CircXRN2 suppresses tumor progression driven by histone lactylation through activating the Hippo pathway in human bladder cancer
Abstract Background Bladder cancer (BCa) is the fourth most common malignant tumor with a poor prognosis worldwide. Further exploration and research are needed to unmask the underlying roles and molecular mechanisms of circular RNAs. In the current study, our findings showed that circXRN2 suppresses...
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| Format: | Article |
| Language: | English |
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BMC
2023-09-01
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| Series: | Molecular Cancer |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12943-023-01856-1 |
| _version_ | 1797577695360450560 |
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| author | Bo Xie Juntao Lin Xianwu Chen Xuejian Zhou Yan Zhang Mengjing Fan Jiayong Xiang Ning He Zhenghui Hu Feifan Wang |
| author_facet | Bo Xie Juntao Lin Xianwu Chen Xuejian Zhou Yan Zhang Mengjing Fan Jiayong Xiang Ning He Zhenghui Hu Feifan Wang |
| author_sort | Bo Xie |
| collection | DOAJ |
| description | Abstract Background Bladder cancer (BCa) is the fourth most common malignant tumor with a poor prognosis worldwide. Further exploration and research are needed to unmask the underlying roles and molecular mechanisms of circular RNAs. In the current study, our findings showed that circXRN2 suppresses tumor progression driven by histone lactylation by activating the Hippo pathway in human bladder cancer. Methods RNA immunoprecipitation (RIP) followed by circRNA sequencing confirmed circXRN2 as the research object. Overexpression of circXRN2 and knockdown of TAZ/YAP further verified the biological functions in T24 and TCCSUP cells. RIP, immunoprecipitation and coimmunoprecipitation were used to elucidate the interaction between circXRN2 and LATS1. A Seahorse metabolic analyzer was used to determine the glycolytic rate. Cleavage under targets and Tagmentation (CUT&Tag) and chromatin immunoprecipitation (ChIP) were employed to ensure the regulatory roles of H3K18 lactylation in the transcriptional activity of LCN2. Results CircXRN2 is aberrantly downregulated in bladder cancer tissues and cell lines. CircXRN2 inhibits the proliferation and migration of tumor cells both in vitro and in vivo. In addition, circXRN2 serves as a negative regulator of glycolysis and lactate production. Mechanistically, circXRN2 prevents LATS1 from SPOP-mediated degradation by binding to the SPOP degron and then activates the Hippo signaling pathway to exert various biological functions. The circXRN2-Hippo pathway regulatory axis further modulates tumor progression by inhibiting H3K18 lactylation and LCN2 expression in human bladder cancer. Conclusions CircXRN2 suppresses tumor progression driven by H3K18 lactylation by activating the Hippo signaling pathway in human bladder cancer. Our results indicated novel therapeutic targets and provided promising strategies for clinical intervention in human bladder cancer. |
| first_indexed | 2024-03-10T22:12:39Z |
| format | Article |
| id | doaj.art-a7c24dbdd5604388bec6f97ff2a4d8bf |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-03-10T22:12:39Z |
| publishDate | 2023-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-a7c24dbdd5604388bec6f97ff2a4d8bf2023-11-19T12:34:23ZengBMCMolecular Cancer1476-45982023-09-0122111810.1186/s12943-023-01856-1CircXRN2 suppresses tumor progression driven by histone lactylation through activating the Hippo pathway in human bladder cancerBo Xie0Juntao Lin1Xianwu Chen2Xuejian Zhou3Yan Zhang4Mengjing Fan5Jiayong Xiang6Ning He7Zhenghui Hu8Feifan Wang9Department of Urology, The First Affiliated Hospital, Zhejiang University School of MedicineDepartment of Urology, The First Affiliated Hospital, Zhejiang University School of MedicineDepartment of Urology, The First Affiliated Hospital, Zhejiang University School of MedicineDepartment of Urology, The First Affiliated Hospital, Zhejiang University School of MedicineDepartment of Urology, The First Affiliated Hospital, Zhejiang University School of MedicineDepartment of Pathology, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Urology, The First Affiliated Hospital, Zhejiang University School of MedicineDepartment of Urology, The First Affiliated Hospital, Zhejiang University School of MedicineDepartment of Urology, The First Affiliated Hospital, Zhejiang University School of MedicineDepartment of Urology, The First Affiliated Hospital, Zhejiang University School of MedicineAbstract Background Bladder cancer (BCa) is the fourth most common malignant tumor with a poor prognosis worldwide. Further exploration and research are needed to unmask the underlying roles and molecular mechanisms of circular RNAs. In the current study, our findings showed that circXRN2 suppresses tumor progression driven by histone lactylation by activating the Hippo pathway in human bladder cancer. Methods RNA immunoprecipitation (RIP) followed by circRNA sequencing confirmed circXRN2 as the research object. Overexpression of circXRN2 and knockdown of TAZ/YAP further verified the biological functions in T24 and TCCSUP cells. RIP, immunoprecipitation and coimmunoprecipitation were used to elucidate the interaction between circXRN2 and LATS1. A Seahorse metabolic analyzer was used to determine the glycolytic rate. Cleavage under targets and Tagmentation (CUT&Tag) and chromatin immunoprecipitation (ChIP) were employed to ensure the regulatory roles of H3K18 lactylation in the transcriptional activity of LCN2. Results CircXRN2 is aberrantly downregulated in bladder cancer tissues and cell lines. CircXRN2 inhibits the proliferation and migration of tumor cells both in vitro and in vivo. In addition, circXRN2 serves as a negative regulator of glycolysis and lactate production. Mechanistically, circXRN2 prevents LATS1 from SPOP-mediated degradation by binding to the SPOP degron and then activates the Hippo signaling pathway to exert various biological functions. The circXRN2-Hippo pathway regulatory axis further modulates tumor progression by inhibiting H3K18 lactylation and LCN2 expression in human bladder cancer. Conclusions CircXRN2 suppresses tumor progression driven by H3K18 lactylation by activating the Hippo signaling pathway in human bladder cancer. Our results indicated novel therapeutic targets and provided promising strategies for clinical intervention in human bladder cancer.https://doi.org/10.1186/s12943-023-01856-1Bladder cancercircXRN2Hippo pathwayHistone lactylationTumor progression |
| spellingShingle | Bo Xie Juntao Lin Xianwu Chen Xuejian Zhou Yan Zhang Mengjing Fan Jiayong Xiang Ning He Zhenghui Hu Feifan Wang CircXRN2 suppresses tumor progression driven by histone lactylation through activating the Hippo pathway in human bladder cancer Molecular Cancer Bladder cancer circXRN2 Hippo pathway Histone lactylation Tumor progression |
| title | CircXRN2 suppresses tumor progression driven by histone lactylation through activating the Hippo pathway in human bladder cancer |
| title_full | CircXRN2 suppresses tumor progression driven by histone lactylation through activating the Hippo pathway in human bladder cancer |
| title_fullStr | CircXRN2 suppresses tumor progression driven by histone lactylation through activating the Hippo pathway in human bladder cancer |
| title_full_unstemmed | CircXRN2 suppresses tumor progression driven by histone lactylation through activating the Hippo pathway in human bladder cancer |
| title_short | CircXRN2 suppresses tumor progression driven by histone lactylation through activating the Hippo pathway in human bladder cancer |
| title_sort | circxrn2 suppresses tumor progression driven by histone lactylation through activating the hippo pathway in human bladder cancer |
| topic | Bladder cancer circXRN2 Hippo pathway Histone lactylation Tumor progression |
| url | https://doi.org/10.1186/s12943-023-01856-1 |
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