Zhao Erhu, Tang Chunling, Jiang Xiaolan, Weng Xiong, Zhong Xiaoxia, Zhang Dunke, Hou Jianbing, Wang Feng, Huang Mengying, Cui Hongjuan
State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, China.
State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, China.
Cell Signal. 2017 Aug;36:222-229. doi: 10.1016/j.cellsig.2017.05.011. Epub 2017 May 12.
Gastric cancer is difficult to cure due to its clinical heterogeneity and the complexity of its molecular mechanisms. KDM2B, a member of the JHDM family, functions as a histone lysine demethylase. However, the role and mechanisms of KDM2B in gastric cancer have not been elucidated. Here, we showed that KDM2B is commonly expressed in gastric cancer cells. The downregulation of KDM2B immediately induces autophagy, followed by the inhibition of proliferation. The compound 3-methyladenine (3-MA), an inhibitor of autophagy, largely rescues autophagy and the inhibition of cell proliferation induced by KDM2B knockdown. In this process, we observed a downregulation of the phosphorylation of Akt and its downstream effectors mTOR and p70S6K and an upregulation of Erk phosphorylation after KDM2B knockdown. In a xenograft model, the downregulation of KDM2B can inhibit tumour growth. The conversion of LC3-I to LC3-II also decreased concomitantly in vivo, which is a hallmark of autophagy. Taken together, our study was the first to demonstrate a novel regulatory role of KDM2B in autophagy and cell growth in gastric cancer cells. Our findings suggest that KDM2B may serve as a novel therapeutic target for gastric cancer therapy.
由于胃癌具有临床异质性及其分子机制的复杂性，因此难以治愈。KDM2B是JHDM家族的成员之一，作为一种组蛋白赖氨酸去甲基化酶发挥作用。然而，KDM2B在胃癌中的作用和机制尚未阐明。在此，我们表明KDM2B在胃癌细胞中普遍表达。KDM2B的下调立即诱导自噬，随后抑制细胞增殖。自噬抑制剂3-甲基腺嘌呤（3-MA）在很大程度上挽救了由KDM2B敲低诱导的自噬和细胞增殖抑制。在此过程中，我们观察到KDM2B敲低后Akt及其下游效应分子mTOR和p70S6K的磷酸化下调，以及Erk磷酸化上调。在异种移植模型中，KDM2B的下调可抑制肿瘤生长。体内LC3-I向LC3-II的转化也随之减少，这是自噬的一个标志。综上所述，我们的研究首次证明了KDM2B在胃癌细胞自噬和细胞生长中具有新的调节作用。我们的研究结果表明，KDM2B可能成为胃癌治疗的一个新的治疗靶点。
