FBXO9 Mediates the Cancer-Promoting Effects of ZNF143 by Degrading FBXW7 and Facilitates Drug Resistance in Hepatocellular Carcinoma
F-box proteins are critical for malignancy because they control the turnover of key proteins that govern multiple cellular processes. F-box protein 9 (FBXO9) belongs to the F-box protein family and exhibits oncogenic properties in hematological malignancies. However, the function and molecular mecha...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-06-01
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| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.930220/full |
| _version_ | 1811329460310376448 |
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| author | Zhenyu Wang Xiaoxia Chen Xiaoxia Chen Lianer Zhou Xinge Zhao Chao Ge Fangyu Zhao Haiyang Xie Taoyang Chen Hua Tian Hong Li Jinjun Li |
| author_facet | Zhenyu Wang Xiaoxia Chen Xiaoxia Chen Lianer Zhou Xinge Zhao Chao Ge Fangyu Zhao Haiyang Xie Taoyang Chen Hua Tian Hong Li Jinjun Li |
| author_sort | Zhenyu Wang |
| collection | DOAJ |
| description | F-box proteins are critical for malignancy because they control the turnover of key proteins that govern multiple cellular processes. F-box protein 9 (FBXO9) belongs to the F-box protein family and exhibits oncogenic properties in hematological malignancies. However, the function and molecular mechanism of FBXO9 in hepatocellular carcinoma (HCC) remain unclear. Here, we report that FBXO9 was remarkably overexpressed in HCC. Loss- and gain-of-function experiments showed that FBXO9 facilitates HCC cell proliferation and metastasis both in vitro and in vivo. Mechanistically, as a direct upstream transcription factor, FBXO9 is regulated by zinc finger protein 143 (ZNF143) and accelerates tumor growth and metastasis by targeting the F-box and WD repeat domain containing 7 (FBXW7) for ubiquitination and degradation. Additionally, we found that with FBXO9 knockdown, HCC cells were more sensitive to treatment with lenvatinib and sorafenib. In summary, our results demonstrate that a ZNF143-FBXO9-FBXW7 signaling regulatory axis may be involved in tumor progression in HCC, and suggest that FBXO9 could be a potential biomarker and therapeutic target for HCC. |
| first_indexed | 2024-04-13T15:44:12Z |
| format | Article |
| id | doaj.art-742fb3269f924f129ef9f0d0b729adb2 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-13T15:44:12Z |
| publishDate | 2022-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-742fb3269f924f129ef9f0d0b729adb22022-12-22T02:41:03ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-06-011210.3389/fonc.2022.930220930220FBXO9 Mediates the Cancer-Promoting Effects of ZNF143 by Degrading FBXW7 and Facilitates Drug Resistance in Hepatocellular CarcinomaZhenyu Wang0Xiaoxia Chen1Xiaoxia Chen2Lianer Zhou3Xinge Zhao4Chao Ge5Fangyu Zhao6Haiyang Xie7Taoyang Chen8Hua Tian9Hong Li10Jinjun Li11State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaState Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaState Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, ChinaState Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaState Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaState Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaState Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of General Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, ChinaDepartment of Pathology, Qi Dong Liver Cancer Institute, Qidong, ChinaState Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaState Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaState Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaF-box proteins are critical for malignancy because they control the turnover of key proteins that govern multiple cellular processes. F-box protein 9 (FBXO9) belongs to the F-box protein family and exhibits oncogenic properties in hematological malignancies. However, the function and molecular mechanism of FBXO9 in hepatocellular carcinoma (HCC) remain unclear. Here, we report that FBXO9 was remarkably overexpressed in HCC. Loss- and gain-of-function experiments showed that FBXO9 facilitates HCC cell proliferation and metastasis both in vitro and in vivo. Mechanistically, as a direct upstream transcription factor, FBXO9 is regulated by zinc finger protein 143 (ZNF143) and accelerates tumor growth and metastasis by targeting the F-box and WD repeat domain containing 7 (FBXW7) for ubiquitination and degradation. Additionally, we found that with FBXO9 knockdown, HCC cells were more sensitive to treatment with lenvatinib and sorafenib. In summary, our results demonstrate that a ZNF143-FBXO9-FBXW7 signaling regulatory axis may be involved in tumor progression in HCC, and suggest that FBXO9 could be a potential biomarker and therapeutic target for HCC.https://www.frontiersin.org/articles/10.3389/fonc.2022.930220/fullhepatocellular carcinomaFBXO9ZNF143FBXW7ubiquitin-proteasome mediated degradationLenvatinib |
| spellingShingle | Zhenyu Wang Xiaoxia Chen Xiaoxia Chen Lianer Zhou Xinge Zhao Chao Ge Fangyu Zhao Haiyang Xie Taoyang Chen Hua Tian Hong Li Jinjun Li FBXO9 Mediates the Cancer-Promoting Effects of ZNF143 by Degrading FBXW7 and Facilitates Drug Resistance in Hepatocellular Carcinoma Frontiers in Oncology hepatocellular carcinoma FBXO9 ZNF143 FBXW7 ubiquitin-proteasome mediated degradation Lenvatinib |
| title | FBXO9 Mediates the Cancer-Promoting Effects of ZNF143 by Degrading FBXW7 and Facilitates Drug Resistance in Hepatocellular Carcinoma |
| title_full | FBXO9 Mediates the Cancer-Promoting Effects of ZNF143 by Degrading FBXW7 and Facilitates Drug Resistance in Hepatocellular Carcinoma |
| title_fullStr | FBXO9 Mediates the Cancer-Promoting Effects of ZNF143 by Degrading FBXW7 and Facilitates Drug Resistance in Hepatocellular Carcinoma |
| title_full_unstemmed | FBXO9 Mediates the Cancer-Promoting Effects of ZNF143 by Degrading FBXW7 and Facilitates Drug Resistance in Hepatocellular Carcinoma |
| title_short | FBXO9 Mediates the Cancer-Promoting Effects of ZNF143 by Degrading FBXW7 and Facilitates Drug Resistance in Hepatocellular Carcinoma |
| title_sort | fbxo9 mediates the cancer promoting effects of znf143 by degrading fbxw7 and facilitates drug resistance in hepatocellular carcinoma |
| topic | hepatocellular carcinoma FBXO9 ZNF143 FBXW7 ubiquitin-proteasome mediated degradation Lenvatinib |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.930220/full |
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