An SETD1A/Wnt/β-catenin feedback loop promotes NSCLC development
Abstract Background SETD1A, a member of SET1/MLL family H3K4 methyltransferases, is involved in the tumorigenesis of numerous cancers. However, the biological role and mechanism of SETD1A in non-small cell lung cancer (NSCLC) remain to be elucidated. Methods The expression of SETD1A, NEAT1, EZH2, an...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-10-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-021-02119-x |
| _version_ | 1818585149665705984 |
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| author | Rui Wang Jian Liu Kai Li Ganghua Yang Sisi Chen Jie Wu Xinming Xie Hong Ren Yamei Pang |
| author_facet | Rui Wang Jian Liu Kai Li Ganghua Yang Sisi Chen Jie Wu Xinming Xie Hong Ren Yamei Pang |
| author_sort | Rui Wang |
| collection | DOAJ |
| description | Abstract Background SETD1A, a member of SET1/MLL family H3K4 methyltransferases, is involved in the tumorigenesis of numerous cancers. However, the biological role and mechanism of SETD1A in non-small cell lung cancer (NSCLC) remain to be elucidated. Methods The expression of SETD1A, NEAT1, EZH2, and β-catenin in NSCLC tissues and cell lines was detected by qRT-PCR, immunohistochemistry and western blotting. The regulatory mechanisms were validated by chromatin immunoprecipitation, co-immunoprepitation and luciferase reporter assay. The self-renewal, cisplatin sensitivity and tumorigenesis of NSCLC cells were analyzed using sphere formation, CCK-8, colony formation assays and xenograft tumor models. Results SETD1A expression was significantly increased in NSCLC and its overexpression predicted a poor prognosis of patients with NSCLC. Functional experiments showed that SETD1A positively regulated cancer stem cell property and negatively regulated cisplatin sensitivity in NSCLC cells via the Wnt/β-catenin pathway. Next, we found that SETD1A positively regulated the Wnt/β-catenin pathway via interacting with and stabilizing β-catenin. The SET domain is dispensable for the interaction between SETD1A and β-catenin. Furthermore, we identified that SETD1A bound to the promoters of NEAT1 and EZH2 to activate gene transcription by inducing H3K4me3 enrichment. Rescue experiments showed that SETD1A promoted the Wnt/β-catenin pathway and exerted its oncogenic functions in NSCLC, at least, partly through NEAT1 and EZH2 upregulation. In addition, SETD1A was proven to be a direct target of the Wnt/β-catenin pathway, thus forming a positive feedback loop in NSCLC cells. Conclusion SETD1A and Wnt/β-catenin pathway form a positive feedback loop and coordinately contribute to NSCLC progression. |
| first_indexed | 2024-12-16T08:32:29Z |
| format | Article |
| id | doaj.art-bf61e0dff4bf4a9080a2c18aa10f6a22 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-16T08:32:29Z |
| publishDate | 2021-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-bf61e0dff4bf4a9080a2c18aa10f6a222022-12-21T22:37:50ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662021-10-0140111710.1186/s13046-021-02119-xAn SETD1A/Wnt/β-catenin feedback loop promotes NSCLC developmentRui Wang0Jian Liu1Kai Li2Ganghua Yang3Sisi Chen4Jie Wu5Xinming Xie6Hong Ren7Yamei Pang8Department of Thoracic Surgery, the First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Thoracic Surgery, the First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Thoracic Surgery, the First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Geriatric Surgery, the First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Thoracic Surgery, the First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Thoracic Surgery, the First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’anDepartment of Thoracic Surgery, the First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’anAbstract Background SETD1A, a member of SET1/MLL family H3K4 methyltransferases, is involved in the tumorigenesis of numerous cancers. However, the biological role and mechanism of SETD1A in non-small cell lung cancer (NSCLC) remain to be elucidated. Methods The expression of SETD1A, NEAT1, EZH2, and β-catenin in NSCLC tissues and cell lines was detected by qRT-PCR, immunohistochemistry and western blotting. The regulatory mechanisms were validated by chromatin immunoprecipitation, co-immunoprepitation and luciferase reporter assay. The self-renewal, cisplatin sensitivity and tumorigenesis of NSCLC cells were analyzed using sphere formation, CCK-8, colony formation assays and xenograft tumor models. Results SETD1A expression was significantly increased in NSCLC and its overexpression predicted a poor prognosis of patients with NSCLC. Functional experiments showed that SETD1A positively regulated cancer stem cell property and negatively regulated cisplatin sensitivity in NSCLC cells via the Wnt/β-catenin pathway. Next, we found that SETD1A positively regulated the Wnt/β-catenin pathway via interacting with and stabilizing β-catenin. The SET domain is dispensable for the interaction between SETD1A and β-catenin. Furthermore, we identified that SETD1A bound to the promoters of NEAT1 and EZH2 to activate gene transcription by inducing H3K4me3 enrichment. Rescue experiments showed that SETD1A promoted the Wnt/β-catenin pathway and exerted its oncogenic functions in NSCLC, at least, partly through NEAT1 and EZH2 upregulation. In addition, SETD1A was proven to be a direct target of the Wnt/β-catenin pathway, thus forming a positive feedback loop in NSCLC cells. Conclusion SETD1A and Wnt/β-catenin pathway form a positive feedback loop and coordinately contribute to NSCLC progression.https://doi.org/10.1186/s13046-021-02119-xSETD1Aβ-CateninNEAT1EZH2NSCLC |
| spellingShingle | Rui Wang Jian Liu Kai Li Ganghua Yang Sisi Chen Jie Wu Xinming Xie Hong Ren Yamei Pang An SETD1A/Wnt/β-catenin feedback loop promotes NSCLC development Journal of Experimental & Clinical Cancer Research SETD1A β-Catenin NEAT1 EZH2 NSCLC |
| title | An SETD1A/Wnt/β-catenin feedback loop promotes NSCLC development |
| title_full | An SETD1A/Wnt/β-catenin feedback loop promotes NSCLC development |
| title_fullStr | An SETD1A/Wnt/β-catenin feedback loop promotes NSCLC development |
| title_full_unstemmed | An SETD1A/Wnt/β-catenin feedback loop promotes NSCLC development |
| title_short | An SETD1A/Wnt/β-catenin feedback loop promotes NSCLC development |
| title_sort | setd1a wnt β catenin feedback loop promotes nsclc development |
| topic | SETD1A β-Catenin NEAT1 EZH2 NSCLC |
| url | https://doi.org/10.1186/s13046-021-02119-x |
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