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Article: Depletion of DNA Polymerase Theta Inhibits Tumor Growth and Promotes Genome Instability through the cGAS-STING-ISG Pathway in Esophageal Squamous Cell Carcinoma

TitleDepletion of DNA Polymerase Theta Inhibits Tumor Growth and Promotes Genome Instability through the cGAS-STING-ISG Pathway in Esophageal Squamous Cell Carcinoma
Authors
KeywordsPOLQ
genomic instability
innate immune response
Issue Date2021
PublisherMDPI AG. The Journal's web site is located at http://www.mdpi.com/journal/cancers/
Citation
Cancers, 2021, v. 13 n. 13, article no. 3204 How to Cite?
AbstractOverexpression of the specialized DNA polymerase theta (POLQ) is frequent in breast, colon and lung cancers and has been correlated with unfavorable clinical outcomes. Here, we aimed to determine the importance and functional role of POLQ in esophageal squamous cell carcinoma (ESCC). Integrated analysis of four RNA-seq datasets showed POLQ was predominantly upregulated in ESCC tumors. High expression of POLQ was also observed in a cohort of 25 Hong Kong ESCC patients and negatively correlated with ESCC patient survival. POLQ knockout (KO) ESCC cells were sensitized to multiple genotoxic agents. Both rH2AX foci staining and the comet assay indicated a higher level of genomic instability in POLQ-depleted cells. Double KO of POLQ and FANCD2, known to promote POLQ recruitment at sites of damage, significantly impaired cell proliferation both in vitro and in vivo, as compared to either single POLQ or FANCD2 KOs. A significantly increased number of micronuclei was observed in POLQ and/or FANCD2 KO ESCC cells. Loss of POLQ and/or FANCD2 also resulted in the activation of cGAS and upregulation of interferon-stimulated genes (ISGs). Our results suggest that high abundance of POLQ in ESCC contributes to the malignant phenotype through genome instability and activation of the cGAS pathway.
DescriptionVol. 13 n. 13 is a Special Issue IECC2021: Exploiting Cancer Vulnerability by Targeting the DNA Damage Response, comprise selected papers from the proceedings of The 1st International Electronic Conference on Cancers (IECC): Exploiting Cancer Vulnerability by Targeting the DNA Damage Response, Virtual Meeting,1-14 February 2021
Persistent Identifierhttp://hdl.handle.net/10722/301261
ISSN
2023 Impact Factor: 4.5
2023 SCImago Journal Rankings: 1.391
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLi, J-
dc.contributor.authorKo, JMY-
dc.contributor.authorDai, W-
dc.contributor.authorYu, Z-
dc.contributor.authorNg, HY-
dc.contributor.authorHoffmann, JS-
dc.contributor.authorLung, ML-
dc.date.accessioned2021-07-27T08:08:30Z-
dc.date.available2021-07-27T08:08:30Z-
dc.date.issued2021-
dc.identifier.citationCancers, 2021, v. 13 n. 13, article no. 3204-
dc.identifier.issn2072-6694-
dc.identifier.urihttp://hdl.handle.net/10722/301261-
dc.descriptionVol. 13 n. 13 is a Special Issue IECC2021: Exploiting Cancer Vulnerability by Targeting the DNA Damage Response, comprise selected papers from the proceedings of The 1st International Electronic Conference on Cancers (IECC): Exploiting Cancer Vulnerability by Targeting the DNA Damage Response, Virtual Meeting,1-14 February 2021-
dc.description.abstractOverexpression of the specialized DNA polymerase theta (POLQ) is frequent in breast, colon and lung cancers and has been correlated with unfavorable clinical outcomes. Here, we aimed to determine the importance and functional role of POLQ in esophageal squamous cell carcinoma (ESCC). Integrated analysis of four RNA-seq datasets showed POLQ was predominantly upregulated in ESCC tumors. High expression of POLQ was also observed in a cohort of 25 Hong Kong ESCC patients and negatively correlated with ESCC patient survival. POLQ knockout (KO) ESCC cells were sensitized to multiple genotoxic agents. Both rH2AX foci staining and the comet assay indicated a higher level of genomic instability in POLQ-depleted cells. Double KO of POLQ and FANCD2, known to promote POLQ recruitment at sites of damage, significantly impaired cell proliferation both in vitro and in vivo, as compared to either single POLQ or FANCD2 KOs. A significantly increased number of micronuclei was observed in POLQ and/or FANCD2 KO ESCC cells. Loss of POLQ and/or FANCD2 also resulted in the activation of cGAS and upregulation of interferon-stimulated genes (ISGs). Our results suggest that high abundance of POLQ in ESCC contributes to the malignant phenotype through genome instability and activation of the cGAS pathway.-
dc.languageeng-
dc.publisherMDPI AG. The Journal's web site is located at http://www.mdpi.com/journal/cancers/-
dc.relation.ispartofCancers-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectPOLQ-
dc.subjectgenomic instability-
dc.subjectinnate immune response-
dc.titleDepletion of DNA Polymerase Theta Inhibits Tumor Growth and Promotes Genome Instability through the cGAS-STING-ISG Pathway in Esophageal Squamous Cell Carcinoma-
dc.typeArticle-
dc.identifier.emailKo, JMY: joko@hku.hk-
dc.identifier.emailDai, W: weidai2@hku.hk-
dc.identifier.emailYu, Z: zvyu@hku.hk-
dc.identifier.emailNg, HY: hyng0812@hku.hk-
dc.identifier.emailLung, ML: mlilung@hku.hk-
dc.identifier.authorityKo, JMY=rp02011-
dc.identifier.authorityDai, W=rp02146-
dc.identifier.authorityYu, Z=rp02756-
dc.identifier.authorityLung, ML=rp00300-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.3390/cancers13133204-
dc.identifier.pmid34206946-
dc.identifier.pmcidPMC8268317-
dc.identifier.scopuseid_2-s2.0-85108642780-
dc.identifier.hkuros323391-
dc.identifier.volume13-
dc.identifier.issue13-
dc.identifier.spagearticle no. 3204-
dc.identifier.epagearticle no. 3204-
dc.identifier.isiWOS:000671319800001-
dc.publisher.placeSwitzerland-

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