JMJD2C promotes colorectal cancer metastasis via regulating histone methylation of MALAT1 promoter and enhancing β-catenin signaling pathway
Abstract Background Our previous work demonstrated that lncRNA-MALAT1 was overexpressed in recurrent colorectal cancer (CRC) and metastatic sites in post-surgical patients. However, the upstream regulatory mechanism of MALAT1 is not well-defined. Histone demethylase JMJD2C holds great potential of e...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-10-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13046-019-1439-x |
| _version_ | 1818543040216694784 |
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| author | Xinnan Wu Ruixiao Li Qing Song Chengcheng Zhang Ru Jia Zhifen Han Lihong Zhou Hua Sui Xuan Liu Huirong Zhu Liu Yang Yan Wang Qing Ji Qi Li |
| author_facet | Xinnan Wu Ruixiao Li Qing Song Chengcheng Zhang Ru Jia Zhifen Han Lihong Zhou Hua Sui Xuan Liu Huirong Zhu Liu Yang Yan Wang Qing Ji Qi Li |
| author_sort | Xinnan Wu |
| collection | DOAJ |
| description | Abstract Background Our previous work demonstrated that lncRNA-MALAT1 was overexpressed in recurrent colorectal cancer (CRC) and metastatic sites in post-surgical patients. However, the upstream regulatory mechanism of MALAT1 is not well-defined. Histone demethylase JMJD2C holds great potential of epigenetic regulating mechanism in tumor diseases, especially the moderating effect on the promoter activity of targeted genes associated closely with tumor development. Therefore, we herein investigated whether JMJD2C could epigeneticly regulate the promoter activity of MALAT1 and the downstream β-catenin signaling pathway, thereby affecting the metastatic abilities of CRC cells. Methods JMJD2C expressions in human CRC samples were detected by real-time PCR and immunohistochemistry staining. Gene silencing and overexpressing efficiencies of JMJD2C were confirmed by real-time PCR and western blot. The migration of CRC cells in vitro were tested by transwell and wound healing assays. The protein expression and cellular localization of JMJD2C and β-catenin were characterized by immunofluorescence staining and western blot. The histone methylation level of MALAT1 promoter region (H3K9me3 and H3K36me3) was tested by ChIP-PCR assays. The promoter activity of MALAT1 was detected by luciferase reporter assay. The expressions of MALAT1 and the downstream β-catenin signaling pathway related genes in CRC cells were detected by real-time PCR and western blot, respectively. The nude mice tail vein metastasis model was established to observe the effect of JMJD2C on the lung metastasis of CRC cells in vivo. Results Our present results indicated that histone demethylase JMJD2C was overexpressed in matched CRC tumor tissues of primary and metastatic foci, and CRC patients with lower JMJD2C expression in primary tumors had better prognosis with longer OS (Overall Survival). The following biological function observation suggested that JMJD2C promoted CRC metastasis in vitro and in vivo. Further molecular mechanism investigation demonstrated that JMJD2C protein translocated into the nuclear, lowered the histone methylation level of MALAT1 promoter in the sites of H3K9me3 and H3K36me3, up-regulated the expression of MALAT1, and enhanced the β-catenin signaling pathway in CRC cells. Conclusion Our data demonstrated that JMJD2C could enhance the metastatic abilities of CRC cells in vitro and in vivo by regulating the histone methylation level of MALAT1 promoter, thereby up-regulating the expression of MALAT1 and enhancing the activity of β-catenin signaling pathway, providing that JMJD2C might be a novel therapeutic target for CRC metastasis. |
| first_indexed | 2024-12-11T22:30:05Z |
| format | Article |
| id | doaj.art-51d388df7b98483085c77165a787ac0f |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-11T22:30:05Z |
| publishDate | 2019-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-51d388df7b98483085c77165a787ac0f2022-12-22T00:48:09ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662019-10-0138111310.1186/s13046-019-1439-xJMJD2C promotes colorectal cancer metastasis via regulating histone methylation of MALAT1 promoter and enhancing β-catenin signaling pathwayXinnan Wu0Ruixiao Li1Qing Song2Chengcheng Zhang3Ru Jia4Zhifen Han5Lihong Zhou6Hua Sui7Xuan Liu8Huirong Zhu9Liu Yang10Yan Wang11Qing Ji12Qi Li13Department of Medical Oncology and Cancer Institute of Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese MedicineDepartment of Medical Oncology and Cancer Institute of Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese MedicineDepartment of Medical Oncology and Cancer Institute of Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese MedicineDepartment of Medical Oncology, Longhua Hospital, Shanghai University of Traditional Chinese MedicineDepartment of Medical Oncology and Cancer Institute of Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese MedicineDepartment of Medical Oncology and Cancer Institute of Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese MedicineDepartment of Medical Oncology and Cancer Institute of Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese MedicineDepartment of Medical Oncology