RNF20/RNF40 supports the aggressive behavior in cervical cancer by regulating a peroxisome-based anti-ferroptotic mechanism
Abstract Background Cervical cancer is the fourth most common cancer entity in women worldwide. Currently, malignant lesions are clinically managed by surgery, conventional chemotherapy, and/or radiotherapy. However, a significant fraction of patients with cervical cancer does not respond to such tr...
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BMC
2025-07-01
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| Series: | Cell Communication and Signaling |
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| Online Access: | https://doi.org/10.1186/s12964-025-02279-9 |
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| author | Shaishavi Jansari Anna Blandau Evangelos Prokakis Daniela Grimm Anja Maria Naßl Stefan Küffer Wiebke Möbius Christian Dullin Fernanda Ramos-Gomes Leona Schüürhuis Lena Fritsche Laura Schridde Matthias Plessner Carolin. A. Bast Fabian A. Gayer Sven Thoms Julia Gallwas Florian Wegwitz |
| author_facet | Shaishavi Jansari Anna Blandau Evangelos Prokakis Daniela Grimm Anja Maria Naßl Stefan Küffer Wiebke Möbius Christian Dullin Fernanda Ramos-Gomes Leona Schüürhuis Lena Fritsche Laura Schridde Matthias Plessner Carolin. A. Bast Fabian A. Gayer Sven Thoms Julia Gallwas Florian Wegwitz |
| author_sort | Shaishavi Jansari |
| collection | DOAJ |
| description | Abstract Background Cervical cancer is the fourth most common cancer entity in women worldwide. Currently, malignant lesions are clinically managed by surgery, conventional chemotherapy, and/or radiotherapy. However, a significant fraction of patients with cervical cancer does not respond to such treatments, highlighting the need for personalized targeted therapies. Histone 2B monoubiquitination (H2Bub1) is an epigenetic marker catalyzed by the RNF20 and RNF40 heterodimeric E3 ligase complex and is strongly involved in the regulation of gene expression. Despite its well-established significance in various malignant diseases, the role of RNF20 and RNF40 in cervical cancer remains poorly understood. Methods We investigated the role of RNF20 and RNF40 in cervical cancer cells by leveraging paraffin-embedded IHC staining on patient material, in vitro functional assays, in vivo CAM assays, flow cytometry, various microscopy-based techniques, ChIP-qPCR, as well as genome-wide transcriptome analysis from cell lines and publicly available datasets. Results We showed that high RNF20 and RNF40 levels correlate with cervical cancer cell aggressiveness and poor patient prognosis. In addition, pathway enrichment analyses identified that the RNF20/RNF40/H2Bub1-axis positively regulates the peroxisome function. Peroxisomes play a key role in lipid metabolism and the homeostasis of reactive oxygen species. Loss of RNF20 and RNF40 leads to downregulation of peroxisome-related genes such as PRDX5, PEX6, and PMVK, and thus impaired peroxisomal biogenesis, ROS metabolism, and increased lipid peroxidation, ultimately resulting in ferroptotic programmed cell death induction. Conclusion Together, our results indicate that interfering with RNF20 and RNF40 driven H2Bub1 and the peroxisome transcriptional program could provide a novel target for a therapeutic approach against aggressive cervical cancer. |
| format | Article |
| id | doaj-art-c978e3b9e12b4f159a8fa3f066f24ed6 |
| institution | Kabale University |
| issn | 1478-811X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
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| series | Cell Communication and Signaling |
| spelling | doaj-art-c978e3b9e12b4f159a8fa3f066f24ed62025-08-20T04:01:36ZengBMCCell Communication and Signaling1478-811X2025-07-0123111710.1186/s12964-025-02279-9RNF20/RNF40 supports the aggressive behavior in cervical cancer by regulating a peroxisome-based anti-ferroptotic mechanismShaishavi Jansari0Anna Blandau1Evangelos Prokakis2Daniela Grimm3Anja Maria Naßl4Stefan Küffer5Wiebke Möbius6Christian Dullin7Fernanda Ramos-Gomes8Leona Schüürhuis9Lena Fritsche10Laura Schridde11Matthias Plessner12Carolin. A. Bast13Fabian A. Gayer14Sven Thoms15Julia Gallwas16Florian Wegwitz17Molecular Gynecology, Department of Gynecology and Obstetrics, University Medical Centre GöttingenMolecular Gynecology, Department of Gynecology and Obstetrics, University Medical Centre GöttingenMolecular Gynecology, Department of Gynecology and Obstetrics, University Medical Centre GöttingenMolecular Gynecology, Department of Gynecology and Obstetrics, University Medical Centre GöttingenMolecular Gynecology, Department of Gynecology and Obstetrics, University Medical Centre GöttingenInstitute