Abstract
BackgroundMitogen- and Stress-Activated Kinase 1 (MSK1) is a nuclear kinase that serves as active link between extracellular signals and the primary response of gene expression. However, the involvement of MSK1 in malignant transformation and cancer development is not well understood. In this study, we aimed to explore the role of MSK1 in Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1)-promoted carcinogenesis of nasopharyngeal carcinoma (NPC).MethodsThe level of MSK1 phosphorylation at Thr581 was detected by the immunohistochemical analysis in NPC tissues and normal nasopharynx tissues, and its correlation with LMP1 was analyzed in NPC tissues and cell lines. Using MSK1 inhibitor H89 or small interfering RNA (siRNA)-MSK1, the effects of MSK1 on LMP1-promoted CNE1 cell proliferation and transformation were evaluated by CCK-8 assay, flow cytometry and focus-forming assay respectively. Furthermore, the regulatory role of MSK1-mediated histone H3 phosphorylation at Ser10 on the promoter activity and expression of Fra-1 or c-Jun was determined by reporter gene assay and western blotting analysis.ResultsImmunohistochemical analysis revealed that the level of MSK1 phosphorylation at Thr581 was significantly higher in the poorly differentiated NPC tissues than that in normal nasopharynx tissues (P < 0.001). Moreover, high level of phosphorylated MSK1 was positively correlated with the expression of LMP1 in NPC tissues (r = 0.393, P = 0.002) and cell lines. MSK1 inhibitor H89 or knockdown of MSK1 by siRNA dramatically suppressed LMP1-promoted CNE1 cell proliferation, which was associated with the induction of cell cycle arrest at G0/G1 phase. In addition, the anchorage-independent growth promoted by LMP1 was blocked in MSK1 knockdown cells. When the activity or expression of MSK1 was inhibited, LMP1-induced promoter activities of Fra-1 and c-Jun as well as their protein levels were greatly reduced. It was found that only H3 WT, but not mutant H3 S10A, dramatically increased LMP1 induction of Fra-1 and c-Jun genes compared with mock cells.ConclusionIncreased MSK1 activity is critically important for LMP1-promoted cell proliferation and transformation in NPC, which may be correlated with its induction of Fra-1 and c-Jun through phosphorylation of histone H3 at Ser10.
Highlights
Mitogen- and Stress-Activated Kinase 1 (MSK1) is a nuclear kinase that serves as active link between extracellular signals and the primary response of gene expression
MSK1-mediated histone H3 phosphorylation at Ser10 is critical for epidermal growth factor (EGF), 12-O-tetradecanoylphorbol-13-acetate (TPA) and oncogene (e.g. H-ras)-induced cell transformation, which is associated with the induction of immediate-early (IE) genes such as c-Fos, c-Jun and c-Myc [11,12,13]
The level of MSK1 phosphorylation at Thr581 and its correlation with latent membrane protein 1 (LMP1) in nasopharyngeal carcinoma (NPC) tissues In order to assess the activation of MSK1 in the tumorigenesis of NPC, we analyzed the level of MSK1 phosphorylation at Thr581 in 53 archived paraffin-embedded NPC specimens and 36 adjacent/normal nasopharynx specimens using immunohistochemical staining
Summary
Mitogen- and Stress-Activated Kinase 1 (MSK1) is a nuclear kinase that serves as active link between extracellular signals and the primary response of gene expression. We aimed to explore the role of MSK1 in Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1)-promoted carcinogenesis of nasopharyngeal carcinoma (NPC). The C-terminal tail of LMP1 provides docking sites for the recruitment and activation of signaling adapter proteins, which triggers various downstream oncogenic signaling pathways, such as NF-κB, MAPK, PI3K and JAK/STAT pathways [5] It is largely unknown what key effector proteins are induced and essentially promote cell transformation in the LMP1-triggered signaling events. Our previous study demonstrated that phosphorylation of histone H3 at Ser mediated by MSK1 might be a crucial epigenetic change in LMP1-promoted carcinogenesis of NPC [18]. It is not completely clear whether the activation of MSK1 directly affects LMP1-promoted cell proliferation and transformation in NPC
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