RBX1 regulates PKM alternative splicing to facilitate anaplastic thyroid carcinoma metastasis and aerobic glycolysis by destroying the SMAR1/HDAC6 complex
Abstract Background Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancies, frequently accompanied by metastasis and aerobic glycolysis. Cancer cells adjust their metabolism by modulating the PKM alternative splicing and facilitating PKM2 isoform expression. Therefore, identif...
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| Format: | Article |
| Language: | English |
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BMC
2023-02-01
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| Series: | Cell & Bioscience |
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| Online Access: | https://doi.org/10.1186/s13578-023-00987-8 |
| _version_ | 1797863412707885056 |
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| author | Debin Xu Jichun Yu Yuting Yang Yunyan Du Hongcheng Lu Shouhua Zhang Qian Feng Yi Yu Liang Hao Jun Shao Leifeng Chen |
| author_facet | Debin Xu Jichun Yu Yuting Yang Yunyan Du Hongcheng Lu Shouhua Zhang Qian Feng Yi Yu Liang Hao Jun Shao Leifeng Chen |
| author_sort | Debin Xu |
| collection | DOAJ |
| description | Abstract Background Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancies, frequently accompanied by metastasis and aerobic glycolysis. Cancer cells adjust their metabolism by modulating the PKM alternative splicing and facilitating PKM2 isoform expression. Therefore, identifying factors and mechanisms that control PKM alternative splicing is significant for overcoming the current challenges in ATC treatment. Results In this study, the expression of RBX1 was largely enhanced in the ATC tissues. Our clinical tests suggested that high RBX1 expression was significantly related to poor survival. The functional analysis indicated that RBX1 facilitated the metastasis of ATC cells by enhancing the Warburg effect, and PKM2 played a key role in RBX1-mediated aerobic glycolysis. Furthermore, we confirmed that RBX1 regulates PKM alternative splicing and promotes the PKM2-mediated Warburg effect in ATC cells. Moreover, ATC cell migration and aerobic glycolysis induced by RBX1-mediated PKM alternative splicing are dependent on the destruction of the SMAR1/HDAC6 complex. RBX1, as an E3 ubiquitin ligase, degrades SMAR1 in ATC through the ubiquitin–proteasome pathway. Conclusion Overall, our study identified the mechanism underlying the regulation of PKM alternative splicing in ATC cells for the first time and provides evidence about the effect of RBX1 on cellular adaptation to metabolic stress. |
| first_indexed | 2024-04-09T22:36:14Z |
| format | Article |
| id | doaj.art-965d5b5ac71b4f9f98762ab63204fe57 |
| institution | Directory Open Access Journal |
| issn | 2045-3701 |
| language | English |
| last_indexed | 2024-04-09T22:36:14Z |
| publishDate | 2023-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell & Bioscience |
| spelling | doaj.art-965d5b5ac71b4f9f98762ab63204fe572023-03-22T12:29:41ZengBMCCell & Bioscience2045-37012023-02-0113111610.1186/s13578-023-00987-8RBX1 regulates PKM alternative splicing to facilitate anaplastic thyroid carcinoma metastasis and aerobic glycolysis by destroying the SMAR1/HDAC6 complexDebin Xu0Jichun Yu1Yuting Yang2Yunyan Du3Hongcheng Lu4Shouhua Zhang5Qian Feng6Yi Yu7Liang Hao8Jun Shao9Leifeng Chen10Department of Thyroid Surgery, Second Affiliated Hospital of Nanchang UniversityDepartment of Thyroid Surgery, Second Affiliated Hospital of Nanchang UniversityDepartment of Intensive Care Unit, First Affiliated Hospital of Nanchang UniversitySchool of Pharmacy, Nanchang UniversityDepartment of General Surgery, Second Affiliated Hospital of Nanchang UniversityDepartment of General Surgery, Affiliated Children’s Hospital of Nanchang UniversityDepartment of General Surgery, Second Affiliated Hospital of Nanchang UniversityDepartment of Urology, Second Affiliated Hospital of Nanchang UniversityDepartment of Orthopaedics, Second Affiliated Hospital of Nanchang UniversityDepartment of Cardiovascular Surgery, Second Affiliated Hospital of Nanchang UniversityDepartment of General Surgery, Second Affiliated Hospital of Nanchang UniversityAbstract Background Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancies, frequently accompanied by metastasis and aerobic glycolysis. Cancer cells adjust their metabolism by modulating the PKM alternative splicing and facilitating PKM2 isoform expression. Therefore, identifying factors and mechanisms that control PKM alternative splicing is significant for overcoming the current challenges in ATC treatment. Results In this study, the expression of RBX1 was largely enhanced in the ATC tissues. Our clinical tests suggested that high RBX1 expression was significantly related to poor survival. The functional analysis indicated that RBX1 facilitated the metastasis of ATC cells by enhancing the Warburg effect, and PKM2 played a key role in RBX1-mediated aerobic glycolysis. Furthermore, we confirmed that RBX1 regulates PKM alternative splicing and promotes the PKM2-mediated Warburg effect in ATC cells. Moreover, ATC cell migration and aerobic glycolysis induced by RBX1-mediated PKM alternative splicing are dependent on the destruction of the SMAR1/HDAC6 complex. RBX1, as an E3 ubiquitin ligase, degrades SMAR1 in ATC through the ubiquitin–proteasome pathway. Conclusion Overall, our study identified the mechanism underlying the regulation of PKM alternative splicing in ATC cells for the first time and provides evidence about the effect of RBX1 on cellular adaptation to metabolic stress.https://doi.org/10.1186/s13578-023-00987-8Anaplastic thyroid carcinomaRBX1MetastasisPKM2Aerobic glycolysis |
| spellingShingle | Debin Xu Jichun Yu Yuting Yang Yunyan Du Hongcheng Lu Shouhua Zhang Qian Feng Yi Yu Liang Hao Jun Shao Leifeng Chen RBX1 regulates PKM alternative splicing to facilitate anaplastic thyroid carcinoma metastasis and aerobic glycolysis by destroying the SMAR1/HDAC6 complex Cell & Bioscience Anaplastic thyroid carcinoma RBX1 Metastasis PKM2 Aerobic glycolysis |
| title | RBX1 regulates PKM alternative splicing to facilitate anaplastic thyroid carcinoma metastasis and aerobic glycolysis by destroying the SMAR1/HDAC6 complex |
| title_full | RBX1 regulates PKM alternative splicing to facilitate anaplastic thyroid carcinoma metastasis and aerobic glycolysis by destroying the SMAR1/HDAC6 complex |
| title_fullStr | RBX1 regulates PKM alternative splicing to facilitate anaplastic thyroid carcinoma metastasis and aerobic glycolysis by destroying the SMAR1/HDAC6 complex |
| title_full_unstemmed | RBX1 regulates PKM alternative splicing to facilitate anaplastic thyroid carcinoma metastasis and aerobic glycolysis by destroying the SMAR1/HDAC6 complex |
| title_short | RBX1 regulates PKM alternative splicing to facilitate anaplastic thyroid carcinoma metastasis and aerobic glycolysis by destroying the SMAR1/HDAC6 complex |
| title_sort | rbx1 regulates pkm alternative splicing to facilitate anaplastic thyroid carcinoma metastasis and aerobic glycolysis by destroying the smar1 hdac6 complex |
| topic | Anaplastic thyroid carcinoma RBX1 Metastasis PKM2 Aerobic glycolysis |
| url | https://doi.org/10.1186/s13578-023-00987-8 |
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