JMJD2A sensitizes gastric cancer to chemotherapy by cooperating with CCDC8
JMJD2A sensitizes gastric cancer to chemotherapy by cooperating with CCDC8
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DOI：
10.1007/s10120-019-01024-9
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发表时间：
2019-11-01
期刊：
影响因子：
7.4
通讯作者：
Takayama, Tetsuji
中科院分区：
文献类型：
--
作者：
Nakagawa, Tadahiko;Sato, Yasushi;Takayama, Tetsuji
背景 组蛋白赖氨酸脱甲基酶 JMJD2 家族中含有 Jumonji 结构域的蛋白 2A (JMJD2A) 与肿瘤发生有关。然而，其表达及其在胃癌（GC）耐药性中的作用仍不清楚。在这里，我们研究了 JMJD2A 在 GC 化疗敏感性中的作用及其在 GC 中的临床相关性。方法 我们从先前鉴定的基因特征中选择了 12 个相关基因，这些基因可以预测 GC 对多西他赛、顺铂和 S-1 (DCS) 治疗的敏感性。在 GC 细胞系中使用 siRNA 敲低每个基因，并进行细胞活力测定。分别使用 qRT-PCR 和免疫组织化学评估 GC 细胞系和组织中的 JMJD2A 表达。使用全基因表达阵列和免疫沉淀检查与药物敏感性相关的 JMJD2A 下游靶点。结果 在 12 个候选基因中，JMJD2A 的下调对 GC 对抗癌药物的敏感性影响最大，并且使 5-FU、顺铂和多西紫杉醇的 IC50 值分别增加 15.3、2.7 和 4.0 倍。 JMJD2A 在 12 种 GC 细胞系中普遍表达，其在 GC 组织中的过度表达与 34 名 DCS 治疗患者的肿瘤消退呈正相关。 JMJD2A 敲低 GC 细胞的全基因表达阵列显示，促凋亡卷曲螺旋结构域 8 (CCDC8)（JMJD2A 的下游靶标）的表达显着下降。使用免疫沉淀验证了 CCDC8 和 JMJD2A 之间的直接相互作用。 CCDC8 抑制恢复了对多西他赛、顺铂和 S-1 的耐药性。结论 我们的结果表明，JMJD2A 是影响 GC 化疗敏感性的新型表观遗传因素，JMJD2A/CCDC8 是潜在的 GC 治疗靶点。
Background Jumonji domain-containing protein 2A (JMJD2A) of the JMJD2 family of histone lysine demethylases has been implicated in tumorigenesis. However, its expression and role in gastric cancer (GC) drug resistance remain unknown. Here, we investigated the role of JMJD2A in GC chemotherapeutic susceptibility and its clinical relevance in GC. Methods We selected 12 relevant genes from previously identified gene signatures that can predict GC susceptibility to docetaxel, cisplatin, and S-1 (DCS) therapy. Each gene was knocked down using siRNA in GC cell lines, and cell viability assays were performed. JMJD2A expression in GC cell lines and tissues was assessed using qRT-PCR and immunohistochemistry, respectively. A JMJD2A downstream target related to drug susceptibility was examined using whole-gene expression array and immunoprecipitation. Results Among the 12 candidate genes, down-regulation of JMJD2A showed the maximum effect on GC susceptibility to anti-cancer drugs and increased the IC50 values for 5-FU, cisplatin, and docetaxel 15.3-, 2.7-, and 4.0-fold, respectively. JMJD2A was universally expressed in 12 GC cell lines, and its overexpression in GC tissue was positively correlated with tumor regression in 34 DCS-treated patients. A whole-gene expression array of JMJD2A-knockdown GC cells demonstrated a significant decrease in the expression of pro-apoptotic coiled-coil domain containing 8 (CCDC8), a downstream target of JMJD2A. Direct interaction between CCDC8 and JMJD2A was verified using immunoprecipitation. CCDC8 inhibition restored drug resistance to docetaxel, cisplatin, and S-1. Conclusions Our results indicate that JMJD2A is a novel epigenetic factor affecting GC chemotherapeutic susceptibility, and JMJD2A/CCDC8 is a potential GC therapeutic target.