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- Publisher Website: 10.3390/cancers13133204
- Scopus: eid_2-s2.0-85108642780
- PMID: 34206946
- WOS: WOS:000671319800001
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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
Title | Depletion of DNA Polymerase Theta Inhibits Tumor Growth and Promotes Genome Instability through the cGAS-STING-ISG Pathway in Esophageal Squamous Cell Carcinoma |
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Authors | |
Keywords | POLQ genomic instability innate immune response |
Issue Date | 2021 |
Publisher | MDPI 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? |
Abstract | Overexpression 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. |
Description | Vol. 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 Identifier | http://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 Field | Value | Language |
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dc.contributor.author | Li, J | - |
dc.contributor.author | Ko, JMY | - |
dc.contributor.author | Dai, W | - |
dc.contributor.author | Yu, Z | - |
dc.contributor.author | Ng, HY | - |
dc.contributor.author | Hoffmann, JS | - |
dc.contributor.author | Lung, ML | - |
dc.date.accessioned | 2021-07-27T08:08:30Z | - |
dc.date.available | 2021-07-27T08:08:30Z | - |
dc.date.issued | 2021 | - |
dc.identifier.citation | Cancers, 2021, v. 13 n. 13, article no. 3204 | - |
dc.identifier.issn | 2072-6694 | - |
dc.identifier.uri | http://hdl.handle.net/10722/301261 | - |
dc.description | Vol. 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.abstract | Overexpression 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.language | eng | - |
dc.publisher | MDPI AG. The Journal's web site is located at http://www.mdpi.com/journal/cancers/ | - |
dc.relation.ispartof | Cancers | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject | POLQ | - |
dc.subject | genomic instability | - |
dc.subject | innate immune response | - |
dc.title | Depletion of DNA Polymerase Theta Inhibits Tumor Growth and Promotes Genome Instability through the cGAS-STING-ISG Pathway in Esophageal Squamous Cell Carcinoma | - |
dc.type | Article | - |
dc.identifier.email | Ko, JMY: joko@hku.hk | - |
dc.identifier.email | Dai, W: weidai2@hku.hk | - |
dc.identifier.email | Yu, Z: zvyu@hku.hk | - |
dc.identifier.email | Ng, HY: hyng0812@hku.hk | - |
dc.identifier.email | Lung, ML: mlilung@hku.hk | - |
dc.identifier.authority | Ko, JMY=rp02011 | - |
dc.identifier.authority | Dai, W=rp02146 | - |
dc.identifier.authority | Yu, Z=rp02756 | - |
dc.identifier.authority | Lung, ML=rp00300 | - |
dc.description.nature | published_or_final_version | - |
dc.identifier.doi | 10.3390/cancers13133204 | - |
dc.identifier.pmid | 34206946 | - |
dc.identifier.pmcid | PMC8268317 | - |
dc.identifier.scopus | eid_2-s2.0-85108642780 | - |
dc.identifier.hkuros | 323391 | - |
dc.identifier.volume | 13 | - |
dc.identifier.issue | 13 | - |
dc.identifier.spage | article no. 3204 | - |
dc.identifier.epage | article no. 3204 | - |
dc.identifier.isi | WOS:000671319800001 | - |
dc.publisher.place | Switzerland | - |