JMJD6 promotes melanoma carcinogenesis through regulation of the alternative splicing of PAK1, a key MAPK signaling component
Abstract Background Melanoma, originated from melanocytes located on the basal membrane of the epithelial tissue, is the most aggressive form of skin cancer that accounts for 75% of skin cancer-related death. Although it is believed that BRAF mutation and the mitogen-activated protein kinase (MAPK)...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2017-11-01
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| Series: | Molecular Cancer |
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| Online Access: | http://link.springer.com/article/10.1186/s12943-017-0744-2 |
| _version_ | 1811314617498992640 |
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| author | Xujun Liu Wenzhe Si Xinhua Liu Lin He Jie Ren Ziran Yang Jianguo Yang Wanjin Li Shumeng Liu Fei Pei Xiaohan Yang Luyang Sun |
| author_facet | Xujun Liu Wenzhe Si Xinhua Liu Lin He Jie Ren Ziran Yang Jianguo Yang Wanjin Li Shumeng Liu Fei Pei Xiaohan Yang Luyang Sun |
| author_sort | Xujun Liu |
| collection | DOAJ |
| description | Abstract Background Melanoma, originated from melanocytes located on the basal membrane of the epithelial tissue, is the most aggressive form of skin cancer that accounts for 75% of skin cancer-related death. Although it is believed that BRAF mutation and the mitogen-activated protein kinase (MAPK) pathway play critical roles in the pathogenesis of melanoma, how the MAPK signaling is regulated in melanoma carcinogenesis is still not fully understood. Methods We characterized JMJD6 expression in melanoma tissue array by immunohistochemistry analysis. We used human melanoma A375, 451Lu and SK-MEL-1 cell lines for in vitro proliferation and invasion experiments, and xenograft transplanted mice using murine melanoma B16F10 cells by bioluminescence imaging for in vivo tumor growth and pulmonary metastasis assessments. Endothelial tube formation assay, chicken yolk sac membrane assay and matrigel plug assay were performed to test the effect of JMJD6 on the angiogenic potential in vitro and in vivo. Results Here we report that the jumonji C domain-containing demethylase/hydroxylase JMJD6 is markedly up-regulated in melanoma. We found that high expression of JMJD6 is closely correlated with advanced clinicopathologic stage, aggressiveness, and poor prognosis of melanoma. RNA-seq showed that knockdown of JMJD6 affects the alternative splicing of a panel of transcripts including that encoding for PAK1, a key component in MAPK signaling pathway. We demonstrated that JMJD6 enhances the MAPK signaling and promotes multiple cellular processes including melanogenesis, proliferation, invasion, and angiogenesis in melanoma cells. Interestingly, JMJD6 is transcriptionally activated by c-Jun, generating a feedforward loop to drive the development and progression of melanoma. Conclusions Our results indicate that JMJD6 is critically involved in melanoma carcinogenesis, supporting the pursuit of JMJD6 as a potential biomarker for melanoma aggressiveness and a target for melanoma intervention. |
| first_indexed | 2024-04-13T11:15:42Z |
| format | Article |
| id | doaj.art-884853d979524cb0baaf96a8fa01dba1 |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-04-13T11:15:42Z |
| publishDate | 2017-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-884853d979524cb0baaf96a8fa01dba12022-12-22T02:49:00ZengBMCMolecular Cancer1476-45982017-11-0116111810.1186/s12943-017-0744-2JMJD6 promotes melanoma carcinogenesis through regulation of the alternative splicing of PAK1, a key MAPK signaling componentXujun Liu0Wenzhe Si1Xinhua Liu2Lin He3Jie Ren4Ziran Yang5Jianguo Yang6Wanjin Li7Shumeng Liu8Fei Pei9Xiaohan Yang10Luyang Sun11Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science CenterKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science CenterDepartment of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical UniversityKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science CenterKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science CenterKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science CenterKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science CenterKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science CenterKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science CenterDepartment of Pathology, School of Basic Medical Sciences, Peking University Health Science CenterKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science CenterKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science CenterAbstract Background Melanoma, originated from melanocytes located on the basal membrane of the epithelial tissue, is the most aggressive form of skin cancer that accounts for 75% of skin cancer-related death. Although it is believed that BRAF mutation and the mitogen-activated protein kinase (MAPK) pathway play critical roles in the pathogenesis of melanoma, how the MAPK signaling is regulated in melanoma carcinogenesis is still not fully understood. Methods We characterized JMJD6 expression in melanoma tissue array by immunohistochemistry analysis. We used human melanoma A375, 451Lu and SK-MEL-1 cell lines for in vitro proliferation and invasion experiments, and xenograft transplanted mice using murine melanoma B16F10 cells by bioluminescence imaging for in vivo tumor growth and pulmonary metastasis assessments. Endothelial tube formation assay, chicken yolk sac membrane assay and matrigel plug assay were performed to test the effect of JMJD6 on the angiogenic potential in vitro and in vivo. Results Here we report that the jumonji C domain-containing demethylase/hydroxylase JMJD6 is markedly up-regulated in melanoma. We found that high expression of JMJD6 is closely correlated with advanced clinicopathologic stage, aggressiveness, and poor prognosis of melanoma. RNA-seq showed that knockdown of JMJD6 affects the alternative splicing of a panel of transcripts including that encoding for PAK1, a key component in MAPK signaling pathway. We demonstrated that JMJD6 enhances the MAPK signaling and promotes multiple cellular processes including melanogenesis, proliferation, invasion, and angiogenesis in melanoma cells. Interestingly, JMJD6 is transcriptionally activated by c-Jun, generating a feedforward loop to drive the development and progression of melanoma. Conclusions Our results indicate that JMJD6 is critically involved in melanoma carcinogenesis, supporting the pursuit of JMJD6 as a potential biomarker for melanoma aggressiveness and a target for melanoma intervention.http://link.springer.com/article/10.1186/s12943-017-0744-2JMJD6PAK1MAPKMelanomaAlternative splicing |
| spellingShingle | Xujun Liu Wenzhe Si Xinhua Liu Lin He Jie Ren Ziran Yang Jianguo Yang Wanjin Li Shumeng Liu Fei Pei Xiaohan Yang Luyang Sun JMJD6 promotes melanoma carcinogenesis through regulation of the alternative splicing of PAK1, a key MAPK signaling component Molecular Cancer JMJD6 PAK1 MAPK Melanoma Alternative splicing |
| title | JMJD6 promotes melanoma carcinogenesis through regulation of the alternative splicing of PAK1, a key MAPK signaling component |
| title_full | JMJD6 promotes melanoma carcinogenesis through regulation of the alternative splicing of PAK1, a key MAPK signaling component |
| title_fullStr | JMJD6 promotes melanoma carcinogenesis through regulation of the alternative splicing of PAK1, a key MAPK signaling component |
| title_full_unstemmed | JMJD6 promotes melanoma carcinogenesis through regulation of the alternative splicing of PAK1, a key MAPK signaling component |
| title_short | JMJD6 promotes melanoma carcinogenesis through regulation of the alternative splicing of PAK1, a key MAPK signaling component |
| title_sort | jmjd6 promotes melanoma carcinogenesis through regulation of the alternative splicing of pak1 a key mapk signaling component |
| topic | JMJD6 PAK1 MAPK Melanoma Alternative splicing |
| url | http://link.springer.com/article/10.1186/s12943-017-0744-2 |
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