FTO facilitates cancer metastasis by modifying the m6A level of FAP to induce integrin/FAK signaling in non-small cell lung cancer
Abstract Background Emerging evidence suggests the critical roles of N6-methyladenosine (m6A) RNA modification in tumorigenesis and tumor progression. However, the role of m6A in non-small cell lung cancer (NSCLC) is still unclear. This study aimed to explore the role of the m6A demethylase fat mass...
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| Format: | Article |
| Language: | English |
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BMC
2023-11-01
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| Series: | Cell Communication and Signaling |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12964-023-01343-6 |
| _version_ | 1797636791499489280 |
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| author | Lirong Gao Anqi Wang Yuling Chen Xin Cai Yue Li Jian Zhao Yang Zhang Weijie Zhang Jianjie Zhu Yuanyuan Zeng Zeyi Liu Jian-an Huang |
| author_facet | Lirong Gao Anqi Wang Yuling Chen Xin Cai Yue Li Jian Zhao Yang Zhang Weijie Zhang Jianjie Zhu Yuanyuan Zeng Zeyi Liu Jian-an Huang |
| author_sort | Lirong Gao |
| collection | DOAJ |
| description | Abstract Background Emerging evidence suggests the critical roles of N6-methyladenosine (m6A) RNA modification in tumorigenesis and tumor progression. However, the role of m6A in non-small cell lung cancer (NSCLC) is still unclear. This study aimed to explore the role of the m6A demethylase fat mass and obesity-associated protein (FTO) in the tumor metastasis of NSCLC. Methods A human m6A epitranscriptomic microarray analysis was used to identify downstream targets of FTO. Quantitative real-time PCR (qRT‒PCR) and western blotting were employed to evaluate the expression levels of FTO and FAP in NSCLC cell lines and tissues. Gain-of-function and loss-of-function assays were conducted in vivo and in vitro to assess the effects of FTO and FAP on NSCLC metastasis. M6A-RNA immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP), luciferase reporter assays, and RNA stability assays were used to explore the mechanism of FTO action. Co-immunoprecipitation (co-IP) assays were used to determine the mechanism of FAP in NSCLC metastasis. Results FTO was upregulated and predicted poor prognosis in patients with NSCLC. FTO promoted cell migration and invasion in NSCLC, and the FAK inhibitor defactinib (VS6063) suppressed NSCLC metastasis induced by overexpression of FTO. Mechanistically, FTO facilitated NSCLC metastasis by modifying the m6A level of FAP in a YTHDF2-dependent manner. Moreover, FTO-mediated metastasis formation depended on the interactions between FAP and integrin family members, which further activated the FAK signaling. Conclusion Our current findings provided valuable insights into the role of FTO-mediated m6A demethylation modification in NSCLC metastasis. FTO was identified as a contributor to NSCLC metastasis through the activation of the FAP/integrin/FAK signaling, which may be a potential therapeutic target for NSCLC. Video Abstract |
| first_indexed | 2024-03-11T12:40:11Z |
| format | Article |
| id | doaj.art-f4daf79621f148759e861a8a8b3fc8ab |
| institution | Directory Open Access Journal |
| issn | 1478-811X |
| language | English |
| last_indexed | 2024-03-11T12:40:11Z |
| publishDate | 2023-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj.art-f4daf79621f148759e861a8a8b3fc8ab2023-11-05T12:25:08ZengBMCCell Communication and Signaling1478-811X2023-11-0121111810.1186/s12964-023-01343-6FTO facilitates cancer metastasis by modifying the m6A level of FAP to induce integrin/FAK signaling in non-small cell lung cancerLirong Gao0Anqi Wang1Yuling Chen2Xin Cai3Yue Li4Jian Zhao5Yang Zhang6Weijie Zhang7Jianjie Zhu8Yuanyuan Zeng9Zeyi Liu10Jian-an Huang11Department of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Soochow UniversityDepartment of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Soochow UniversityDepartment of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Soochow UniversityDepartment of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Soochow UniversityDepartment of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Soochow UniversityDepartment