Ras-AKT signaling represses the phosphorylation of histone H1.5 at threonine 10 via GSK3 to promote the progression of glioma
Background Histone H1.5 has been considered as a novel cancer marker as its expression is associated with various human cancers. The objective of this study was to explore the effects of H1.5 phosphorylation in Ras-driven growth and migration of glioma cells.Methods The plasmids for expression of wi...
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Taylor & Francis Group
2019-12-01
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| Series: | Artificial Cells, Nanomedicine, and Biotechnology |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/21691401.2019.1638795 |
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| author | Ben Sang Jianjing Sun Dongxu Yang Zhen Xu Yuzhen Wei |
| author_facet | Ben Sang Jianjing Sun Dongxu Yang Zhen Xu Yuzhen Wei |
| author_sort | Ben Sang |
| collection | DOAJ |
| description | Background Histone H1.5 has been considered as a novel cancer marker as its expression is associated with various human cancers. The objective of this study was to explore the effects of H1.5 phosphorylation in Ras-driven growth and migration of glioma cells.Methods The plasmids for expression of wide-type of Ras or RasG12V/Y40C were transfected into A172 cells. The expression levels of phosphorylated AKT and H1.5T10ph were tested by Western blot. The effects of H1.5T10ph on A172 cells growth and migration were determined by MTT, soft-agar colony formation, and transwell assay. qRT-PCR and ChIP assay were utilized to assess the role of H1.5T10ph in the transcription of Ras downstream genes. Besides, qRT-PCR and Western blot analysis were carried out to reveal the enzymes which were responsible for phosphorylating H1.5.Results H1.5T10ph was down-regulated by Ras mutation, which accompanied by the activation of AKT signaling. Ras-driven A172 cells growth and migration were inhibited when H1.5T10ph was overexpressed. Additionally, H1.5T10ph was able to regulate the transcription of Ras downstream genes, including CYR61, IGFBP3, WNT16B, NT5E, GDF15, and CARD16. Further experiments revealed that Ras-AKT signaling repressed H1.5T10ph expression through degradation of GSK3, and the degradation was dependent on MDM2 mediation.Conclusion Ras-AKT signaling driven the growth and migration of glioma cells possibly through repressing the phosphorylation of H1.5 at threonine 10. Ras-AKT activation repressed H1.5T10ph through MDM2-dependent degradation of GSK3. The findings provide a better understanding of Ras’s oncogenic functions which further suggest Ras as a therapeutic target for glioma. |
| format | Article |
| id | doaj-art-0099d1c2dada45bd9d16d2f0faddd51b |
| institution | Kabale University |
| issn | 2169-1401 2169-141X |
| language | English |
| publishDate | 2019-12-01 |
| publisher | Taylor & Francis Group |
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| series | Artificial Cells, Nanomedicine, and Biotechnology |
| spelling | doaj-art-0099d1c2dada45bd9d16d2f0faddd51b2025-08-20T03:51:24ZengTaylor & Francis GroupArtificial Cells, Nanomedicine, and Biotechnology2169-14012169-141X2019-12-014712882289010.1080/21691401.2019.1638795Ras-AKT signaling represses the phosphorylation of histone H1.5 at threonine 10 via GSK3 to promote the progression of gliomaBen Sang0Jianjing Sun1Dongxu Yang2Zhen Xu3Yuzhen Wei4Department of Neurosurgery, Jining No. 1 People's Hospital, Jining, Shandong, ChinaDepartment of Endocrinology, Jining No. 1 People's Hospital, Jining, Shandong, ChinaDepartment of Neurosurgery, Affiliated Hospital of Jining Medical University, Jining, Shandong, ChinaDepartment of Neurosurgery, Jining No. 1 People's Hospital, Jining, Shandong, ChinaDepartment of Neurosurgery, Jining No. 1 People's Hospital, Jining, Shandong, ChinaBackground Histone H1.5 has been considered as a novel cancer marker as its expression is associated with various human cancers. The objective of this study was to explore the effects of H1.5 phosphorylation in Ras-driven growth and migration of glioma cells.Methods The plasmids for expression of wide-type of Ras or RasG12V/Y40C were transfected into A172 cells. The expression levels of phosphorylated AKT and H1.5T10ph were tested by Western blot. The effects of H1.5T10ph on A172 cells growth and migration were determined by MTT, soft-agar colony formation, and transwell assay. qRT-PCR and ChIP assay were utilized to assess the role of H1.5T10ph in the transcription of Ras downstream genes. Besides, qRT-PCR and Western blot analysis were carried out to reveal the enzymes which were responsible for phosphorylating H1.5.Results H1.5T10ph was down-regulated by Ras mutation, which accompanied by the activation of AKT signaling. Ras-driven A172 cells growth and migration were inhibited when H1.5T10ph was overexpressed. Additionally, H1.5T10ph was able to regulate the transcription of Ras downstream genes, including CYR61, IGFBP3, WNT16B, NT5E, GDF15, and CARD16. Further experiments revealed that Ras-AKT signaling repressed H1.5T10ph expression through degradation of GSK3, and the degradation was dependent on MDM2 mediation.Conclusion Ras-AKT signaling driven the growth and migration of glioma cells possibly through repressing the phosphorylation of H1.5 at threonine 10. Ras-AKT activation repressed H1.5T10ph through MDM2-dependent degradation of GSK3. The findings provide a better understanding of Ras’s oncogenic functions which further suggest Ras as a therapeutic target for glioma.https://www.tandfonline.com/doi/10.1080/21691401.2019.1638795GliomaRas mutationAKT signalingH1.5 phosphorylationGSK3 |
| spellingShingle | Ben Sang Jianjing Sun Dongxu Yang Zhen Xu Yuzhen Wei Ras-AKT signaling represses the phosphorylation of histone H1.5 at threonine 10 via GSK3 to promote the progression of glioma Artificial Cells, Nanomedicine, and Biotechnology Glioma Ras mutation AKT signaling H1.5 phosphorylation GSK3 |
| title | Ras-AKT signaling represses the phosphorylation of histone H1.5 at threonine 10 via GSK3 to promote the progression of glioma |
| title_full | Ras-AKT signaling represses the phosphorylation of histone H1.5 at threonine 10 via GSK3 to promote the progression of glioma |
| title_fullStr | Ras-AKT signaling represses the phosphorylation of histone H1.5 at threonine 10 via GSK3 to promote the progression of glioma |
| title_full_unstemmed | Ras-AKT signaling represses the phosphorylation of histone H1.5 at threonine 10 via GSK3 to promote the progression of glioma |
| title_short | Ras-AKT signaling represses the phosphorylation of histone H1.5 at threonine 10 via GSK3 to promote the progression of glioma |
| title_sort | ras akt signaling represses the phosphorylation of histone h1 5 at threonine 10 via gsk3 to promote the progression of glioma |
| topic | Glioma Ras mutation AKT signaling H1.5 phosphorylation GSK3 |
| url | https://www.tandfonline.com/doi/10.1080/21691401.2019.1638795 |
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