Abstract
BackgroundIncreased histone H3 phosphorylation is an essential regulatory mechanism for neoplastic cell transformation. We aimed to explore the role of histone H3 phosphorylation at serine10 (p-H3Ser10) in Epstein-Barr virus (EBV) latent membrane protein-1 (LMP1)-induced carcinogenesis of nasopharyngeal carcinoma (NPC).MethodsThe expression of p-H3Ser10 was detected by the immunohistochemical analysis in NPC, chronic nasopharyngitis and normal nasopharynx tissues, and its correlation with LMP1 was analyzed in NPC tissues and cell lines. Using the small interfering RNA (siRNA)-H3 and histone H3 mutant (S10A), the effect of histone H3 Ser10 motif on LMP1-induced CNE1 cell proliferation, transformation and activator protein-1 (AP-1) activation were evaluated by CCK-8, focus-forming and reporter gene assay respectively. Mitogen- and stress-activated kinase 1 (MSK1) kinase activity and phosphorylation were detected by in vitro kinase assay and western blot. Using MSK1 inhibitor H89 or siRNA-MSK1, the regulatory role of MSK1 on histone H3 phosphorylation and AP-1 activation were analyzed.ResultsImmunohistochemical analysis revealed that the expression of p-H3Ser10 was significantly higher in the poorly differentiated NPC tissues than that in chronic nasopharyngitis (p <0.05) and normal nasopharynx tissues (p <0.001). Moreover, high level of p-H3Ser10 was positively correlated with the expression of LMP1 in NPC tissues (χ2=6.700, p =0.01; C=0.350) and cell lines. The knockdown and mutant (S10A) of histone H3 suppressed LMP1-induced CNE1 cell proliferation, foci formation and AP-1 activation. In addition, LMP1 could increase MSK1 kinase activity and phosphorylation. MSK1 inhibitor H89 or knockdown of MSK1 by siRNA blocked LMP1-induced phosphorylation of histone H3 at Ser10 and AP-1 activation.ConclusionEBV-LMP1 can induce phosphorylation of histone H3 at Ser10 via MSK1. Increased phosphorylation of histone H3 at Ser10 is likely a crucial regulatory mechanism involved in LMP1-induced carcinogenesis of NPC.
Highlights
Increased histone H3 phosphorylation is an essential regulatory mechanism for neoplastic cell transformation
Expression of histone H3 phosphorylation at Ser10 and its correlation with latent membrane protein-1 (LMP1) in nasopharyngeal carcinoma (NPC) tissues In order to assess the role of histone H3 phosphorylation at Ser10 in the tumorigenesis of NPC, we analyzed the expression level of histone H3 phosphorylation in 48 archived paraffin-embedded NPC specimens, 15 chronic nasopharyngitis specimens and 36 adjacent/normal nasopharynx specimens using immunohistochemical staining
We showed the relationship of Mitogen- and stress-activated kinase 1 (MSK1)-mediated histone H3 phosphorylation and activator protein-1 (AP-1) transactivation promoted by LMP1 in CNE1 cells
Summary
Increased histone H3 phosphorylation is an essential regulatory mechanism for neoplastic cell transformation. Posttranslational modifications of histone, such as methylation, acetylation, phosphorylation and ubiquitination, are known to play an important role in modulating chromatin structure and regulating gene expression [1]. Phosphorylation of histone H3 at Ser was observed in interphase after cell stimulation with growth factor, stresses and chemical compounds, and associated with the transcriptional activation of immediateearly (IE) genes, including proto-oncogenes c-fos and c-jun [3,4]. Constitutive activation of Ras-mitogenactivated protein kinase (MAPK) pathway in oncogenetransformed (e.g. H-ras) mouse fibroblasts elevated the level of phosphorylated histone H3 at Ser, accompanying with the aberrant expression of c-fos, c-myc and uPA gene [6,7]. Much less is known about the role of histone H3 phosphorylation at Ser in neoplastic cell transformation and carcinogenesis
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