Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity
Abstract
The accumulation of senescent cells (SnCs) is a causal factor of various age-related diseases as well as some of the side effects of chemotherapy. Pharmacological elimination of SnCs (senolysis) has the potential to be developed into novel therapeutic strategies to treat these diseases and pathological conditions. Here we show that ubiquitin-specific peptidase 7 (USP7) is a novel target for senolysis because inhibition of USP7 with an inhibitor or genetic depletion of USP7 by RNA interference induces apoptosis selectively in SnCs. The senolytic activity of USP7 inhibitors is likely attributable in part to the promotion of the human homolog of mouse double minute 2 (MDM2) ubiquitination and degradation by the ubiquitin–proteasome system. This degradation increases the levels of p53, which in turn induces the pro-apoptotic proteins PUMA, NOXA, and FAS and inhibits the interaction of BCL-XL and BAK to selectively induce apoptosis in SnCs. Further, we show that treatment with a USP7 inhibitor can effectively eliminate SnCs and suppress the senescence-associated secretory phenotype (SASP) induced by doxorubicin in mice. These findings suggest that small molecule USP7 inhibitors are novel senolytics that can be exploited to reduce chemotherapy-induced toxicities and treat age-related diseases.
- Authors:
-
[1];
[1];
[2];
[1]
- Univ. of Florida, Gainesville, FL (United States)
- Buck Inst. for Research on Aging, Novato, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
- Publication Date:
- Research Org.:
- Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC); National Institute on Aging
- OSTI Identifier:
- 1615307
- Grant/Contract Number:
- AC02-05CH11231; R01AG009909; R01AG063801; R56AG056372; R01CA211963; R01CA219836
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Aging Cell
- Additional Journal Information:
- Journal Volume: 19; Journal Issue: 3; Journal ID: ISSN 1474-9718
- Publisher:
- Anatomical Society - Wiley
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; apoptosis; MDM2; p53; Senescence; senolytics; USP7
Citation Formats
He, Yonghan, Li, Wen, Lv, Dongwen, Zhang, Xin, Zhang, Xuan, Ortiz, Yuma T., Budamagunta, Vivekananda, Campisi, Judith, Zheng, Guangrong, and Zhou, Daohong. Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity. United States: N. p., 2020.
Web. doi:10.1111/acel.13117.
He, Yonghan, Li, Wen, Lv, Dongwen, Zhang, Xin, Zhang, Xuan, Ortiz, Yuma T., Budamagunta, Vivekananda, Campisi, Judith, Zheng, Guangrong, & Zhou, Daohong. Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity. United States. https://doi.org/10.1111/acel.13117
He, Yonghan, Li, Wen, Lv, Dongwen, Zhang, Xin, Zhang, Xuan, Ortiz, Yuma T., Budamagunta, Vivekananda, Campisi, Judith, Zheng, Guangrong, and Zhou, Daohong. Sun .
"Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity". United States. https://doi.org/10.1111/acel.13117. https://www.osti.gov/servlets/purl/1615307.
@article{osti_1615307,
title = {Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity},
author = {He, Yonghan and Li, Wen and Lv, Dongwen and Zhang, Xin and Zhang, Xuan and Ortiz, Yuma T. and Budamagunta, Vivekananda and Campisi, Judith and Zheng, Guangrong and Zhou, Daohong},
abstractNote = {The accumulation of senescent cells (SnCs) is a causal factor of various age-related diseases as well as some of the side effects of chemotherapy. Pharmacological elimination of SnCs (senolysis) has the potential to be developed into novel therapeutic strategies to treat these diseases and pathological conditions. Here we show that ubiquitin-specific peptidase 7 (USP7) is a novel target for senolysis because inhibition of USP7 with an inhibitor or genetic depletion of USP7 by RNA interference induces apoptosis selectively in SnCs. The senolytic activity of USP7 inhibitors is likely attributable in part to the promotion of the human homolog of mouse double minute 2 (MDM2) ubiquitination and degradation by the ubiquitin–proteasome system. This degradation increases the levels of p53, which in turn induces the pro-apoptotic proteins PUMA, NOXA, and FAS and inhibits the interaction of BCL-XL and BAK to selectively induce apoptosis in SnCs. Further, we show that treatment with a USP7 inhibitor can effectively eliminate SnCs and suppress the senescence-associated secretory phenotype (SASP) induced by doxorubicin in mice. These findings suggest that small molecule USP7 inhibitors are novel senolytics that can be exploited to reduce chemotherapy-induced toxicities and treat age-related diseases.},
doi = {10.1111/acel.13117},
journal = {Aging Cell},
number = 3,
volume = 19,
place = {United States},
year = {Sun Feb 16 00:00:00 EST 2020},
month = {Sun Feb 16 00:00:00 EST 2020}
}
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Figures / Tables:
FIGURE 1: Inhibition of USP7 activity selectively downregulates MDM2 expression and partially restores p53 expression in senescent cells (SnCs). (a) Western blotting analysis of p53, MDM2 p21, and USP7 protein levels in nonradiated (non-IR) and radiated WI-38 fibroblasts at indicated time points. Representative images of Western blots are shown. (b)more »
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