TRAF4 Promotes the Proliferation of Glioblastoma by Stabilizing SETDB1 to Activate the AKT Pathway
The process of ubiquitination regulates the degradation, transport, interaction, and stabilization of substrate proteins, and is crucial for cell signal transduction and function. TNF receptor-associated factor 4, TRAF4, is a member of the TRAF family and is involved in the process of ubiquitination...
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MDPI AG
2022-09-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/17/10161 |
| _version_ | 1797494950170984448 |
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| author | Hongyu Gu Shunqin Zhu Cheng Peng Zekun Wei Yang Shen Chaoyu Yuan He Yang Hongjuan Cui Liqun Yang |
| author_facet | Hongyu Gu Shunqin Zhu Cheng Peng Zekun Wei Yang Shen Chaoyu Yuan He Yang Hongjuan Cui Liqun Yang |
| author_sort | Hongyu Gu |
| collection | DOAJ |
| description | The process of ubiquitination regulates the degradation, transport, interaction, and stabilization of substrate proteins, and is crucial for cell signal transduction and function. TNF receptor-associated factor 4, TRAF4, is a member of the TRAF family and is involved in the process of ubiquitination as an E3 ubiquitin protein ligase. Here, we found that TRAF4 expression correlates with glioma subtype and grade, and that TRAF4 is significantly overexpressed in glioblastoma and predicts poor prognosis. Knockdown of TRAF4 significantly inhibited the growth, proliferation, migration, and invasion of glioblastoma cells. Mechanistically, we found that TRAF4 only interacts with the Tudor domain of the AKT pathway activator SETDB1. TRAF4 mediates the atypical ubiquitination of SETDB1 to maintain its stability and function, thereby promoting the activation of the AKT pathway. Restoring SETDB1 expression in TRAF4 knockdown glioblastoma cells partially restored cell growth and proliferation. Collectively, our findings reveal a novel mechanism by which TRAF4 mediates AKT pathway activation, suggesting that TRAF4 may serve as a biomarker and promising therapeutic target for glioblastoma. |
| first_indexed | 2024-03-10T01:41:35Z |
| format | Article |
| id | doaj.art-a2d1e4052c9d4b7e9d7ef846c2b2ad92 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T01:41:35Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-a2d1e4052c9d4b7e9d7ef846c2b2ad922023-11-23T13:24:02ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-09-0123171016110.3390/ijms231710161TRAF4 Promotes the Proliferation of Glioblastoma by Stabilizing SETDB1 to Activate the AKT PathwayHongyu Gu0Shunqin Zhu1Cheng Peng2Zekun Wei3Yang Shen4Chaoyu Yuan5He Yang6Hongjuan Cui7Liqun Yang8State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400715, ChinaState Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400715, ChinaState Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400715, ChinaState Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400715, ChinaState Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400715, ChinaState Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400715, ChinaState Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400715, ChinaState Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400715, ChinaState Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400715, ChinaThe process of ubiquitination regulates the degradation, transport, interaction, and stabilization of substrate proteins, and is crucial for cell signal transduction and function. TNF receptor-associated factor 4, TRAF4, is a member of the TRAF family and is involved in the process of ubiquitination as an E3 ubiquitin protein ligase. Here, we found that TRAF4 expression correlates with glioma subtype and grade, and that TRAF4 is significantly overexpressed in glioblastoma and predicts poor prognosis. Knockdown of TRAF4 significantly inhibited the growth, proliferation, migration, and invasion of glioblastoma cells. Mechanistically, we found that TRAF4 only interacts with the Tudor domain of the AKT pathway activator SETDB1. TRAF4 mediates the atypical ubiquitination of SETDB1 to maintain its stability and function, thereby promoting the activation of the AKT pathway. Restoring SETDB1 expression in TRAF4 knockdown glioblastoma cells partially restored cell growth and proliferation. Collectively, our findings reveal a novel mechanism by which TRAF4 mediates AKT pathway activation, suggesting that TRAF4 may serve as a biomarker and promising therapeutic target for glioblastoma.https://www.mdpi.com/1422-0067/23/17/10161glioblastomaTRAF4SETDB1AKTubiquitination |
| spellingShingle | Hongyu Gu Shunqin Zhu Cheng Peng Zekun Wei Yang Shen Chaoyu Yuan He Yang Hongjuan Cui Liqun Yang TRAF4 Promotes the Proliferation of Glioblastoma by Stabilizing SETDB1 to Activate the AKT Pathway International Journal of Molecular Sciences glioblastoma TRAF4 SETDB1 AKT ubiquitination |
| title | TRAF4 Promotes the Proliferation of Glioblastoma by Stabilizing SETDB1 to Activate the AKT Pathway |
| title_full | TRAF4 Promotes the Proliferation of Glioblastoma by Stabilizing SETDB1 to Activate the AKT Pathway |
| title_fullStr | TRAF4 Promotes the Proliferation of Glioblastoma by Stabilizing SETDB1 to Activate the AKT Pathway |
| title_full_unstemmed | TRAF4 Promotes the Proliferation of Glioblastoma by Stabilizing SETDB1 to Activate the AKT Pathway |
| title_short | TRAF4 Promotes the Proliferation of Glioblastoma by Stabilizing SETDB1 to Activate the AKT Pathway |
| title_sort | traf4 promotes the proliferation of glioblastoma by stabilizing setdb1 to activate the akt pathway |
| topic | glioblastoma TRAF4 SETDB1 AKT ubiquitination |
| url | https://www.mdpi.com/1422-0067/23/17/10161 |
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