of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Soochow UniversityDepartment of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Soochow UniversityDepartment of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Soochow UniversityDepartment of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Soochow UniversityDepartment of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Soochow UniversityDepartment of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Soochow UniversityDepartment of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Soochow UniversityAbstract Background Emerging evidence suggests the critical roles of N6-methyladenosine (m6A) RNA modification in tumorigenesis and tumor progression. However, the role of m6A in non-small cell lung cancer (NSCLC) is still unclear. This study aimed to explore the role of the m6A demethylase fat mass and obesity-associated protein (FTO) in the tumor metastasis of NSCLC. Methods A human m6A epitranscriptomic microarray analysis was used to identify downstream targets of FTO. Quantitative real-time PCR (qRT‒PCR) and western blotting were employed to evaluate the expression levels of FTO and FAP in NSCLC cell lines and tissues. Gain-of-function and loss-of-function assays were conducted in vivo and in vitro to assess the effects of FTO and FAP on NSCLC metastasis. M6A-RNA immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP), luciferase reporter assays, and RNA stability assays were used to explore the mechanism of FTO action. Co-immunoprecipitation (co-IP) assays were used to determine the mechanism of FAP in NSCLC metastasis. Results FTO was upregulated and predicted poor prognosis in patients with NSCLC. FTO promoted cell migration and invasion in NSCLC, and the FAK inhibitor defactinib (VS6063) suppressed NSCLC metastasis induced by overexpression of FTO. Mechanistically, FTO facilitated NSCLC metastasis by modifying the m6A level of FAP in a YTHDF2-dependent manner. Moreover, FTO-mediated metastasis formation depended on the interactions between FAP and integrin family members, which further activated the FAK signaling. Conclusion Our current findings provided valuable insights into the role of FTO-mediated m6A demethylation modification in NSCLC metastasis. FTO was identified as a contributor to NSCLC metastasis through the activation of the FAP/integrin/FAK signaling, which may be a potential therapeutic target for NSCLC. Video Abstracthttps://doi.org/10.1186/s12964-023-01343-6N6-methyladenosine (m6A)Fat mass and obesity-associated protein (FTO)Fibroblast activation protein (FAP)CarcinomaNon-Small-Cell Lung (NSCLC)Metastasis |
| spellingShingle | Lirong Gao Anqi Wang Yuling Chen Xin Cai Yue Li Jian Zhao Yang Zhang Weijie Zhang Jianjie Zhu Yuanyuan Zeng Zeyi Liu Jian-an Huang FTO facilitates cancer metastasis by modifying the m6A level of FAP to induce integrin/FAK signaling in non-small cell lung cancer Cell Communication and Signaling N6-methyladenosine (m6A) Fat mass and obesity-associated protein (FTO) Fibroblast activation protein (FAP) Carcinoma Non-Small-Cell Lung (NSCLC) Metastasis |
| title | FTO facilitates cancer metastasis by modifying the m6A level of FAP to induce integrin/FAK signaling in non-small cell lung cancer |
| title_full | FTO facilitates cancer metastasis by modifying the m6A level of FAP to induce integrin/FAK signaling in non-small cell lung cancer |
| title_fullStr | FTO facilitates cancer metastasis by modifying the m6A level of FAP to induce integrin/FAK signaling in non-small cell lung cancer |
| title_full_unstemmed | FTO facilitates cancer metastasis by modifying the m6A level of FAP to induce integrin/FAK signaling in non-small cell lung cancer |
| title_short | FTO facilitates cancer metastasis by modifying the m6A level of FAP to induce integrin/FAK signaling in non-small cell lung cancer |
| title_sort | fto facilitates cancer metastasis by modifying the m6a level of fap to induce integrin fak signaling in non small cell lung cancer |
| topic | N6-methyladenosine (m6A) Fat mass and obesity-associated protein (FTO) Fibroblast activation protein (FAP) Carcinoma Non-Small-Cell Lung (NSCLC) Metastasis |
| url | https://doi.org/10.1186/s12964-023-01343-6 |
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