ZHX2 mediates proteasome inhibitor resistance via regulating nuclear translocation of NF-κB in multiple myeloma.
ZHX2 mediates proteasome inhibitor resistance via regulating nuclear translocation of NF-κB in multiple myeloma.
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DOI：
10.1002/cam4.3347
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发表时间：
2020-10
期刊：
影响因子：
4
通讯作者：
Liu P
中科院分区：
文献类型：
--
作者：
Jiang J;Sun Y;Xu J;Xu T;Xu Z;Liu P
多发性骨髓瘤（MM）是一种无法治愈的血液系统恶性肿瘤。尽管蛋白酶体抑制剂和免疫调节剂显著改善了患者的结局，但一些患者对治疗反应不佳，几乎所有患者都会复发。多发性骨髓瘤中蛋白酶体抑制剂耐药的机制尚未完全阐明。ZHX 2是一种通过蛋白酶体降解的转录调节因子，在不同的癌症中具有致癌或抑瘤作用，但ZHX 2在骨髓瘤中的作用尚不清楚。在这项研究中，我们的目的是证明ZHX 2对MM蛋白酶体抑制剂耐药性的影响和机制。分析来自基因表达Omnibus（GEO）的GSE 24080基因表达谱数据集，以评估ZHX 2表达水平与MM生存率之间的关系。流式细胞仪检测ZHX 2基因敲低后BTZ对MM细胞增殖和凋亡的影响。WB和免疫荧光法检测ZHX 2基因敲除后NF-κB核转位情况，真实的时间定量PCR检测NF-κB靶基因表达。采用免疫共沉淀法（Co-IP）和WB检测ZHX 2与NF-κB的相互作用。我们发现ZHX 2的高表达与患者的临床结局较差相关。此外，ZHX 2在RPMI-8226和MM. 1 S细胞系中表达相对较高，BTZ处理后ZHX 2蛋白水平上调。ZHX 2基因的敲低可显著增强MM细胞对BTZ的敏感性，抑制NF-κB核转位，降低NF-κB靶基因的mRNA表达。还揭示了ZHX 2直接结合NF-κB。我们的研究表明，ZHX 2可以通过调节NF-κB的核转位来促进MM细胞对蛋白酶体抑制剂的耐药性。本研究旨在阐明ZHX 2在MM蛋白酶体抑制剂耐药中的作用及其机制。我们发现ZHX 2可以调节NF-κB的核转位，并与MM细胞对蛋白酶体抑制剂的耐药有关。
Multiple myeloma (MM) is an incurable hematological malignancy. Although proteasome inhibitors and immunomodulators have significantly improved patient outcomes, some patients respond poorly to treatment and almost all patients will relapse. Mechanisms of proteasome inhibitor resistance in multiple myeloma have not been fully elucidated. ZHX2 is a transcription regulator degraded via proteasome and presents both oncogenic or tumor suppressive effect in different cancers, however, it is still unknown that the role of ZHX2 in myeloma. In this study, we aim to demonstrate the effect and mechanism of ZHX2 on proteasome inhibitor resistance in MM. GSE24080 gene expression profile datasets from Gene Expression Omnibus (GEO) were analyzed to evaluate the relationship between ZHX2 expression level and survival in MM. Expression of ZHX2 in human MM cell lines at baseline and after bortezomib (BTZ) treatment was determined by Western blotting (WB). The proliferation and apoptosis rate of MM cells treated with BTZ after the knockdown of ZHX2 were analyzed by flow cytometry. Nuclear translocation of NF‐κB after the knockdown of ZHX2 was evaluated by WB and immunofluorescence, and the expression of NF‐κB target genes was measured by real‐time quantitative PCR. Co‐immunoprecipitation (Co‐IP) and WB were used to detect the interaction of ZHX2 with NF‐κB. We found that higher ZHX2 expression was correlated with poorer clinical outcomes of patients. In addition, ZHX2 expression was relatively higher in RPMI‐8226 and MM.1S cell lines and the level of ZHX2 protein was upregulated after BTZ treatment. Knockdown of ZHX2 significantly enhanced the sensitivity of MM cells to BTZ, inhibited nuclear translocation of NF‐κB, and reduced mRNA expression of NF‐κB target genes. It was also revealed that ZHX2 directly binds to NF‐κB. Our study showed that ZHX2 can promote proteasome inhibitor resistance in MM cells by regulating the nuclear translocation of NF‐κB. In this study, we aimed to demonstrate the effect and mechanism of ZHX2 on proteasome inhibitor resistance in MM. We found that ZHX2 can regulate the nuclear translocation of NF‐κB and is related to myeloma cell resistance to proteasome inhibitor.
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DOI：
10.1126/science.aap8411
发表时间：
2018-07-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Zhang J;Wu T;Simon J;Takada M;Saito R;Fan C;Liu XD;Jonasch E;Xie L;Chen X;Yao X;Teh BT;Tan P;Zheng X;Li M;Lawrence C;Fan J;Geng J;Liu X;Hu L;Wang J;Liao C;Hong K;Zurlo G;Parker JS;Auman JT;Perou CM;Rathmell WK;Kim WY;Kirschner MW;Kaelin WG Jr;Baldwin AS;Zhang Q
通讯作者：
Zhang Q
影响因子：
28.2
作者：
Yao, Xiaosai;Tan, Jing;Tan, Patrick
通讯作者：
Tan, Patrick
影响因子：
168.9
作者：
Roellig, Christoph;Knop, Stefan;Bornhaeuser, Martin
通讯作者：
Bornhaeuser, Martin
影响因子：
5.8
作者：
Nikesitch N;Lee JM;Ling S;Roberts TL
通讯作者：
Roberts TL
DOI：
10.1161/atvbaha.118.311266
发表时间：
2018-09
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Erbilgin A;Seldin MM;Wu X;Mehrabian M;Zhou Z;Qi H;Dabirian KS;Sevag Packard RR;Hsieh W;Bensinger SJ;Sinha S;Lusis AJ
通讯作者：
Lusis AJ