and Cancer Institute of Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese MedicineDepartment of Medical Oncology and Cancer Institute of Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese MedicineDepartment of Medical Oncology and Cancer Institute of Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese MedicineDepartment of Medical Oncology and Cancer Institute of Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese MedicineDepartment of Medical Oncology and Cancer Institute of Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese MedicineDepartment of Medical Oncology and Cancer Institute of Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese MedicineDepartment of Medical Oncology and Cancer Institute of Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese MedicineAbstract Background Our previous work demonstrated that lncRNA-MALAT1 was overexpressed in recurrent colorectal cancer (CRC) and metastatic sites in post-surgical patients. However, the upstream regulatory mechanism of MALAT1 is not well-defined. Histone demethylase JMJD2C holds great potential of epigenetic regulating mechanism in tumor diseases, especially the moderating effect on the promoter activity of targeted genes associated closely with tumor development. Therefore, we herein investigated whether JMJD2C could epigeneticly regulate the promoter activity of MALAT1 and the downstream β-catenin signaling pathway, thereby affecting the metastatic abilities of CRC cells. Methods JMJD2C expressions in human CRC samples were detected by real-time PCR and immunohistochemistry staining. Gene silencing and overexpressing efficiencies of JMJD2C were confirmed by real-time PCR and western blot. The migration of CRC cells in vitro were tested by transwell and wound healing assays. The protein expression and cellular localization of JMJD2C and β-catenin were characterized by immunofluorescence staining and western blot. The histone methylation level of MALAT1 promoter region (H3K9me3 and H3K36me3) was tested by ChIP-PCR assays. The promoter activity of MALAT1 was detected by luciferase reporter assay. The expressions of MALAT1 and the downstream β-catenin signaling pathway related genes in CRC cells were detected by real-time PCR and western blot, respectively. The nude mice tail vein metastasis model was established to observe the effect of JMJD2C on the lung metastasis of CRC cells in vivo. Results Our present results indicated that histone demethylase JMJD2C was overexpressed in matched CRC tumor tissues of primary and metastatic foci, and CRC patients with lower JMJD2C expression in primary tumors had better prognosis with longer OS (Overall Survival). The following biological function observation suggested that JMJD2C promoted CRC metastasis in vitro and in vivo. Further molecular mechanism investigation demonstrated that JMJD2C protein translocated into the nuclear, lowered the histone methylation level of MALAT1 promoter in the sites of H3K9me3 and H3K36me3, up-regulated the expression of MALAT1, and enhanced the β-catenin signaling pathway in CRC cells. Conclusion Our data demonstrated that JMJD2C could enhance the metastatic abilities of CRC cells in vitro and in vivo by regulating the histone methylation level of MALAT1 promoter, thereby up-regulating the expression of MALAT1 and enhancing the activity of β-catenin signaling pathway, providing that JMJD2C might be a novel therapeutic target for CRC metastasis.http://link.springer.com/article/10.1186/s13046-019-1439-xHistone demethylase JMJD2CMALAT1β-Catenin signaling pathwayColorectal cancerMetastasis |
| spellingShingle | Xinnan Wu Ruixiao Li Qing Song Chengcheng Zhang Ru Jia Zhifen Han Lihong Zhou Hua Sui Xuan Liu Huirong Zhu Liu Yang Yan Wang Qing Ji Qi Li JMJD2C promotes colorectal cancer metastasis via regulating histone methylation of MALAT1 promoter and enhancing β-catenin signaling pathway Journal of Experimental & Clinical Cancer Research Histone demethylase JMJD2C MALAT1 β-Catenin signaling pathway Colorectal cancer Metastasis |
| title | JMJD2C promotes colorectal cancer metastasis via regulating histone methylation of MALAT1 promoter and enhancing β-catenin signaling pathway |
| title_full | JMJD2C promotes colorectal cancer metastasis via regulating histone methylation of MALAT1 promoter and enhancing β-catenin signaling pathway |
| title_fullStr | JMJD2C promotes colorectal cancer metastasis via regulating histone methylation of MALAT1 promoter and enhancing β-catenin signaling pathway |
| title_full_unstemmed | JMJD2C promotes colorectal cancer metastasis via regulating histone methylation of MALAT1 promoter and enhancing β-catenin signaling pathway |
| title_short | JMJD2C promotes colorectal cancer metastasis via regulating histone methylation of MALAT1 promoter and enhancing β-catenin signaling pathway |
| title_sort | jmjd2c promotes colorectal cancer metastasis via regulating histone methylation of malat1 promoter and enhancing β catenin signaling pathway |
| topic | Histone demethylase JMJD2C MALAT1 β-Catenin signaling pathway Colorectal cancer Metastasis |
| url | http://link.springer.com/article/10.1186/s13046-019-1439-x |
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