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AURKB 通过激活 表达促进胃癌进展。

AURKB promotes gastric cancer progression via activation of expression.

机构信息

The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.

出版信息

Aging (Albany NY). 2020 Jan 25;12(2):1304-1321. doi: 10.18632/aging.102684.

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 and . Silencing AURKB expression inhibits gastric cell proliferation and arrests the cell cycle in G/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 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 and . 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 expression, suggesting AURKB as a promising therapeutic target in gastric cancer.

摘要

极光激酶 B(AURKB)触发组蛋白 H3 丝氨酸 10 上的磷酸化(H3S10ph),这对于哺乳动物有丝分裂期间的染色体浓缩和胞质分裂很重要。然而,AURKB 如何在病理条件下作为癌蛋白精确控制细胞周期并促进肿瘤发生仍然很大程度上未知。在这里,我们报告 AURKB 促进胃癌细胞增殖和 。沉默 AURKB 表达抑制胃细胞增殖并将细胞周期阻滞在 G/M 期。我们证明细胞周期蛋白 D1(CCND1)是 AURKB 的直接下游靶标,在胃癌细胞增殖中起关键作用。AURKB 通过在 基因启动子中介导 H3S10ph 来激活 CCND1 的表达。此外,我们表明 AURKB 的特异性抑制剂 AZD1152 可以抑制胃癌细胞中 CCND1 的表达并抑制细胞增殖和 。重要的是,我们发现高 AURKB 和 CCND1 表达水平与胃癌患者的总生存时间较短相关。这项研究表明 AURKB 通过表观遗传激活 表达促进胃癌发生,提示 AURKB 是胃癌有希望的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7432/7053608/6d8e33d893ae/aging-12-102684-g001.jpg

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