DNA polymerase iota promotes EMT and metastasis of esophageal squamous cell carcinoma by interacting with USP7 to stabilize HIF-1α.

Autor: Gao A; Suzhou Cancer Center Core Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, P.R. China., Zhang M; Department of Radiation Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, P.R. China., Zhu SQ; Suzhou Cancer Center Core Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, P.R. China., Zou S; Suzhou Cancer Center Core Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, P.R. China., Chen H; Suzhou Cancer Center Core Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, P.R. China., Li X; Suzhou Cancer Center Core Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, P.R. China., He C; Suzhou Cancer Center Core Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, P.R. China., Zhou L; Suzhou Cancer Center Core Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, P.R. China., Mei Y; Suzhou Cancer Center Core Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, P.R. China., Ding W; Department of Pathology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA., Zhou J; Suzhou Cancer Center Core Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, P.R. China. zhoujundong330@163.com., Zhou Y; Department of Thoracic Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China. chirurgeonzhouyue@163.com., Cao Y; Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China. caoyuandong@jsph.org.cn.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2024 Feb 24; Vol. 15 (2), pp. 171. Date of Electronic Publication: 2024 Feb 24.
DOI: 10.1038/s41419-024-06552-6
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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