Ras-AKT signaling represses the phosphorylation of histone H1.5 at threonine 10 via GSK3 to promote the progression of glioma
Authors: Zhen Xu
Dongxu Yang
Jianjing Sun
Yuzhen Wei
Ben Sang
Journal: Artificial Cells Nanomedicine and Biotechnology (2019)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: AKT signaling; GSK3; Glioma; H1.5 phosphorylation; Ras mutation.
Affiliations: Department of Neurosurgery, Jining No. 1 People's Hospital, Jining, Shandong, China;, Affiliated Jining No. 1 People‚Äôs Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, China;, Department of Endocrinology, Jining No. 1 People's Hospital, Jining, Shandong, China;, Department of Neurosurgery, Affiliated Hospital of Jining Medical University, Jining, Shandong, China

Abstract:  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. 

Retracted: No

PubPeer comments:
 I have highlighted in green two FACS plots that appear identical in 3 of 4 quadrants. I have highlighted in purple two FACS plots that appear identical in the lower left quadrant.  , 
 Dearu00a0Prof.Cinarau00a0Pruiniviridis Iu00a0reallyu00a0appreciateu00a0youru00a0carefulu00a0reviewingu00a0ofu00a0ouru00a0paper,u00a0whichu00a0willu00a0beu00a0helpfulu00a0foru00a0usu00a0tou00a0improveu00a0theu00a0qualityu00a0ofu00a0theu00a0research.u00a0Theu00a0firstu00a0author,u00a0Mengchuanu00a0Xu,u00a0graduatedu00a0andu00a0leftu00a0ouru00a0university,u00a0whou00a0concentratedu00a0onu00a0theu00a0experimentsu00a0ofu00a0thisu00a0study.u00a0Onu00a0theu00a0oneu00a0hand,u00a0Iu00a0haveu00a0connectedu00a0withu00a0himu00a0tou00a0provide further explanation.u00a0Onu00a0theu00a0otheru00a0hand,u00a0Iu00a0haveu00a0toldu00a0theu00a0otheru00a0postgraduatesu00a0tou00a0repeatu00a0hisu00a0experiments,u00a0Iu00a0wouldu00a0provideu00a0theu00a0repeatedu00a0resultsu00a0ofu00a0othersu00a0whenu00a0theyu00a0finished. Bestu00a0regards Shugangu00a0Li , 
 #1 Dearu00a0Prof.Cinarau00a0Pruiniviridis Iu00a0reallyu00a0appreciateu00a0youru00a0carefulu00a0reviewingu00a0ofu00a0ouru00a0paper,u00a0whichu00a0willu00a0beu00a0helpfulu00a0foru00a0usu00a0tou00a0improveu00a0theu00a0qualityu00a0ofu00a0theu00a0research.u00a0Theu00a0firstu00a0author,u00a0Mengchuanu00a0Xu,u00a0graduatedu00a0andu00a0leftu00a0ouru00a0university,u00a0whou00a0concentratedu00a0onu00a0theu00a0experimentsu00a0ofu00a0thisu00a0study.u00a0Onu00a0theu00a0oneu00a0hand,u00a0Iu00a0haveu00a0connectedu00a0withu00a0himu00a0tou00a0provide further explanation.u00a0Onu00a0theu00a0otheru00a0hand,u00a0Iu00a0haveu00a0toldu00a0theu00a0otheru00a0postgraduatesu00a0tou00a0repeatu00a0hisu00a0experiments,u00a0Iu00a0wouldu00a0provideu00a0theu00a0repeatedu00a0resultsu00a0ofu00a0othersu00a0whenu00a0theyu00a0finished. Bestu00a0regards Shugangu00a0Li , 
 #1 I found a non-Institutional email address for the first author and have added it to this thread. , 
 #1 If you run a FACS experiment, you may also find quadrants are identical in terms of dot plot distribution. This is normal. , 
 #1 Dear Prof. Cinara Pruniniviridis I am Mengchuan Xu, the first author of this article. I am very grateful to gain your attention to this paper. In the flow cytometry experiments, we performed parallel experiments and similar trends of the results were found. The antagonistic effect of proanthocyanidins on arsenic-induced apoptosisuff0cas showed in Figure 2, is one of the parallel flow cytometry experiments results. Here, the other parallel result, which confirmed the reliability of the results, was also provided (see the attachment). I reverently hope you and other experts review it. Best regards Mengchuan Xu  , 
 2021 retraction. https: www.hindawi.com journals omcl 2021 3547620 Oxidative Medicine and Cellular Longevity has retracted the article titled u201cProanthocyanidins Antagonize Arsenic-Induced Oxidative Damage and Promote Arsenic Methylation through Activation of the Nrf2 Signaling Pathwayu201d [1]. As raised on PubPeer [2], the article was found to contain images with signs of duplication in Figure 2, specifically the lower left of the flow cytometry shown in panels 2(a)1, 2(a)2, 2(b)3, and 2(b)4. We asked the authors to provide the original uncropped and unadjusted images used to create all the figures, and all the raw data, i.e. all the underlying measurements for the statistics and averages shown in the graphs and tables. The authors did not provide the original images and raw data. However, they provided a corrected figure, which is available as Supplementary Materials. We consulted our Editorial Board, who recommended retraction. References M. Xu, Q. Niu, Y. Hu, G. Feng, H. Wang, and S. Li, u201cProanthocyanidins Antagonize Arsenic-Induced Oxidative Damage and Promote Arsenic Methylation through Activation of the Nrf2 Signaling Pathway,u201d Oxidative Medicine and Cellular Longevity, vol. 2019, Article ID 8549035, 19 pages, 2019. u201cProanthocyanidins Antagonize Arsenic-Induced Oxidative Damage and Promote Arsenic Methylation through Activation of the Nrf2 Signaling Pathway, PubPeer,u201d June 2019, https: pubpeer.com publications F36945569F53345B9852F46240240B. ,