RNA binding motif protein 10 suppresses lung cancer progression by controlling alternative splicing of eukaryotic translation initiation factor 4H
Background: RNA splicing defects are emerging molecular hallmarks of cancer. The gene encoding splicing factor RNA binding motif protein 10 (RBM10) has been found frequently mutated in various types of cancer, particularly lung adenocarcinoma (LUAD), but how RBM10 affects cancer pathogenesis remains...
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| Format: | Article |
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Elsevier
2020-11-01
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| Series: | EBioMedicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396420304436 |
| _version_ | 1819319431093813248 |
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| author | Sirui Zhang Yufang Bao Xianfeng Shen Yunjian Pan Yue Sun Man Xiao Kexuan Chen Huanhuan Wei Ji Zuo David Saffen Wei-Xing Zong Yihua Sun Zefeng Wang Yongbo Wang |
| author_facet | Sirui Zhang Yufang Bao Xianfeng Shen Yunjian Pan Yue Sun Man Xiao Kexuan Chen Huanhuan Wei Ji Zuo David Saffen Wei-Xing Zong Yihua Sun Zefeng Wang Yongbo Wang |
| author_sort | Sirui Zhang |
| collection | DOAJ |
| description | Background: RNA splicing defects are emerging molecular hallmarks of cancer. The gene encoding splicing factor RNA binding motif protein 10 (RBM10) has been found frequently mutated in various types of cancer, particularly lung adenocarcinoma (LUAD), but how RBM10 affects cancer pathogenesis remains to be determined. Moreover, the functional roles and clinical significance of RBM10 mutation-associated splicing events in LUAD are largely unknown. Methods: RBM10 mutations and their functional impacts were examined in LUAD patients from a Chinese patient cohort and The Cancer Genome Atlas (TCGA). Alternative splicing (AS) changes induced by RBM10 mutations in LUAD were identified by RNA sequencing and correlated with patient survival. Functions of RBM10 and the splice variants of eukaryotic translation initiation factor 4H containing or lacking exon 5 (EIF4H-L and EIF4H-S respectively) in LUAD development and progression were examined by cellular phenotypic assays and xenograft tumour formation. Findings: RBM10 mutations in LUAD generally lead to loss-of-function and cause extensive alterations in splicing events that can serve as prognostic predictors. RBM10 suppresses LUADprogression largely by regulating alternative splicing of EIF4H exon 5. Loss of RBM10 in LUAD enhances the expression of EIF4H-L in LUAD. EIF4H-L, but not EIF4H-S, is critical for LUAD cell proliferation, survival and tumourigenesis. Interpretation: Our study demonstrates a new molecular mechanism underlying RBM10 suppressive functions in lung cancer and the therapeutic value of RBM10-regulated AS events, providing important mechanistic and translational insights into splicing defects in cancer. |
| first_indexed | 2024-12-24T11:03:34Z |
| format | Article |
| id | doaj.art-29f1f99692e3423ca848ddddb7179f19 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-24T11:03:34Z |
| publishDate | 2020-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-29f1f99692e3423ca848ddddb7179f192022-12-21T16:58:40ZengElsevierEBioMedicine2352-39642020-11-0161103067RNA binding motif protein 10 suppresses lung cancer progression by controlling alternative splicing of eukaryotic translation initiation factor 4HSirui Zhang0Yufang Bao1Xianfeng Shen2Yunjian Pan3Yue Sun4Man Xiao5Kexuan Chen6Huanhuan Wei7Ji Zuo8David Saffen9Wei-Xing Zong10Yihua Sun11Zefeng Wang12Yongbo Wang13Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, ChinaDepartment of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, ChinaDepartment of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, ChinaDepartment of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, ChinaDepartment of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, ChinaDepartment of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, ChinaDepartment of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, ChinaCAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, ChinaDepartment of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, ChinaDepartment of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, ChinaDepartment of Chemical Biology, Rutgers University, Piscataway, NJ 08854, USADepartment of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Co-corresponding authorCAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Co-corresponding authorDepartment of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Corresponding author at: Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, ChinaBackground: RNA splicing defects are emerging molecular hallmarks of cancer. The gene encoding splicing factor RNA binding motif protein 10 (RBM10) has been found frequently mutated in various types of cancer, particularly lung adenocarcinoma (LUAD), but how RBM10 affects cancer pathogenesis remains to be determined. Moreover, the functional roles and clinical significance of RBM10 mutation-associated splicing events in LUAD are largely unknown. Methods: RBM10 mutations and their functional impacts were examined in LUAD patients from a Chinese patient cohort and The Cancer Genome Atlas (TCGA). Alternative splicing (AS) changes induced by RBM10 mutations in LUAD were identified by RNA sequencing and correlated with patient survival. Functions of RBM10 and the splice variants of eukaryotic translation initiation factor 4H containing or lacking exon 5 (EIF4H-L and EIF4H-S respectively) in LUAD development and progression were examined by cellular phenotypic assays and xenograft tumour formation. Findings: RBM10 mutations in LUAD generally lead to loss-of-function and cause extensive alterations in splicing events that can serve as prognostic predictors. RBM10 suppresses LUADprogression largely by regulating alternative splicing of EIF4H exon 5. Loss of RBM10 in LUAD enhances the expression of EIF4H-L in LUAD. EIF4H-L, but not EIF4H-S, is critical for LUAD cell proliferation, survival and tumourigenesis. Interpretation: Our study demonstrates a new molecular mechanism underlying RBM10 suppressive functions in lung cancer and the therapeutic value of RBM10-regulated AS events, providing important mechanistic and translational insights into splicing defects in cancer.http://www.sciencedirect.com/science/article/pii/S2352396420304436RBM10Lung cancerAlternative splicingEIF4H |
| spellingShingle | Sirui Zhang Yufang Bao Xianfeng Shen Yunjian Pan Yue Sun Man Xiao Kexuan Chen Huanhuan Wei Ji Zuo David Saffen Wei-Xing Zong Yihua Sun Zefeng Wang Yongbo Wang RNA binding motif protein 10 suppresses lung cancer progression by controlling alternative splicing of eukaryotic translation initiation factor 4H EBioMedicine RBM10 Lung cancer Alternative splicing EIF4H |
| title | RNA binding motif protein 10 suppresses lung cancer progression by controlling alternative splicing of eukaryotic translation initiation factor 4H |
| title_full | RNA binding motif protein 10 suppresses lung cancer progression by controlling alternative splicing of eukaryotic translation initiation factor 4H |
| title_fullStr | RNA binding motif protein 10 suppresses lung cancer progression by controlling alternative splicing of eukaryotic translation initiation factor 4H |
| title_full_unstemmed | RNA binding motif protein 10 suppresses lung cancer progression by controlling alternative splicing of eukaryotic translation initiation factor 4H |
| title_short | RNA binding motif protein 10 suppresses lung cancer progression by controlling alternative splicing of eukaryotic translation initiation factor 4H |
| title_sort | rna binding motif protein 10 suppresses lung cancer progression by controlling alternative splicing of eukaryotic translation initiation factor 4h |
| topic | RBM10 Lung cancer Alternative splicing EIF4H |
| url | http://www.sciencedirect.com/science/article/pii/S2352396420304436 |
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