of Pathology, University Medical Centre GöttingenDepartment of Neurogenetics (Electron Microscopy), Max-Planck-Institute for Multidisciplinary Sciences (City Campus)Translational Molecular Imaging, Max-Planck-Institute for Multidisciplinary Sciences (City Campus)Translational Molecular Imaging, Max-Planck-Institute for Multidisciplinary Sciences (City Campus)Molecular Gynecology, Department of Gynecology and Obstetrics, University Medical Centre GöttingenMolecular Gynecology, Department of Gynecology and Obstetrics, University Medical Centre GöttingenInstitute of Pathology, University Medical Centre GöttingenDepartment of Biochemistry and Molecular Medicine, Medical School OWL, Bielefeld UniversityMolecular Gynecology, Department of Gynecology and Obstetrics, University Medical Centre GöttingenDepartment of Urology, University Medical Centre GöttingenDepartment of Biochemistry and Molecular Medicine, Medical School OWL, Bielefeld UniversityMolecular Gynecology, Department of Gynecology and Obstetrics, University Medical Centre GöttingenMolecular Gynecology, Department of Gynecology and Obstetrics, University Medical Centre GöttingenAbstract Background Cervical cancer is the fourth most common cancer entity in women worldwide. Currently, malignant lesions are clinically managed by surgery, conventional chemotherapy, and/or radiotherapy. However, a significant fraction of patients with cervical cancer does not respond to such treatments, highlighting the need for personalized targeted therapies. Histone 2B monoubiquitination (H2Bub1) is an epigenetic marker catalyzed by the RNF20 and RNF40 heterodimeric E3 ligase complex and is strongly involved in the regulation of gene expression. Despite its well-established significance in various malignant diseases, the role of RNF20 and RNF40 in cervical cancer remains poorly understood. Methods We investigated the role of RNF20 and RNF40 in cervical cancer cells by leveraging paraffin-embedded IHC staining on patient material, in vitro functional assays, in vivo CAM assays, flow cytometry, various microscopy-based techniques, ChIP-qPCR, as well as genome-wide transcriptome analysis from cell lines and publicly available datasets. Results We showed that high RNF20 and RNF40 levels correlate with cervical cancer cell aggressiveness and poor patient prognosis. In addition, pathway enrichment analyses identified that the RNF20/RNF40/H2Bub1-axis positively regulates the peroxisome function. Peroxisomes play a key role in lipid metabolism and the homeostasis of reactive oxygen species. Loss of RNF20 and RNF40 leads to downregulation of peroxisome-related genes such as PRDX5, PEX6, and PMVK, and thus impaired peroxisomal biogenesis, ROS metabolism, and increased lipid peroxidation, ultimately resulting in ferroptotic programmed cell death induction. Conclusion Together, our results indicate that interfering with RNF20 and RNF40 driven H2Bub1 and the peroxisome transcriptional program could provide a novel target for a therapeutic approach against aggressive cervical cancer.https://doi.org/10.1186/s12964-025-02279-9Cervical cancerRNF20/RNF40H2Bub1PeroxisomesFerroptosis |
| spellingShingle | Shaishavi Jansari Anna Blandau Evangelos Prokakis Daniela Grimm Anja Maria Naßl Stefan Küffer Wiebke Möbius Christian Dullin Fernanda Ramos-Gomes Leona Schüürhuis Lena Fritsche Laura Schridde Matthias Plessner Carolin. A. Bast Fabian A. Gayer Sven Thoms Julia Gallwas Florian Wegwitz RNF20/RNF40 supports the aggressive behavior in cervical cancer by regulating a peroxisome-based anti-ferroptotic mechanism Cell Communication and Signaling Cervical cancer RNF20/RNF40 H2Bub1 Peroxisomes Ferroptosis |
| title | RNF20/RNF40 supports the aggressive behavior in cervical cancer by regulating a peroxisome-based anti-ferroptotic mechanism |
| title_full | RNF20/RNF40 supports the aggressive behavior in cervical cancer by regulating a peroxisome-based anti-ferroptotic mechanism |
| title_fullStr | RNF20/RNF40 supports the aggressive behavior in cervical cancer by regulating a peroxisome-based anti-ferroptotic mechanism |
| title_full_unstemmed | RNF20/RNF40 supports the aggressive behavior in cervical cancer by regulating a peroxisome-based anti-ferroptotic mechanism |
| title_short | RNF20/RNF40 supports the aggressive behavior in cervical cancer by regulating a peroxisome-based anti-ferroptotic mechanism |
| title_sort | rnf20 rnf40 supports the aggressive behavior in cervical cancer by regulating a peroxisome based anti ferroptotic mechanism |
| topic | Cervical cancer RNF20/RNF40 H2Bub1 Peroxisomes Ferroptosis |
| url | https://doi.org/10.1186/s12964-025-02279-9 |
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