Identification of MORF4L1 as an endogenous substrate of CRBN and its potential role as a therapeutic target in cancer
Abstract The ubiquitin-proteasome system (UPS) is essential for cellular homeostasis, regulating the degradation of proteins involved in key processes such as cell cycle, apoptosis, and DNA repair. Dysregulation of the UPS is implicated in hepatocellular carcinoma (HCC), contributing to tumor progre...
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Nature Portfolio
2025-01-01
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| Online Access: | https://doi.org/10.1038/s41598-024-82941-3 |
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| author | Luyao Zhang Shunfang Liu Jingliang He Zhongke Hu Lan Zhu Hongyi Huang Qi Gao Dan Wang Lu Chen Xingyu Zhang Ruotong Liu Jiayun Wang Yizhuo Song Kaile Zeng Xiuming Li Yulu Chen Xun Zou Shaojie Ma Xiujun Wang Guofeng Xu Wei Liu Bin Liu |
| author_facet | Luyao Zhang Shunfang Liu Jingliang He Zhongke Hu Lan Zhu Hongyi Huang Qi Gao Dan Wang Lu Chen Xingyu Zhang Ruotong Liu Jiayun Wang Yizhuo Song Kaile Zeng Xiuming Li Yulu Chen Xun Zou Shaojie Ma Xiujun Wang Guofeng Xu Wei Liu Bin Liu |
| author_sort | Luyao Zhang |
| collection | DOAJ |
| description | Abstract The ubiquitin-proteasome system (UPS) is essential for cellular homeostasis, regulating the degradation of proteins involved in key processes such as cell cycle, apoptosis, and DNA repair. Dysregulation of the UPS is implicated in hepatocellular carcinoma (HCC), contributing to tumor progression and therapeutic resistance. The cereblon (CRBN) E3 ubiquitin ligase complex is a crucial component of the UPS, particularly in modulating protein degradation in response to small-molecule modulators like thalidomide. However, the endogenous substrates of CRBN in solid tumors like HCC remain poorly characterized. Here, we identify MORF4L1, a member of the MRG family involved in chromatin remodeling and DNA damage response, as a substrate of CRBN. Using proteomic analysis, co-immunoprecipitation, and structural modeling, we demonstrate that CRBN promotes MORF4L1 degradation under physiological conditions, which is further enhanced by the modulator CC-885. Importantly, MORF4L1 is upregulated in multiple cancers, including HCC, suggesting a broader role in tumorigenesis. Our findings reveal MORF4L1 as a physiological CRBN substrate and highlight the therapeutic potential of targeting CRBN substrates in cancer. |
| format | Article |
| id | doaj-art-45689d4707c7456a87bef40ef37991ba |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-45689d4707c7456a87bef40ef37991ba2025-01-19T12:21:34ZengNature PortfolioScientific Reports2045-23222025-01-0115111210.1038/s41598-024-82941-3Identification of MORF4L1 as an endogenous substrate of CRBN and its potential role as a therapeutic target in cancerLuyao Zhang0Shunfang Liu1Jingliang He2Zhongke Hu3Lan Zhu4Hongyi Huang5Qi Gao6Dan Wang7Lu Chen8Xingyu Zhang9Ruotong Liu10Jiayun Wang11Yizhuo Song12Kaile Zeng13Xiuming Li14Yulu Chen15Xun Zou16Shaojie Ma17Xiujun Wang18Guofeng Xu19Wei Liu20Bin Liu21Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean UniversityDepartment of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and TechnologyJiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean UniversityJiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean UniversityCancer Center and Department of Pharmacology and Toxicology, Medical College of WisconsinCancer Center and Department of Pharmacology and Toxicology, Medical College of WisconsinJiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean UniversityJiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean UniversityJiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean UniversityJiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean UniversityJiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean UniversityJiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean UniversityJiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean UniversityJiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean UniversityJiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean UniversityJiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean UniversityJiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean UniversityJiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean UniversityJiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean UniversityDepartment of Pediatric Urology, Xinhua Hospital Affiliated to ShanghaiJiao Tong University School of MedicineCancer Center and Department of Pharmacology and Toxicology, Medical College of WisconsinJiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean UniversityAbstract The ubiquitin-proteasome system (UPS) is essential for cellular homeostasis, regulating the degradation of proteins involved in key processes such as cell cycle, apoptosis, and DNA repair. Dysregulation of the UPS is implicated in hepatocellular carcinoma (HCC), contributing to tumor progression and therapeutic resistance. The cereblon (CRBN) E3 ubiquitin ligase complex is a crucial component of the UPS, particularly in modulating protein degradation in response to small-molecule modulators like thalidomide. However, the endogenous substrates of CRBN in solid tumors like HCC remain poorly characterized. Here, we identify MORF4L1, a member of the MRG family involved in chromatin remodeling and DNA damage response, as a substrate of CRBN. Using proteomic analysis, co-immunoprecipitation, and structural modeling, we demonstrate that CRBN promotes MORF4L1 degradation under physiological conditions, which is further enhanced by the modulator CC-885. Importantly, MORF4L1 is upregulated in multiple cancers, including HCC, suggesting a broader role in tumorigenesis. Our findings reveal MORF4L1 as a physiological CRBN substrate and highlight the therapeutic potential of targeting CRBN substrates in cancer.https://doi.org/10.1038/s41598-024-82941-3MORF4L1CRBNCC-885Ubiquitin-proteasome systemHepatocellular carcinoma (HCC)Protein degradation |
| spellingShingle | Luyao Zhang Shunfang Liu Jingliang He Zhongke Hu Lan Zhu Hongyi Huang Qi Gao Dan Wang Lu Chen Xingyu Zhang Ruotong Liu Jiayun Wang Yizhuo Song Kaile Zeng Xiuming Li Yulu Chen Xun Zou Shaojie Ma Xiujun Wang Guofeng Xu Wei Liu Bin Liu Identification of MORF4L1 as an endogenous substrate of CRBN and its potential role as a therapeutic target in cancer Scientific Reports MORF4L1 CRBN CC-885 Ubiquitin-proteasome system Hepatocellular carcinoma (HCC) Protein degradation |
| title | Identification of MORF4L1 as an endogenous substrate of CRBN and its potential role as a therapeutic target in cancer |
| title_full | Identification of MORF4L1 as an endogenous substrate of CRBN and its potential role as a therapeutic target in cancer |
| title_fullStr | Identification of MORF4L1 as an endogenous substrate of CRBN and its potential role as a therapeutic target in cancer |
| title_full_unstemmed | Identification of MORF4L1 as an endogenous substrate of CRBN and its potential role as a therapeutic target in cancer |
| title_short | Identification of MORF4L1 as an endogenous substrate of CRBN and its potential role as a therapeutic target in cancer |
| title_sort | identification of morf4l1 as an endogenous substrate of crbn and its potential role as a therapeutic target in cancer |
| topic | MORF4L1 CRBN CC-885 Ubiquitin-proteasome system Hepatocellular carcinoma (HCC) Protein degradation |
| url | https://doi.org/10.1038/s41598-024-82941-3 |
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