Ras-PI3K pathway promotes osteosarcoma progression via regulating VRK1-mediated H2A phosphorylation at threonine 120

Abstract

Background: Ras-PI3K pathway aberrant activation plays an important role in the occurrence and development of osteosarcoma. This study investigated the functions of Ras-PI3K pathway specific activation on histone H2A phosphorylation at threonine 120 (H2A T120ph) in osteosarcoma cells, along with the possible internal molecular mechanisms. Methods: Cell transfection was done to alter Ras G12V/Y40C , H2A T120ph and vaccinia-related kinase 1 (VRK1) expression. Then, cell viability, proliferation, migration and cell cycle distribution were assessed, respectively. qRT-PCR was utilized to measure the VRK1 and Ras-PI3K pathway downstream genes (CYR61, IGFBP3, WNT16B, NT5E, GDF15 and CARD16) expression. Chromatin immunoprecipitation (ChIP) was conducted to evaluate the input levels of H2A T120ph and VRK1 in the promoter regions of Ras-PI3K pathway downstream genes. Results: Ras-PI3K specific activation promoted histone H2A T120ph. H2A T120ph participated in the oncogenic functions of Ras-PI3K pathway on osteosarcoma by modulating the transcription of Ras-PI3K-targeted genes. Moreover, VRK1 contributed to the Ras-PI3K specific activation-induced up-regulation of H2A T120ph and osteosarcoma progression. Ras-PI3K pathway-specific activation-induced up-regulation of H2A T120ph was achieved by up-regulation of VRK1. Conclusions: Ras-PI3K pathway activation promoted osteosarcoma progression might be via up-regulating VRK1-mediated H2A T120ph. We proposed that VRK1 and H2A T120ph could be the potential targets for osteosarcoma diagnosis and treatment. HIGHLIGHTS 1. H2A T120ph is specifically promoted by Ras-PI3K pathway activation. 2. H2A T120ph joins in the oncogenic effects of Ras-PI3K pathway on osteosarcoma. 3. H2A T120ph regulates the transcription of Ras-PI3K-targeted genes. 4. VRK1 takes part in the regulatory function of Ras-PI3K pathway on H2A T120ph .

Development and Validation of A Seven-microRNA Signature as a Novel Prognostic Biomarker for Bladder Cancer

“…H, C et al [27]. clari ed that the MAPK pathway played a crucial role in the invasion and metastasis of bladder cancer cells.S, C et al [28]have found that the upregulation of myosin light chain kinase (MYLK) and activation of cGMP-PKG signaling pathway can silence serine / arginine repeat matrix protein 2-selective splicing (SRRM2-AS), thus inhibiting nasopharyngeal carcinoma cell proliferation, colony formation, angiogenesis, blocking the cell cycle and enhancing apoptosis.Studies by Xu, X, et al [29] found that the Pi3K pathway was speci cally activated, vaccine-associated kinase 1 was up-regulateed (VRK1), and then histone H2A was induced to be up-regulated, eventually promoting the progression of osteosarcoma. S, J, et al [30]clari ed that the signaling pathway of transforming growth factor-β (TGF-β) was involved in many cellular processes in mature organisms and developing embryos.…”

Amicis Omnia Sunt Communia: NF-κB Inhibition as an Alternative to Overcome Osteosarcoma Heterogeneity

“…The PI3K/AKT pathway is frequently hyperactivated in OS and contributes to increased proliferation and invasion, inhibition of apoptosis, angiogenesis, and chemoresistance [ 91 , 92 ]. Moreover, activation of this pathway has been associated with lung metastasis and poorer prognosis [ 93 ].…”