Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity

He, Yonghan; Li, Wen; Lv, Dongwen; Zhang, Xin; Zhang, Xuan; Ortiz, Yuma T.; Budamagunta, Vivekananda; Campisi, Judith; Zheng, Guangrong; Zhou, Daohong

doi:10.1111/acel.13117

Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity

Journal Article · Sat Feb 15 23:00:00 EST 2020 · Aging Cell

DOI:https://doi.org/10.1111/acel.13117· OSTI ID:1615307

^[1]; Li, Wen ^[1]; ^[1]; Zhang, Xin ^[1]; Zhang, Xuan ^[1]; Ortiz, Yuma T. ^[1]; Budamagunta, Vivekananda ^[1]; ^[2]; Zheng, Guangrong ^[1]; ^[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)

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.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC); National Institute on Aging

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1615307

Journal Information:: Aging Cell, Journal Name: Aging Cell Journal Issue: 3 Vol. 19; ISSN 1474-9718

Publisher:: Anatomical Society - WileyCopyright Statement

Country of Publication:: United States

Language:: English

References (50)

Resistance to UV-induced apoptosis in human keratinocytes during accelerated senescence is associated with functional inactivation of p53 Chaturvedi, V.; Qin, J. -Z.; Stennett, L. Journal of Cellular Physiology, Vol. 198, Issue 1 https://doi.org/10.1002/jcp.10392	journal	January 2003
Small-molecule inhibitors of USP7 induce apoptosis through oxidative and endoplasmic reticulum stress in cancer cells Lee, Gibok; Oh, Taek-In; Um, Ki Bum Biochemical and Biophysical Research Communications, Vol. 470, Issue 1 https://doi.org/10.1016/j.bbrc.2016.01.021	journal	January 2016
USP7 inhibitor P5091 inhibits Wnt signaling and colorectal tumor growth An, Tao; Gong, Yaxiao; Li, Xue Biochemical Pharmacology, Vol. 131 https://doi.org/10.1016/j.bcp.2017.02.011	journal	May 2017
Modes of p53 Regulation Kruse, Jan-Philipp; Gu, Wei Cell, Vol. 137, Issue 4 https://doi.org/10.1016/j.cell.2009.04.050	journal	May 2009
Senescent fibroblasts resist apoptosis by downregulating caspase-3 Marcotte, Richard; Lacelle, Chantale; Wang, Eugenia Mechanisms of Ageing and Development, Vol. 125, Issue 10-11 https://doi.org/10.1016/j.mad.2004.07.007	journal	October 2004
Cellular senescence and radiation-induced pulmonary fibrosis He, Yonghan; Thummuri, Dinesh; Zheng, Guangrong Translational Research, Vol. 209 https://doi.org/10.1016/j.trsl.2019.03.006	journal	July 2019
Relevance of the p53–MDM2 axis to aging Wu, Danyi; Prives, Carol Cell Death & Differentiation, Vol. 25, Issue 1 https://doi.org/10.1038/cdd.2017.187	journal	December 2017
USP7 inhibitor P22077 inhibits neuroblastoma growth via inducing p53-mediated apoptosis Fan, Y-H; Cheng, J.; Vasudevan, S. A. Cell Death & Disease, Vol. 4, Issue 10 https://doi.org/10.1038/cddis.2013.400	journal	October 2013
Senescent Cells: A Novel Therapeutic Target for Aging and Age-Related Diseases Naylor, R. M.; Baker, D. J.; van Deursen, J. M. Clinical Pharmacology & Therapeutics, Vol. 93, Issue 1 https://doi.org/10.1038/clpt.2012.193	journal	December 2012
Naturally occurring p16Ink4a-positive cells shorten healthy lifespan Baker, Darren J.; Childs, Bennett G.; Durik, Matej Nature, Vol. 530, Issue 7589 https://doi.org/10.1038/nature16932	journal	February 2016
SCFFbxo22-KDM4A targets methylated p53 for degradation and regulates senescence Johmura, Yoshikazu; Sun, Jia; Kitagawa, Kyoko Nature Communications, Vol. 7, Issue 1 https://doi.org/10.1038/ncomms10574	journal	February 2016
Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL Yosef, Reut; Pilpel, Noam; Tokarsky-Amiel, Ronit Nature Communications, Vol. 7, Issue 1 https://doi.org/10.1038/ncomms11190	journal	April 2016
Senescent cells: an emerging target for diseases of ageing Childs, Bennett G.; Gluscevic, Martina; Baker, Darren J. Nature Reviews Drug Discovery, Vol. 16, Issue 10 https://doi.org/10.1038/nrd.2017.116	journal	July 2017
A functional genetic screen defines the AKT-induced senescence signaling network Chan, Keefe T.; Blake, Shaun; Zhu, Haoran Cell Death & Differentiation, Vol. 27, Issue 2 https://doi.org/10.1038/s41418-019-0384-8	journal	July 2019
