indicated that SIRT7 lacked p53 deacetylation activity [14,27]. Recently, overexpression of SIRT7 led to increased p53 stability, but SIRT7 does not deacetylate p53 in vitro or in HT1080 or NHF cells [36]. Our findings on SIRT7 modulating p53 function through deacetylating STRAP added new insight into SIRT7-p53 regulation and reconciled the controversial studies.…”

The Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy

“…SIRT7 physically binds and deacetylates P300/CBP-associated factor (PCAF) at K720, and this interaction is enhanced under conditions of glucose deprivation. As a result, PCAF binding to MDM2 is promoted, resulting in a triggering of MDM2 degradation via the ubiquitin-dependent proteasome pathway (Lu Y. F. et al, 2020). Finally, in p21-KO lymphomas, p27 Kip1 (CDKN1B) functions in a p21-independent manner to induce cell cycle arrest after SAHA treatment (Newbold et al, 2014).…”

“…A novel SIRT7 inhibitor has been identified to inhibit tumor growth by blockade of the direct interaction of SIRT7 and p53 (Vakhrusheva et al, 2008;Kim J. H. et al, 2019). However, there are also several reports demonstrating an indirect interaction between SIRT7 and p53 (Barber et al, 2012;Lu Y. F. et al, 2020;Yu et al, 2020). Thus, it is urgent to develop specific SIRT inhibitors for cancer therapy according to reasonable mechanisms.…”

The complex role of SIRT7 in p53 stabilization: nucleophosmin joins the debate

“…In a recent study, it was shown that under glucose starvation SIRT7 elevates p53 protein levels by destabilizing MDM2. 6 Mechanistically, SIRT7 deacetylates the acetyltransferase PCAF (p300/CBP-associated factor) thereby promoting binding of PCAF to MDM2, which will eventually destabilize MDM2 (Figure 1b). 6 Interestingly, we found that SIRT7 has no impact on MDM2 stability following UVirradiation, indicating that SIRT7 inhibits MDM2 either by deacetylating NPM or PCAF.…”