The interplay of UBE2T and Mule in regulating Wnt/β-catenin activation to promote hepatocellular carcinoma progression
Abstract Emerging evidence indicates the role of cancer stem cells (CSCs) in tumor relapse and therapeutic resistance in patients with hepatocellular carcinoma (HCC). To identify novel targets against liver CSCs, an integrative analysis of publicly available datasets involving HCC clinical and stemn...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2021-02-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-021-03403-6 |
| _version_ | 1818459725918896128 |
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| author | Nicole Pui Yu Ho Carmen Oi Ning Leung Tin Lok Wong Eunice Yuen Ting Lau Martina Mang Leng Lei Etienne Ho Kit Mok Hoi Wing Leung Man Tong Irene Oi Lin Ng Jing Ping Yun Stephanie Ma Terence Kin Wah Lee |
| author_facet | Nicole Pui Yu Ho Carmen Oi Ning Leung Tin Lok Wong Eunice Yuen Ting Lau Martina Mang Leng Lei Etienne Ho Kit Mok Hoi Wing Leung Man Tong Irene Oi Lin Ng Jing Ping Yun Stephanie Ma Terence Kin Wah Lee |
| author_sort | Nicole Pui Yu Ho |
| collection | DOAJ |
| description | Abstract Emerging evidence indicates the role of cancer stem cells (CSCs) in tumor relapse and therapeutic resistance in patients with hepatocellular carcinoma (HCC). To identify novel targets against liver CSCs, an integrative analysis of publicly available datasets involving HCC clinical and stemness-related data was employed to select genes that play crucial roles in HCC via regulation of liver CSCs. We revealed an enrichment of an interstrand cross-link repair pathway, in which ubiquitin-conjugating enzyme E2 T (UBE2T) was the most significantly upregulated. Consistently, our data showed that UBE2T was upregulated in enriched liver CSC populations. Clinically, UBE2T overexpression in HCC was further confirmed at mRNA and protein levels and was correlated with advanced tumor stage and poor patient survival. UBE2T was found to be critically involved in the regulation of liver CSCs, as evidenced by increases in self-renewal, drug resistance, tumorigenicity, and metastasis abilities. Mule, an E3 ubiquitin ligase, was identified to be the direct protein binding partner of UBE2T. Rather than the canonical role of acting as a mediator to transfer ubiquitin to E3 ligases, UBE2T is surprisingly able to physically bind and regulate the protein expression of Mule via ubiquitination. Mule was found to directly degrade β-catenin protein, and UBE2T was found to mediate liver CSC functions through direct regulation of Mule-mediated β-catenin degradation; this effect was abolished when the E2 activity of UBE2T was impaired. In conclusion, we revealed a novel UBE2T/Mule/β-catenin signaling cascade that is involved in the regulation of liver CSCs, which provides an attractive potential therapeutic target for HCC. |
| first_indexed | 2024-12-14T23:18:56Z |
| format | Article |
| id | doaj.art-e24394bef0094c0fa49316ffef7fef79 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-14T23:18:56Z |
| publishDate | 2021-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-e24394bef0094c0fa49316ffef7fef792022-12-21T22:44:01ZengNature Publishing GroupCell Death and Disease2041-48892021-02-0112211410.1038/s41419-021-03403-6The interplay of UBE2T and Mule in regulating Wnt/β-catenin activation to promote hepatocellular carcinoma progressionNicole Pui Yu Ho0Carmen Oi Ning Leung1Tin Lok Wong2Eunice Yuen Ting Lau3Martina Mang Leng Lei4Etienne Ho Kit Mok5Hoi Wing Leung6Man Tong7Irene Oi Lin Ng8Jing Ping Yun9Stephanie Ma10Terence Kin Wah Lee11Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic UniversityDepartment of Applied Biology and Chemical Technology, The Hong Kong Polytechnic UniversitySchool of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong KongDepartment of Clinical Oncology, Queen Elizabeth HospitalDepartment of Applied Biology and Chemical Technology, The Hong Kong Polytechnic UniversityDepartment of Applied Biology and Chemical Technology, The Hong Kong Polytechnic UniversityDepartment of Applied Biology and Chemical Technology, The Hong Kong Polytechnic UniversitySchool of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong KongDepartment of Pathology, Queen Mary Hospital, The University of Hong KongDepartment of Pathology, Sun Yat Sen University Cancer CenterSchool of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong KongDepartment of Applied Biology and Chemical Technology, The Hong Kong Polytechnic UniversityAbstract Emerging evidence indicates the role of cancer stem cells (CSCs) in tumor relapse and therapeutic resistance in patients with hepatocellular carcinoma (HCC). To identify novel targets against liver CSCs, an integrative analysis of publicly available datasets involving HCC clinical and stemness-related data was employed to select genes that play crucial roles in HCC via regulation of liver CSCs. We revealed an enrichment of an interstrand cross-link repair pathway, in which ubiquitin-conjugating enzyme E2 T (UBE2T) was the most significantly upregulated. Consistently, our data showed that UBE2T was upregulated in enriched liver CSC populations. Clinically, UBE2T overexpression in HCC was further confirmed at mRNA and protein levels and was correlated with advanced tumor stage and poor patient survival. UBE2T was found to be critically involved in the regulation of liver CSCs, as evidenced by increases in self-renewal, drug resistance, tumorigenicity, and metastasis abilities. Mule, an E3 ubiquitin ligase, was identified to be the direct protein binding partner of UBE2T. Rather than the canonical role of acting as a mediator to transfer ubiquitin to E3 ligases, UBE2T is surprisingly able to physically bind and regulate the protein expression of Mule via ubiquitination. Mule was found to directly degrade β-catenin protein, and UBE2T was found to mediate liver CSC functions through direct regulation of Mule-mediated β-catenin degradation; this effect was abolished when the E2 activity of UBE2T was impaired. In conclusion, we revealed a novel UBE2T/Mule/β-catenin signaling cascade that is involved in the regulation of liver CSCs, which provides an attractive potential therapeutic target for HCC.https://doi.org/10.1038/s41419-021-03403-6 |
| spellingShingle | Nicole Pui Yu Ho Carmen Oi Ning Leung Tin Lok Wong Eunice Yuen Ting Lau Martina Mang Leng Lei Etienne Ho Kit Mok Hoi Wing Leung Man Tong Irene Oi Lin Ng Jing Ping Yun Stephanie Ma Terence Kin Wah Lee The interplay of UBE2T and Mule in regulating Wnt/β-catenin activation to promote hepatocellular carcinoma progression Cell Death and Disease |
| title | The interplay of UBE2T and Mule in regulating Wnt/β-catenin activation to promote hepatocellular carcinoma progression |
| title_full | The interplay of UBE2T and Mule in regulating Wnt/β-catenin activation to promote hepatocellular carcinoma progression |
| title_fullStr | The interplay of UBE2T and Mule in regulating Wnt/β-catenin activation to promote hepatocellular carcinoma progression |
| title_full_unstemmed | The interplay of UBE2T and Mule in regulating Wnt/β-catenin activation to promote hepatocellular carcinoma progression |
| title_short | The interplay of UBE2T and Mule in regulating Wnt/β-catenin activation to promote hepatocellular carcinoma progression |
| title_sort | interplay of ube2t and mule in regulating wnt β catenin activation to promote hepatocellular carcinoma progression |
| url | https://doi.org/10.1038/s41419-021-03403-6 |
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