Prostate carcinogenesis: inflammatory storms de Bono, Johann S.; Guo, Christina; Gurel, Bora Nature Reviews Cancer, Vol. 20, Issue 8 https://doi.org/10.1038/s41568-020-0267-9	journal	June 2020
Gasdermin D pore structure reveals preferential release of mature interleukin-1 Xia, Shiyu; Zhang, Zhibin; Magupalli, Venkat Giri Nature, Vol. 593, Issue 7860 https://doi.org/10.1038/s41586-021-03478-3	journal	April 2021
Role of cyclin-dependent kinase inhibitors in the growth arrest at senescence in human prostate epithelial and uroepithelial cells Schwarze, Steven R.; Shi, Yan; Fu, Vivian X. Oncogene, Vol. 20, Issue 57 https://doi.org/10.1038/sj.onc.1205049	journal	December 2001
Control of apoptosis by p53 Fridman, Jordan S.; Lowe, Scott W. Oncogene, Vol. 22, Issue 56 https://doi.org/10.1038/sj.onc.1207116	journal	December 2003
Decline and fall of the tumor suppressor Hinkal, George; Donehower, Lawrence A. Proceedings of the National Academy of Sciences, Vol. 104, Issue 47 https://doi.org/10.1073/pnas.0709330104	journal	November 2007
Regulation of p53 during senescence in normal human keratinocytes Kim, Reuben H.; Kang, Mo K.; Kim, Terresa Aging Cell, Vol. 14, Issue 5 https://doi.org/10.1111/acel.12364	journal	July 2015
Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors Zhu, Yi; Tchkonia, Tamara; Fuhrmann-Stroissnigg, Heike Aging Cell, Vol. 15, Issue 3 https://doi.org/10.1111/acel.12445	journal	March 2016
Multiple facets of p53 in senescence induction and maintenance Johmura, Yoshikazu; Nakanishi, Makoto Cancer Science, Vol. 107, Issue 11 https://doi.org/10.1111/cas.13060	journal	November 2016
Senescent intimal foam cells are deleterious at all stages of atherosclerosis Childs, B. G.; Baker, D. J.; Wijshake, T. Science, Vol. 354, Issue 6311 https://doi.org/10.1126/science.aaf6659	journal	October 2016
p53-Independent Regulation of p21Waf1/Cip1 Expression and Senescence by Chk2 Aliouat-Denis, C. -M. Molecular Cancer Research, Vol. 3, Issue 11 https://doi.org/10.1158/1541-7786.mcr-05-0121	journal	November 2005
Cellular senescence and the senescent secretory phenotype: therapeutic opportunities Tchkonia, Tamara; Zhu, Yi; van Deursen, Jan Journal of Clinical Investigation, Vol. 123, Issue 3 https://doi.org/10.1172/jci64098	journal	March 2013
MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer Tisato, Veronica; Voltan, Rebecca; Gonelli, Arianna Journal of Hematology & Oncology, Vol. 10, Issue 1 https://doi.org/10.1186/s13045-017-0500-5	journal	July 2017
Temporally distinct roles of ATM and ROS in genotoxic-stress-dependent induction and maintenance of cellular senescence Nair, R. R.; Bagheri, M.; Saini, D. K. Journal of Cell Science, Vol. 128, Issue 2 https://doi.org/10.1242/jcs.159517	journal	November 2014
The curcumin analog EF24 is a novel senolytic agent Li, Wen; He, Yonghan; Zhang, Rongping Aging, Vol. 11, Issue 2 https://doi.org/10.18632/aging.101787	journal	January 2019
Therapeutic inhibition of USP7-PTEN network in chronic lymphocytic leukemia: a strategy to overcome TP53 mutated/deleted clones Carrà, Giovanna; Panuzzo, Cristina; Torti, Davide Oncotarget, Vol. 8, Issue 22 https://doi.org/10.18632/oncotarget.16348	journal	March 2017
USP7: Target Validation and Drug Discovery for Cancer Therapy Zhou, Jin; Wang, Jinzheng; Chen, Chao Medicinal Chemistry, Vol. 14, Issue 1 https://doi.org/10.2174/1573406413666171020115539	journal	January 2018
The limited in vitro lifetime of human diploid cell strains Hayflick, L. Experimental Cell Research, Vol. 37, Issue 3 https://doi.org/10.1016/0014-4827(65)90211-9	journal	March 1965
A Dynamic Role of HAUSP in the p53-Mdm2 Pathway Li, Muyang; Brooks, Christopher L.; Kon, Ning Molecular Cell, Vol. 13, Issue 6 https://doi.org/10.1016/S1097-2765(04)00157-1	journal	March 2004
A Small Molecule Inhibitor of Ubiquitin-Specific Protease-7 Induces Apoptosis in Multiple Myeloma Cells and Overcomes Bortezomib Resistance Chauhan, Dharminder; Tian, Ze; Nicholson, Benjamin Cancer Cell, Vol. 22, Issue 3 https://doi.org/10.1016/j.ccr.2012.08.007	journal	September 2012
Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging Baar, Marjolein P.; Brandt, Renata M. C.; Putavet, Diana A. Cell, Vol. 169, Issue 1 https://doi.org/10.1016/j.cell.2017.02.031	journal	March 2017
USP7: Structure, substrate specificity, and inhibition Pozhidaeva, Alexandra; Bezsonova, Irina DNA Repair, Vol. 76 https://doi.org/10.1016/j.dnarep.2019.02.005	journal	April 2019
CHIP-dependent p53 regulation occurs specifically during cellular senescence Sisoula, Christina; Trachana, Varvara; Patterson, Cam Free Radical Biology and Medicine, Vol. 50, Issue 1 https://doi.org/10.1016/j.freeradbiomed.2010.10.701	journal	January 2011
Transcription-independent p53 apoptosis: an alternative route to death Speidel, Daniel Trends in Cell Biology, Vol. 20, Issue 1 https://doi.org/10.1016/j.tcb.2009.10.002	journal	January 2010
Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders Baker, Darren J.; Wijshake, Tobias; Tchkonia, Tamar Nature, Vol. 479, Issue 7372 https://doi.org/10.1038/nature10600	journal	November 2011
Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice Chang, Jianhui; Wang, Yingying; Shao, Lijian Nature Medicine, Vol. 22, Issue 1 https://doi.org/10.1038/nm.4010	journal	December 2015
HAUSP deubiquitinates and stabilizes N-Myc in neuroblastoma Tavana, Omid; Li, Dawei; Dai, Chao Nature Medicine, Vol. 22, Issue 10 https://doi.org/10.1038/nm.4180	journal	September 2016
Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment Jeon, Ok Hee; Kim, Chaekyu; Laberge, Remi-Martin Nature Medicine, Vol. 23, Issue 6 https://doi.org/10.1038/nm.4324	journal	April 2017
Improved vectors and genome-wide libraries for CRISPR screening Sanjana, Neville E.; Shalem, Ophir; Zhang, Feng Nature Methods, Vol. 11, Issue 8 https://doi.org/10.1038/nmeth.3047	journal	July 2014
Senescence and aging: the critical roles of p53 Rufini, A.; Tucci, P.; Celardo, I. Oncogene, Vol. 32, Issue 43 https://doi.org/10.1038/onc.2012.640	journal	February 2013
Declining p53 function in the aging process: A possible mechanism for the increased tumor incidence in older populations Feng, Z.; Hu, W.; Teresky, A. K. Proceedings of the National Academy of Sciences, Vol. 104, Issue 42 https://doi.org/10.1073/pnas.0708043104	journal	October 2007
Reversal of human cellular senescence: roles of the p53 and p16 pathways Beausejour, C. M. The EMBO Journal, Vol. 22, Issue 16 https://doi.org/10.1093/emboj/cdg417	journal	August 2003
p53-Independent Regulation of p21Waf1/Cip1 Expression and Senescence by Chk2 Aliouat-Denis, C. -M. Molecular Cancer Research, Vol. 3, Issue 11 https://doi.org/10.1158/1541-7786.MCR-05-0121	journal	November 2005
Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse Demaria, Marco; O'Leary, Monique N.; Chang, Jianhui Cancer Discovery, Vol. 7, Issue 2 https://doi.org/10.1158/2159-8290.CD-16-0241	journal	December 2016
Cellular senescence and the senescent secretory phenotype: therapeutic opportunities Tchkonia, Tamara; Zhu, Yi; van Deursen, Jan Journal of Clinical Investigation, Vol. 123, Issue 3 https://doi.org/10.1172/JCI64098	journal	March 2013
Phenotype Specific Analyses Reveal Distinct Regulatory Mechanism for Chronically Activated p53 Kirschner, Kristina; Samarajiwa, Shamith A.; Cairns, Jonathan M. PLOS Genetics, Vol. 11, Issue 3 https://doi.org/10.1371/journal.pgen.1005053	journal	March 2015
New agents that target senescent cells: the flavone, fisetin, and the BCL-X_L inhibitors, A1331852 and A1155463 Zhu, Yi; Doornebal, Ewald J.; Pirtskhalava, Tamar Aging, Vol. 9, Issue 3 https://doi.org/10.18632/aging.101202	journal	March 2017

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Additional file 1 of Endothelial progenitor cells systemic administration alleviates multi-organ senescence by down-regulating USP7/p300 pathway in chronic obstructive pulmonary disease Wang, Wenhua; Peng, Huaihuai; Zeng, Menghao figshare https://doi.org/10.6084/m9.figshare.24761381	image	January 2023