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RBX1 regulates PKM alternative splicing to facilitate anaplastic thyroid carcinoma metastasis and aerobic glycolysis by destroying the SMAR1/HDAC6 complex

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 fac...

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Autores principales: Xu, Debin, Yu, Jichun, Yang, Yuting, Du, Yunyan, Lu, Hongcheng, Zhang, Shouhua, Feng, Qian, Yu, Yi, Hao, Liang, Shao, Jun, Chen, Leifeng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9945352/
https://www.ncbi.nlm.nih.gov/pubmed/36810109
http://dx.doi.org/10.1186/s13578-023-00987-8
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author Xu, Debin
Yu, Jichun
Yang, Yuting
Du, Yunyan
Lu, Hongcheng
Zhang, Shouhua
Feng, Qian
Yu, Yi
Hao, Liang
Shao, Jun
Chen, Leifeng
author_facet Xu, Debin
Yu, Jichun
Yang, Yuting
Du, Yunyan
Lu, Hongcheng
Zhang, Shouhua
Feng, Qian
Yu, Yi
Hao, Liang
Shao, Jun
Chen, Leifeng
author_sort Xu, Debin
collection PubMed
description 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13578-023-00987-8.
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spelling pubmed-99453522023-02-23 RBX1 regulates PKM alternative splicing to facilitate anaplastic thyroid carcinoma metastasis and aerobic glycolysis by destroying the SMAR1/HDAC6 complex Xu, Debin Yu, Jichun Yang, Yuting Du, Yunyan Lu, Hongcheng Zhang, Shouhua Feng, Qian Yu, Yi Hao, Liang Shao, Jun Chen, Leifeng Cell Biosci Research 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13578-023-00987-8. BioMed Central 2023-02-21 /pmc/articles/PMC9945352/ /pubmed/36810109 http://dx.doi.org/10.1186/s13578-023-00987-8 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Xu, Debin
Yu, Jichun
Yang, Yuting
Du, Yunyan
Lu, Hongcheng
Zhang, Shouhua
Feng, Qian
Yu, Yi
Hao, Liang
Shao, Jun
Chen, Leifeng
RBX1 regulates PKM alternative splicing to facilitate anaplastic thyroid carcinoma metastasis and aerobic glycolysis by destroying the SMAR1/HDAC6 complex
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 Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9945352/
https://www.ncbi.nlm.nih.gov/pubmed/36810109
http://dx.doi.org/10.1186/s13578-023-00987-8
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