Phosphorylation of Histone H3 at Serine 10 Is Indispensable for Neoplastic Cell Transformation

Abstract

Very little is known about the role of histone H3 phosphorylation in malignant transformation and cancer development. Here, we examine the function of H3 phosphorylation in cell transformation in vivo. Introduction of small interfering RNA-H3 into JB6 cells resulted in decreased epidermal growth factor (EGF)-induced cell transformation. In contrast, wildtype histone H3 (H3 WT)-overexpressing cells markedly stimulated EGF-induced cell transformation, whereas the H3 mutant S10A cells suppressed transformation. When H3 WT was overexpressed, EGF induction of c-fos and c-jun promoter activity was significantly increased compared with control cells but not in the H3 mutant S10A or S28A cells. In addition, activator protein-1 activity in H3 WT-overexpressing cells was markedly up-regulated by EGF in contrast to the H3 mutant S10A or S28A cells. These results indicate that the phosphorylation of histone H3 at Ser 10 is an essential regulatory mechanism for EGF-induced neoplastic cell transformation. (Cancer Res 2005; 65(13): 5818-27)

Mechanism of action of the Aurora kinase inhibitor CCT129202 and in vivo quantification of biological activity

“…Our own results are consistent with these previous studies because we showed that inhibition of Aurora A by CCT129202 resulted in the stabilization of p53 levels in tumor cells. Second, Aurora B has been shown to phosphorylate histone H3 at Ser 10 , and phosphorylation of histone H3 is associated with the induction of neoplastic transformation (41). Consistent with this, we showed that CCT129202 is a potent inhibitor of the phosphorylation of histone H3 in tumor cells.…”

The Prolyl Isomerase Pin1 Enhances HER-2 Expression and Cellular Transformation via Its Interaction with Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase 1

“…In addition, TPA and EGF are associated with a neoplastic cell transformation in JB6 Cl41 cells (46)(47)(48). Our results show that the overexpression of Pin1 induced a neoplastic cell transformation in JB6 Cl41 cells, and EGF enhanced the Pin1-induced cell transformation (Fig.…”

Exposure to estrogen and ionizing radiation causes epigenetic dysregulation, activation of mitogen-activated protein kinase pathways, and genome instability in the mammary gland of ACI rats

“…Recent data suggest that H3 histone phosphorylation is a major contributing factor for genome and chromosome instability and thus may play a role in cellular transformation and carcinogenesis. 60,61 Indeed, our results that demonstrated a substantial increase in histone H3S10 phosphorylation correspond to previous findings of overexpression of Aurora-A and chromosomal instability during breast carcinogenesis in ACI rats. 62 Furthermore, previous studies have demonstrated that genotoxic DNA-damaging agents can induce phosphorylation of H3S10 through the activation of the MAPK pathway.…”