DNTTIP1 promotes nasopharyngeal carcinoma metastasis via recruiting HDAC1 to DUSP2 promoter and activating ERK signaling pathway.
DNTTIP1 promotes nasopharyngeal carcinoma metastasis via recruiting HDAC1 to DUSP2 promoter and activating ERK signaling pathway.
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DNTTIP1通过招募HDAC1到DUSP2启动子并激活ERK信号通路促进鼻咽癌转移
DOI：
10.1016/j.ebiom.2022.104100
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发表时间：
2022-07
期刊：
影响因子：
11.1
通讯作者：
Xia, Yunfei
中科院分区：
文献类型：
--
作者：
Ding, Shirong;Gao, Ying;Lv, Dongming;Tao, Yalan;Liu, Songran;Chen, Chen;Huang, Zilu;Zheng, Shuohan;Hu, Yujun;Chow, Larry Ka-Yue;Wei, Yinghong;Feng, Ping;Dai, Wei;Wang, Xin;Xia, Yunfei
远处转移仍然是鼻咽癌患者（NPC）患者治疗失败的主要原因，这使得鉴定有效的转移性NPC治疗靶标至关重要。先前的研究表明，脱氧核苷酸转移酶末端相互作用蛋白1（DNTTIP1）与各种类型的癌症的发展有关。但是，尚未探索其在NPC中的作用和机制。
对三对NPC和正常鼻咽组织进行RNA-Seq分析。通过免疫组织化学检测到NPC试样中的DNTTIP1表达。体外和体内测定用于研究DNTTIP1的功能。使用RT-QPCR，Western印迹，RNA-Seq，荧光素酶报告基因测定，CHIP分析和CO-IP分析确定分子机制。
发现DNTTIP1在NPC组织中显着上调。此外，DNTTIP1在体外和体内促进了NPC的生长和转移。 NPC中DNTTIP1的上调表明临床结果不佳。从机械上讲，DNTTIP1通过将HDAC1募集到其启动子中抑制了DUSP2基因表达，并维持了组蛋白H3K27的脱乙酰化状态。 DUSP2的下调导致ERK信号传导异常激活和MMP2水平升高，从而促进NPC转移。 Chidamide是一种HDAC抑制剂，通过调节DNTTIP1/HDAC1-DUSP2轴来抑制NPC转移。
我们的发现表明，DNTTIP1不仅调节NPC转移，而且独立预测了NPC预后。此外，奇达酰胺靶向DNTTIP1/HDAC1可能会使NPC转移患者受益。
这项工作得到了中国国家自然科学基金会（第81872464、82073243号）的支持。
Distant metastasis remains the leading cause of treatment failure in patients with nasopharyngeal carcinoma (NPC), making it critical to identify efficient therapeutic targets for metastatic NPC. Previous studies have demonstrated that deoxynucleotidyltransferase terminal-interacting protein 1 (DNTTIP1) is associated with the development of various types of cancer. However, its role and mechanism in NPC have not been explored. RNA-seq profiling was performed for three pairs of NPC and normal nasopharynx tissues. DNTTIP1 expression in NPC specimens was detected by immunohistochemistry. In vitro and in vivo assays were used to investigate the function of DNTTIP1. The molecular mechanism was determined using RT-qPCR, western blotting, RNA-seq, luciferase reporter assays, ChIP assays, and co-IP assays. DNTTIP1 was found to be significantly upregulated in NPC tissues. Furthermore, DNTTIP1 promoted NPC growth and metastasis in vitro and in vivo. Upregulation of DNTTIP1 in NPC indicated poor clinical outcomes. Mechanistically, DNTTIP1 suppressed DUSP2 gene expression via recruiting HDAC1 to its promoter and maintaining a deacetylated state of histone H3K27. The downregulation of DUSP2 resulted in aberrant activation of the ERK signaling and elevated MMP2 levels, promoting NPC metastasis. Chidamide, an HDAC inhibitor, was shown to suppress NPC metastasis by regulating the DNTTIP1/HDAC1-DUSP2 axis. Our findings demonstrate that DNTTIP1 not only regulates NPC metastasis but also independently predicts NPC prognosis. Furthermore, targeting DNTTIP1/HDAC1 by Chidamide may benefit NPC patients with metastasis. This work was supported by the National Natural Science Foundation of China (No. 81872464, 82073243).
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影响因子：
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作者：
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DOI：
10.1073/pnas.2026165118
发表时间：
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影响因子：
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作者：
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DOI：
10.1200/jco.21.00396
发表时间：
2021-10-10
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
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Hong S;Zhang Y;Yu G;Peng P;Peng J;Jia J;Wu X;Huang Y;Yang Y;Lin Q;Xi X;Xu M;Chen D;Lu X;Wang R;Cao X;Chen X;Lin Z;Xiong J;Lin Q;Xie C;Li Z;Pan J;Li J;Wu S;Lian Y;Yang Q;Zhao C;Fang W;Zhang L
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影响因子：
46.9
作者：
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