Abstract
Aurora kinase B (AURKB) triggers the phosphorylation of serine 10 on histone H3 (H3S10ph), which is important for chromosome condensation and cytokinesis during mitosis in mammals. However, how exactly AURKB controls cell cycle and contributes to tumorigenesis as an oncoprotein under pathological conditions remains largely unknown. Here, we report that AURKB promotes gastric cancer cell proliferation in vitro and in vivo. Silencing AURKB expression inhibits gastric cell proliferation and arrests the cell cycle in G2/M phase. We demonstrate that cyclin D1 (CCND1) is a direct downstream target of AURKB that plays a key role in gastric cancer cell proliferation. AURKB is able to activate the expression of CCND1 through mediating H3S10ph in the promoter of the CCND1 gene. Furthermore, we show that AZD1152, a specific inhibitor of AURKB, can suppress the expression of CCND1 in the gastric cancer cells and inhibit cell proliferation in vitro and in vivo. Importantly, we found that high AURKB and CCND1 expression levels are correlated with shorter overall survival of gastric cancer patients. This study demonstrates that AURKB promotes gastric tumorigenesis potentially through epigenetically activating CCND1 expression, suggesting AURKB as a promising therapeutic target in gastric cancer.
Highlights
Gastric cancer is the fifth most common cancer and the third leading cause of cancer-related death worldwide [1]
We knocked down Aurora kinase B (AURKB) in two gastric cancer cell lines (AURKB-KD), SGC7901 and BGC823, by RNAi, which reduced AURKB expression to less than 70% of that in cells transfected with the scrambled negative control (NC) (Figure 1A and 1B)
We found that when AURKB expression was knocked down, the proliferation of gastric cancer cells was significantly slower than that of scrambled control cells (Figure 1C)
Summary
Gastric cancer is the fifth most common cancer and the third leading cause of cancer-related death worldwide [1]. In spite of significant advances in early diagnosis and treatment including radiotherapy and chemotherapy, the overall survival rate of gastric cancer patients still remains poor, with a five-year overall survival rate of approximately 30% or less [2]. AURKA is mainly involved in centrosome maturation, separation and bipolar spindle assembly whereas AURKC is primarily involved in the movement of chromosomes during mitosis in mammalian cells [3, 4]. Studies have demonstrated that the CPC plays central roles in mitosis, mediating the correction of chromosomemicrotubule attachment errors, the activation of the spindle assembly checkpoint, and the regulation of chromosome segregation and cytokinesis [5]. Previous studies indicate that AURKB can phosphorylate histone H3 on serine 10 (H3S10) and serine 28 (H3S28), which associates with chromosome number stability and chromatin condensation during mitosis [4]
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