DNA polymerase iota promotes EMT and metastasis of esophageal squamous cell carcinoma by interacting with USP7 to stabilize HIF-1α
Abstract Esophageal squamous cell carcinoma (ESCC) is one of the most lethal cancer types, with a low 5-year survival rate of ~20%. Our prior research has suggested that DNA Polymerase iota (Pol ι), a member of Y-family DNA polymerase, plays a crucial role in the invasion and metastasis of ESCC. How...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2024-02-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-024-06552-6 |
| _version_ | 1797273034080387072 |
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| author | Aidi Gao Mingxia Zhang Shuang qi Zhu Shitao Zou Hengrui Chen Xiaoqin Li Chao He Liangsu Zhou Yan Mei Weiqun Ding Jundong Zhou Yue Zhou Yuandong Cao |
| author_facet | Aidi Gao Mingxia Zhang Shuang qi Zhu Shitao Zou Hengrui Chen Xiaoqin Li Chao He Liangsu Zhou Yan Mei Weiqun Ding Jundong Zhou Yue Zhou Yuandong Cao |
| author_sort | Aidi Gao |
| collection | DOAJ |
| description | Abstract Esophageal squamous cell carcinoma (ESCC) is one of the most lethal cancer types, with a low 5-year survival rate of ~20%. Our prior research has suggested that DNA Polymerase iota (Pol ι), a member of Y-family DNA polymerase, plays a crucial role in the invasion and metastasis of ESCC. However, the underlying mechanism is not well understood. In this study, we utilized ChIP-PCR and luciferase reporter assays to investigate the binding of HIF-1α to the promoter of the Pol ι gene. Transwell, wound healing, and mouse models were employed to assess the impact of Pol ι and HIF-1α on the motility of ESCC cells. Co-immunoprecipitation and Western blot were carried out to explore the interaction between Pol ι and HIF-1α, while qRT-PCR and Western blot were conducted to confirm the regulation of Pol ι and HIF-1α on their downstream targets. Our results demonstrate that HIF-1α activates the transcription of the Pol ι gene in ESCC cells under hypoxic conditions. Furthermore, the knockdown of Pol ι impeded HIF-1α-induced invasion and metastasis. Additionally, we found that Pol ι regulates the expression of genes involved in epithelial-mesenchymal transition (EMT) and initiates EMT through the stabilization of HIF-1α. Mechanistically, Pol ι maintains the protein stability of HIF-1α by recruiting USP7 to mediate the deubiquitination of HIF-1α, with the residues 446–578 of Pol being crucial for the interaction between Pol ι and USP7. Collectively, our findings unveil a novel feedforward molecular axis of HIF-1α- Pol ι -USP7 in ESCC that contributes to ESCC metastasis. Hence, our results present an attractive target for intervention in ESCC. |
| first_indexed | 2024-03-07T14:37:46Z |
| format | Article |
| id | doaj.art-62f9c06512bd4192a699b4d4c3579565 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-07T14:37:46Z |
| publishDate | 2024-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-62f9c06512bd4192a699b4d4c35795652024-03-05T20:31:00ZengNature Publishing GroupCell Death and Disease2041-48892024-02-0115211310.1038/s41419-024-06552-6DNA polymerase iota promotes EMT and metastasis of esophageal squamous cell carcinoma by interacting with USP7 to stabilize HIF-1αAidi Gao0Mingxia Zhang1Shuang qi Zhu2Shitao Zou3Hengrui Chen4Xiaoqin Li5Chao He6Liangsu Zhou7Yan Mei8Weiqun Ding9Jundong Zhou10Yue Zhou11Yuandong Cao12Suzhou Cancer Center Core Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical UniversityDepartment of Radiation Oncology, the First Affiliated Hospital of Anhui Medical UniversitySuzhou Cancer Center Core Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical UniversitySuzhou Cancer Center Core Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical UniversitySuzhou Cancer Center Core Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical UniversitySuzhou Cancer Center Core Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical UniversitySuzhou Cancer Center Core Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical UniversitySuzhou Cancer Center Core Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical UniversitySuzhou Cancer Center Core Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical UniversityDepartment of Pathology, University of Oklahoma Health Science CenterSuzhou Cancer Center Core Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical UniversityDepartment of Thoracic Surgery, First Affiliated Hospital of Nanjing Medical UniversityDepartment of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical UniversityAbstract Esophageal squamous cell carcinoma (ESCC) is one of the most lethal cancer types, with a low 5-year survival rate of ~20%. Our prior research has suggested that DNA Polymerase iota (Pol ι), a member of Y-family DNA polymerase, plays a crucial role in the invasion and metastasis of ESCC. However, the underlying mechanism is not well understood. In this study, we utilized ChIP-PCR and luciferase reporter assays to investigate the binding of HIF-1α to the promoter of the Pol ι gene. Transwell, wound healing, and mouse models were employed to assess the impact of Pol ι and HIF-1α on the motility of ESCC cells. Co-immunoprecipitation and Western blot were carried out to explore the interaction between Pol ι and HIF-1α, while qRT-PCR and Western blot were conducted to confirm the regulation of Pol ι and HIF-1α on their downstream targets. Our results demonstrate that HIF-1α activates the transcription of the Pol ι gene in ESCC cells under hypoxic conditions. Furthermore, the knockdown of Pol ι impeded HIF-1α-induced invasion and metastasis. Additionally, we found that Pol ι regulates the expression of genes involved in epithelial-mesenchymal transition (EMT) and initiates EMT through the stabilization of HIF-1α. Mechanistically, Pol ι maintains the protein stability of HIF-1α by recruiting USP7 to mediate the deubiquitination of HIF-1α, with the residues 446–578 of Pol being crucial for the interaction between Pol ι and USP7. Collectively, our findings unveil a novel feedforward molecular axis of HIF-1α- Pol ι -USP7 in ESCC that contributes to ESCC metastasis. Hence, our results present an attractive target for intervention in ESCC.https://doi.org/10.1038/s41419-024-06552-6 |
| spellingShingle | Aidi Gao Mingxia Zhang Shuang qi Zhu Shitao Zou Hengrui Chen Xiaoqin Li Chao He Liangsu Zhou Yan Mei Weiqun Ding Jundong Zhou Yue Zhou Yuandong Cao DNA polymerase iota promotes EMT and metastasis of esophageal squamous cell carcinoma by interacting with USP7 to stabilize HIF-1α Cell Death and Disease |
| title | DNA polymerase iota promotes EMT and metastasis of esophageal squamous cell carcinoma by interacting with USP7 to stabilize HIF-1α |
| title_full | DNA polymerase iota promotes EMT and metastasis of esophageal squamous cell carcinoma by interacting with USP7 to stabilize HIF-1α |
| title_fullStr | DNA polymerase iota promotes EMT and metastasis of esophageal squamous cell carcinoma by interacting with USP7 to stabilize HIF-1α |
| title_full_unstemmed | DNA polymerase iota promotes EMT and metastasis of esophageal squamous cell carcinoma by interacting with USP7 to stabilize HIF-1α |
| title_short | DNA polymerase iota promotes EMT and metastasis of esophageal squamous cell carcinoma by interacting with USP7 to stabilize HIF-1α |
| title_sort | dna polymerase iota promotes emt and metastasis of esophageal squamous cell carcinoma by interacting with usp7 to stabilize hif 1α |
| url | https://doi.org/10.1038/s41419-024-06552-6 |
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