AURKB promotes gastric cancer progression via activation of CCND1 expression
AURKB promotes gastric cancer progression via activation of CCND1 expression
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AURKB 通过激活 CCND1 表达促进胃癌进展
DOI：
10.18632/aging.102684
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发表时间：
2020-01-31
期刊：
影响因子：
5.2
通讯作者：
Zhao, Quan
中科院分区：
文献类型：
--
作者：
Nie, Min;Wang, Yadong;Zhao, Quan
极光激酶 B (AURKB) 触发组蛋白 H3 (H3S10ph) 上丝氨酸 10 的磷酸化，这对于哺乳动物有丝分裂期间的染色体浓缩和胞质分裂非常重要。然而，AURKB 在病理条件下如何控制细胞周期并作为癌蛋白促进肿瘤发生仍然很大程度上未知。在这里，我们报告 AURKB 在体外和体内促进胃癌细胞增殖。沉默 AURKB 表达可抑制胃细胞增殖并使细胞周期停滞在 G2/M 期。我们证明细胞周期蛋白 D1 (CCND1) 是 AURKB 的直接下游靶标，在胃癌细胞增殖中发挥关键作用。 AURKB 能够通过介导 CCND1 基因启动子中的 H3S10ph 来激活 CCND1 的表达。此外，我们还发现，AURKB 的特异性抑制剂 AZD1152 可以抑制胃癌细胞中 CCND1 的表达，并在体外和体内抑制细胞增殖。重要的是，我们发现高 AURKB 和 CCND1 表达水平与胃癌患者较短的总生存期相关。这项研究表明，AURKB 可能通过表观遗传激活 CCND1 表达来促进胃肿瘤发生，表明 AURKB 是胃癌的一个有前途的治疗靶点。
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.