ZHX2 enhances the cytotoxicity of chemotherapeutic drugs in liver tumor cells by repressing MDR1 via interfering with NF-YA.
ZHX2 enhances the cytotoxicity of chemotherapeutic drugs in liver tumor cells by repressing MDR1 via interfering with NF-YA.
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ZHX2通过干扰NF-YA抑制MDR1增强化疗药物对肝肿瘤细胞的细胞毒性
DOI：
10.18632/oncotarget.2832
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发表时间：
2015-01-20
期刊：
影响因子：
--
通讯作者：
Ma C
中科院分区：
文献类型：
--
作者：
Ma H;Yue X;Gao L;Liang X;Yan W;Zhang Z;Shan H;Zhang H;Spear BT;Ma C
我们之前报道了锌指和同源盒2 （ZHX2）在肝细胞癌（HCC）中的抑瘤功能。其他研究表明，ZHX2表达增加与多发性骨髓瘤患者对高剂量化疗的反应改善有关。在这里，我们的目的是测试HCC细胞中增加的ZHX2水平是否会抑制多药耐药1（MDR1）的表达，从而增加对化疗药物的敏感性。我们发现，在不同的HCC细胞系中，ZHX2水平升高与MDR1表达降低相关，并增强了CDDP和ADM的细胞毒性。与此一致的是，在体内，升高的ZHX2显著降低了HepG2细胞中的ADM外排，并大大增加了cddp介导的对肝肿瘤生长的抑制。免疫组化染色显示肝癌组织中ZHX2与MDR1表达呈负相关。荧光素酶报告分析显示，ZHX2抑制MDR1启动子活性，而NF-YA的敲低或NF-Y结合位点的突变消除了ZHX2介导的MDR1转录抑制。Co-IP和ChIP进一步表明，ZHX2与NF-YA相互作用，减少NF-Y与MDR1启动子的结合。综上所述，我们明确了ZHX2抑制nf - y介导的MDR1转录激活，并在体外和体内增强化疗药物对HCC细胞的作用。
We previously reported the tumor suppressor function of Zinc-fingers and homeoboxes 2 (ZHX2) in hepatocellular carcinoma (HCC). Other studies indicate the association of increased ZHX2 expression with improved response to high dose chemotherapy in multiple myeloma. Here, we aim to test whether increased ZHX2 levels in HCC cells repress multidrug resistance 1(MDR1) expression resulting in increased sensitivity to chemotherapeutic drugs. We showed evidence that increased ZHX2 levels correlated with reduced MDR1 expression and enhanced the cytotoxicity of CDDP and ADM in different HCC cell lines. Consistently, elevated ZHX2 significantly reduced ADM efflux in HepG2 cells and greatly increased the CDDP-mediated suppression of liver tumor growth in vivo. Furthermore, immunohistochemical staining demonstrated the inverse correlation of ZHX2 and MDR1 expression in HCC tissues. Luciferase report assay showed that ZHX2 repressed the MDR1 promoter activity, while knockdown of NF-YA or mutating the NF-Y binding site eliminated this ZHX2-mediated repression of MDR1 transcription. Co-IP and ChIP assay further suggested that ZHX2 interacted with NF-YA and reduced NF-Y binding to the MDR1 promoter. Taken together, we clarify that ZHX2 represses NF-Y-mediated activation of MDR1 transcription and, in doing so, enhances the effects of chemotherapeutics in HCC cells both in vitro and in vivo.
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影响因子：
3
作者：
Legartova, S.;Harnicarova-Horakova, A.;Kozubek, S.
通讯作者：
Kozubek, S.
影响因子：
4.8
作者：
Hu, Z;Jin, SK;Scotto, KW
通讯作者：
Scotto, KW
影响因子：
2.7
作者：
Nagel, Stefan;Schneider, Bjoern;MacLeod, Roderick A. F.
通讯作者：
MacLeod, Roderick A. F.
影响因子：
5.3
作者：
Jin, SK;Scotto, KW
通讯作者：
Scotto, KW
影响因子：
64.5
作者：
DORN, A;BOLLEKENS, J;MATHIS, D
通讯作者：
MATHIS, D