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dc.contributor.author
Hao, Suisui
dc.contributor.author
Tong, Jingshan
dc.contributor.author
Jha, Anupma
dc.contributor.author
Risnik, Denise Mariel
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dc.contributor.author
Lizardo, Darleny
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Lu, Xinyan
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Goel, Ajay
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Opresko, Patricia L.
dc.contributor.author
Yu, Jian
dc.contributor.author
Zhang, Lin
dc.date.available
2023-11-14T13:48:21Z
dc.date.issued
2022-12
dc.identifier.citation
Hao, Suisui; Tong, Jingshan; Jha, Anupma; Risnik, Denise Mariel; Lizardo, Darleny; et al.; Synthetical lethality of Werner helicase and mismatch repair deficiency is mediated by p53 and PUMA in colon cancer; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 119; 51; e2211775119; 12-2022; 1-9
dc.identifier.issn
0027-8424
dc.identifier.uri
http://hdl.handle.net/11336/218017
dc.description.abstract
Synthetic lethality is a powerful approach for targeting oncogenic drivers in cancer. Recent studies revealed that cancer cells with microsatellite instability (MSI) require Werner (WRN) helicase for survival; however, the underlying mechanism remains unclear. In this study, we found that WRN depletion strongly induced p53 and its downstream apoptotic target PUMA in MSI colorectal cancer (CRC) cells. p53 or PUMA deletion abolished apoptosis induced by WRN depletion in MSI CRC cells. Importantly, correction of MSI abrogated the activation of p53/PUMA and cell killing, while induction of MSI led to sensitivity in isogenic CRC cells. Rare p53-mutant MSI CRC cells are resistant to WRN depletion due to lack of PUMA induction, which could be restored by wildtype (WT) p53 knock in or reconstitution. WRN depletion or treatment with the RecQ helicase inhibitor ML216 suppressed in vitro and in vivo growth of MSI CRCs in a p53/PUMA-dependent manner. ML216 treatment was efficacious in MSI CRC patient-derived xenografts. Interestingly, p53 gene remains WT in the majority of MSI CRCs. These results indicate a critical role of p53/PUMA-mediated apoptosis in the vulnerability of MSI CRCs to WRN loss, and support WRN as a promising therapeutic target in p53-WT MSI CRCs.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
National Academy of Sciences
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dc.rights
info:eu-repo/semantics/restrictedAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
MISMATCH REPAIR
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P53
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PUMA
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SYNTHETIC LETHAL
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WERNER
dc.subject.classification
Otras Medicina Básica
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dc.subject.classification
Medicina Básica
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dc.subject.classification
CIENCIAS MÉDICAS Y DE LA SALUD
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dc.title
Synthetical lethality of Werner helicase and mismatch repair deficiency is mediated by p53 and PUMA in colon cancer
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2023-11-09T14:53:07Z
dc.journal.volume
119
dc.journal.number
51; e2211775119
dc.journal.pagination
1-9
dc.journal.pais
Estados Unidos
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dc.journal.ciudad
Washington
dc.description.fil
Fil: Hao, Suisui. Univeristy of Pittsburgh. School of Medicine; Estados Unidos. UPMC Hillman Cancer Center; Estados Unidos
dc.description.fil
Fil: Tong, Jingshan. UPMC Hillman Cancer Center; Estados Unidos. Univeristy of Pittsburgh. School of Medicine; Estados Unidos
dc.description.fil
Fil: Jha, Anupma. UPMC Hillman Cancer Center; Estados Unidos
dc.description.fil
Fil: Risnik, Denise Mariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Univeristy of Pittsburgh. School of Medicine; Estados Unidos. UPMC Hillman Cancer Center; Estados Unidos
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Fil: Lizardo, Darleny. Univeristy of Pittsburgh. School of Medicine; Estados Unidos. UPMC Hillman Cancer Center; Estados Unidos
dc.description.fil
Fil: Lu, Xinyan. Univeristy of Pittsburgh. School of Medicine; Estados Unidos. UPMC Hillman Cancer Center; Estados Unidos
dc.description.fil
Fil: Goel, Ajay. Beckman Research Institute of City of Hope Comprehensive Cancer Center; Reino Unido
dc.description.fil
Fil: Opresko, Patricia L.. Univeristy of Pittsburgh. School of Medicine; Estados Unidos. UPMC Hillman Cancer Center; Estados Unidos
dc.description.fil
Fil: Yu, Jian. Univeristy of Pittsburgh. School of Medicine; Estados Unidos. UPMC Hillman Cancer Center; Estados Unidos
dc.description.fil
Fil: Zhang, Lin. Univeristy of Pittsburgh. School of Medicine; Estados Unidos. UPMC Hillman Cancer Center; Estados Unidos
dc.journal.title
Proceedings of the National Academy of Sciences of The United States of America
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dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1073/pnas.2211775119
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://www.pnas.org/doi/10.1073/pnas.2211775119
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