Depletion of DNA Polymerase Theta Inhibits Tumor Growth and Promotes Genome Instability through the cGAS-STING-ISG Pathway in Esophageal Squamous Cell Carcinoma
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 anal...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-06-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/13/13/3204 |
| _version_ | 1797411863364894720 |
|---|---|
| author | Jian Li Josephine Mun-Yee Ko Wei Dai Valen Zhuoyou Yu Hoi Yan Ng Jean-Sébastien Hoffmann Maria Li Lung |
| author_facet | Jian Li Josephine Mun-Yee Ko Wei Dai Valen Zhuoyou Yu Hoi Yan Ng Jean-Sébastien Hoffmann Maria Li Lung |
| author_sort | Jian Li |
| collection | DOAJ |
| description | 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 <i>POLQ</i> was predominantly upregulated in ESCC tumors. High expression of <i>POLQ</i> was also observed in a cohort of 25 Hong Kong ESCC patients and negatively correlated with ESCC patient survival. <i>POLQ</i> 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 <i>POLQ</i>-depleted cells. Double KO of <i>POLQ</i> and <i>FANCD2</i>, known to promote POLQ recruitment at sites of damage, significantly impaired cell proliferation both in vitro and in vivo, as compared to either single <i>POLQ</i> or <i>FANCD2</i> KOs. A significantly increased number of micronuclei was observed in <i>POLQ</i> and/or <i>FANCD2</i> KO ESCC cells. Loss of <i>POLQ</i> and/or <i>FANCD2</i> also resulted in the activation of cGAS and upregulation of interferon-stimulated genes (ISGs). Our results suggest that high abundance of <i>POLQ</i> in ESCC contributes to the malignant phenotype through genome instability and activation of the cGAS pathway. |
| first_indexed | 2024-03-09T04:52:26Z |
| format | Article |
| id | doaj.art-e33afcdeb78a43e99c0836c1a4872db8 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T04:52:26Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-e33afcdeb78a43e99c0836c1a4872db82023-12-03T13:09:54ZengMDPI AGCancers2072-66942021-06-011313320410.3390/cancers13133204Depletion of DNA Polymerase Theta Inhibits Tumor Growth and Promotes Genome Instability through the cGAS-STING-ISG Pathway in Esophageal Squamous Cell CarcinomaJian Li0Josephine Mun-Yee Ko1Wei Dai2Valen Zhuoyou Yu3Hoi Yan Ng4Jean-Sébastien Hoffmann5Maria Li Lung6Department of Clinical Oncology, University of Hong Kong, Hong Kong, ChinaDepartment of Clinical Oncology, University of Hong Kong, Hong Kong, ChinaDepartment of Clinical Oncology, University of Hong Kong, Hong Kong, ChinaDepartment of Clinical Oncology, University of Hong Kong, Hong Kong, ChinaDepartment of Clinical Oncology, University of Hong Kong, Hong Kong, ChinaLaboratoire d’Excellence Toulouse Cancer (TOUCAN), Laboratoire de Pathologie, Institut Universitaire du Cancer-Toulouse, 31037 Toulouse, FranceDepartment of Clinical Oncology, University of Hong Kong, Hong Kong, ChinaOverexpression 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 <i>POLQ</i> was predominantly upregulated in ESCC tumors. High expression of <i>POLQ</i> was also observed in a cohort of 25 Hong Kong ESCC patients and negatively correlated with ESCC patient survival. <i>POLQ</i> 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 <i>POLQ</i>-depleted cells. Double KO of <i>POLQ</i> and <i>FANCD2</i>, known to promote POLQ recruitment at sites of damage, significantly impaired cell proliferation both in vitro and in vivo, as compared to either single <i>POLQ</i> or <i>FANCD2</i> KOs. A significantly increased number of micronuclei was observed in <i>POLQ</i> and/or <i>FANCD2</i> KO ESCC cells. Loss of <i>POLQ</i> and/or <i>FANCD2</i> also resulted in the activation of cGAS and upregulation of interferon-stimulated genes (ISGs). Our results suggest that high abundance of <i>POLQ</i> in ESCC contributes to the malignant phenotype through genome instability and activation of the cGAS pathway.https://www.mdpi.com/2072-6694/13/13/3204POLQgenomic instabilityinnate immune response |
| spellingShingle | Jian Li Josephine Mun-Yee Ko Wei Dai Valen Zhuoyou Yu Hoi Yan Ng Jean-Sébastien Hoffmann Maria Li Lung Depletion of DNA Polymerase Theta Inhibits Tumor Growth and Promotes Genome Instability through the cGAS-STING-ISG Pathway in Esophageal Squamous Cell Carcinoma Cancers POLQ genomic instability innate immune response |
| title | Depletion of DNA Polymerase Theta Inhibits Tumor Growth and Promotes Genome Instability through the cGAS-STING-ISG Pathway in Esophageal Squamous Cell Carcinoma |
| title_full | Depletion of DNA Polymerase Theta Inhibits Tumor Growth and Promotes Genome Instability through the cGAS-STING-ISG Pathway in Esophageal Squamous Cell Carcinoma |
| title_fullStr | Depletion of DNA Polymerase Theta Inhibits Tumor Growth and Promotes Genome Instability through the cGAS-STING-ISG Pathway in Esophageal Squamous Cell Carcinoma |
| title_full_unstemmed | Depletion of DNA Polymerase Theta Inhibits Tumor Growth and Promotes Genome Instability through the cGAS-STING-ISG Pathway in Esophageal Squamous Cell Carcinoma |
| title_short | Depletion of DNA Polymerase Theta Inhibits Tumor Growth and Promotes Genome Instability through the cGAS-STING-ISG Pathway in Esophageal Squamous Cell Carcinoma |
| title_sort | depletion of dna polymerase theta inhibits tumor growth and promotes genome instability through the cgas sting isg pathway in esophageal squamous cell carcinoma |
| topic | POLQ genomic instability innate immune response |
| url | https://www.mdpi.com/2072-6694/13/13/3204 |
| work_keys_str_mv | AT jianli depletionofdnapolymerasethetainhibitstumorgrowthandpromotesgenomeinstabilitythroughthecgasstingisgpathwayinesophagealsquamouscellcarcinoma AT josephinemunyeeko depletionofdnapolymerasethetainhibitstumorgrowthandpromotesgenomeinstabilitythroughthecgasstingisgpathwayinesophagealsquamouscellcarcinoma AT weidai depletionofdnapolymerasethetainhibitstumorgrowthandpromotesgenomeinstabilitythroughthecgasstingisgpathwayinesophagealsquamouscellcarcinoma AT valenzhuoyouyu depletionofdnapolymerasethetainhibitstumorgrowthandpromotesgenomeinstabilitythroughthecgasstingisgpathwayinesophagealsquamouscellcarcinoma AT hoiyanng depletionofdnapolymerasethetainhibitstumorgrowthandpromotesgenomeinstabilitythroughthecgasstingisgpathwayinesophagealsquamouscellcarcinoma AT jeansebastienhoffmann depletionofdnapolymerasethetainhibitstumorgrowthandpromotesgenomeinstabilitythroughthecgasstingisgpathwayinesophagealsquamouscellcarcinoma AT marialilung depletionofdnapolymerasethetainhibitstumorgrowthandpromotesgenomeinstabilitythroughthecgasstingisgpathwayinesophagealsquamouscellcarcinoma |