Acetylation-stabilized chloride intracellular channel 1 exerts a tumor-promoting effect on cervical cancer cells by activating NF-κB
Acetylation-stabilized chloride intracellular channel 1 exerts a tumor-promoting effect on cervical cancer cells by activating NF-κB
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乙酰化稳定的氯离子胞内通道1通过激活NF-κB对宫颈癌细胞发挥促瘤作用
DOI：
10.1007/s13402-020-00582-w
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发表时间：
2021-01
影响因子：
6.6
通讯作者：
Xiuwei Chen
中科院分区：
文献类型：
--
作者：
Wanyue Wang;Xin Li;Ye Xu;Weikang Guo;Hui Yu;Lu Zhang;Yaoxian Wang;Xiuwei Chen
目的子宫颈癌仍然是妇女癌症相关死亡的主要原因，特别是在发展中国家。先前，我们使用无标记蛋白质组学方法发现宫颈癌组织中赖氨酸131的氯细胞内通道1 （CLIC1）乙酰化水平升高。本研究的目的是进一步确定CLIC1表达及其乙酰化在宫颈癌中的作用。方法利用原发病患者样本、细胞和基因表达谱交互分析（GEPIA）数据库（GEPIA .cancer-pku.cn）分析scclic1表达及其对宫颈癌预后的影响。采用细胞计数试剂盒(CCK)-8、流式细胞术、划痕愈合、transwell、Western blotting和共免疫沉淀（Co-IP）试验评估CLIC1对宫颈癌细胞的影响。使用小鼠异种移植模型评估体内肿瘤生长情况。结果我们发现CLIC1在宫颈癌组织和细胞中的表达升高，且CLIC1高表达的患者总生存时间往往较短。表达CLIC1可显著降低宫颈癌细胞在体外的增殖、迁移、侵袭及体内的肿瘤发生。在分子水平上，我们发现细胞核因子κB （NF-κB）活性受到CLIC1的正调控。吡咯烷二硫代氨基甲酸酯（Pyrrolidine dithiocarbamate， PDTC）是NF-κB抑制剂，可减弱CLIC1的促瘤作用。此外，我们发现宫颈癌细胞中CLIC1在K131位点的乙酰化上调，这通过抑制其泛在性来稳定CLIC1。K131的替代抑制了CLIC1的泛素性，促进了宫颈癌细胞的体外增殖、迁移和侵袭以及体内肿瘤的生长。此外，我们发现乙酰转移酶HAT1负责CLIC1在K131位点的乙酰化。结论我们的数据表明，CLIC1在宫颈癌中作为肿瘤启动子，提示通过调节CLIC1表达和/或乙酰化来治疗宫颈癌的潜在策略。
PurposeCervical cancer remains a major cause of cancer-related death in women, especially in developing countries. Previously, we found that the acetylation levels of chloride intracellular channel 1 (CLIC1) at lysine 131 were increased in cervical cancer tissues using a label-free proteomics approach. The aim of this study was to further determine the role of CLIC1 expression and its acetylation in cervical cancer.MethodsCLIC1 expression and its implications for the prognosis of cervical cancer were analyzed using primary patient samples and cells, and the Gene Expression Profiling Interactive Analysis (GEPIA) database (gepia.cancer-pku.cn). The effect of CLIC1 on cervical cancer cells was evaluated using Cell Counting Kit (CCK)-8, flow cytometry, scratch wound healing, transwell, Western blotting and co-immunoprecipitation (Co-IP) assays. In vivo tumor growth was assessed using mouse xenograft models.ResultsWe found that CLIC1 expression was increased in cervical cancer tissues and cells and that patients with a high CLIC1 expression tended to have a shorter overall survival time. Knockdown of CLIC1 significantly reduced in vitro cervical cancer cell proliferation, migration and invasion, and in vivo tumorigenesis. At the molecular level, we found that nuclear factor kappa B (NF-κB) activity was positively regulated by CLIC1. Pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-κB, attenuated the tumor-promoting effect of CLIC1. Moreover, we found that CLIC1 acetylation at K131 was upregulated in cervical cancer cells, which stabilized CLIC1 by inhibiting its ubiquitynation. Substitution of K131 inhibited CLIC1 ubiquitynation and promoted in vitro cervical cancer cell proliferation, migration and invasion, and in vivo tumor growth. In addition, we found that acetyltransferase HAT1 was responsible for CLIC1 acetylation at K131.ConclusionOur data indicate that CLIC1 acts as a tumor promoter in cervical cancer, suggesting a potential treatment strategy for cervical cancer by regulating CLIC1 expression and/or acetylation.
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影响因子：
7.2
作者：
Moore, David H.
通讯作者：
Moore, David H.
影响因子：
25
作者：
Marzi, Sarah J.;Leung, Szi Kay;Mill, Jonathan
通讯作者：
Mill, Jonathan
影响因子：
7.9
作者：
Katayama, Hiroyuki;Tsou, Peiling;Hanash, Samir
通讯作者：
Hanash, Samir
影响因子：
4.2
作者：
Xupeng Yue;Yuanyuan Cui;Q. You;Yanxin Lu;Ju-feng Zhang
通讯作者：
Xupeng Yue;Yuanyuan Cui;Q. You;Yanxin Lu;Ju-feng Zhang
DOI：
10.1101/825539
发表时间：
2019-10
期刊：
bioRxiv
影响因子：
--
作者：
P. A. Agudelo Garcia;M. Parthun
通讯作者：
P. A. Agudelo Garcia;M. Parthun