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 wide-type of Ras or Ras ^G12V/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.