KDM5B demethylates H3K4 to recruit XRCC1 and promote chemoresistance.
KDM5B demethylates H3K4 to recruit XRCC1 and promote chemoresistance.
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KDM5B 使 H3K4 去甲基化以招募 XRCC1 并促进化疗耐药性
DOI：
10.7150/ijbs.25881
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发表时间：
2018
影响因子：
9.2
通讯作者：
Jin H
中科院分区：
文献类型：
--
作者：
Xu W;Zhou B;Zhao X;Zhu L;Xu J;Jiang Z;Chen D;Wei Q;Han M;Feng L;Wang S;Wang X;Zhou J;Jin H
化疗是包括胃癌在内的人类癌症的主要治疗方法。然而，在对化疗药物的反应中，肿瘤细胞可以通过重新编程细胞内代谢和表观遗传网络来维持其内在的稳态，从而产生耐药性。此前，我们建立了顺铂耐药胃癌细胞作为耐药模型，并阐明了XRCC1作为耐药的核心DNA修复机制。本研究探讨了赖氨酸去甲基酶5B （KDM5B）对XRCC1在耐药中的调控作用。我们发现H3K4的甲基化水平在耐药细胞中显著降低。H3K4去甲基化酶的化学抑制剂JIB-04恢复了H3K4的甲基化，阻断了XRCC1和γH2AX的共定位，最终提高了药物敏感性。我们进一步发现，KDM5B在耐药细胞中的表达水平显著升高。KDM5B的敲低增加了H3K4的甲基化水平，阻断了XRCC1在DNA损伤位点的定位，导致药物敏感性增加。在敏感细胞中，过表达KDM5B抑制H3K4甲基化水平，导致顺铂耐药。此外，我们发现KDM5B的翻译后修饰是其在耐药细胞中高表达的原因。通过质谱筛选和共免疫沉淀验证，我们发现分子伴侣HSP90在耐药细胞中与KDM5B形成复合物。有趣的是，HSP90抑制剂17-AAG以时间和剂量依赖的方式诱导KDM5B降解，表明HSP90保护KDM5B免受蛋白质降解。靶向抑制HSP90和KDM5B在体外和体内均可逆转耐药。综上所述，分子伴侣子HSP90与KDM5B相互作用，保护其免受泛素依赖性蛋白酶体降解。增加的KDM5B使H3K4去甲基化，并促进XRCC1的募集来修复受损的DNA。因此，抑制HSP90或KDM5B是一种逆转人类癌症化疗耐药的新方法。
Chemotherapy is the main treatment for human cancers including gastric cancer. However, in response to chemotherapeutic drugs, tumor cells can develop drug resistance by reprogramming intracellular metabolic and epigenetic networks to maintain their intrinsic homeostasis. Previously, we have established cisplatin-resistant gastric cancer cells as a drug resistant model, and elucidated the XRCC1 as the core DNA repair mechanism of drug resistance. This study investigated the regulation of XRCC1 by lysine demethylase 5B (KDM5B) in drug resistance. We found that the methylation level of H3K4 decreased significantly in drug-resistant cells. The chemical inhibitor of H3K4 demethylases, JIB-04, restored the methylation of H3K4 and blocked the co-localization of XRCC1 and γH2AX, eventually improved drug sensitivity. We further found that the expression level of KDM5B increased significantly in drug-resistant cells. Knockdown of KDM5B increased the methylation level of H3K4 and blocked the localization of XRCC1 to the DNA damage site, leads to increased drug sensitivity. In the sensitive cells, overexpression of KDM5B suppressed H3K4 methylation levels, which resulted to resistance to cisplatin. Moreover, we found that the posttranslational modification of KDM5B is responsible for its high expression in drug-resistant cells. Through mass spectrometry screening and co-immunoprecipitation validation, we found that the molecular chaperone HSP90 forms a complex with KDM5B in drug resistance cells. Interestingly, HSP90 inhibitor 17-AAG induced KDM5B degradation in a time-and-dose-dependent manner, indicating that HSP90 protected KDM5B from protein degradation. Targeting inhibition of HSP90 and KDM5B reversed drug resistance both in vitro and in vivo. Taken together, molecular chaperon HSP90 interacted with KDM5B to protect it from ubiquitin-dependent proteasomal degradation. Increased KDM5B demethylated H3K4 and facilitated the recruitment of XRCC1 to repair damaged DNA. Therefore, inhibition of HSP90 or KDM5B represented a novel approach to reverse chemoresistance in human cancers.
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DOI：
10.1083/jcb.201302092
发表时间：
2013-11-11
期刊：
The Journal of cell biology
影响因子：
--
作者：
Mosammaparast N;Kim H;Laurent B;Zhao Y;Lim HJ;Majid MC;Dango S;Luo Y;Hempel K;Sowa ME;Gygi SP;Steen H;Harper JW;Yankner B;Shi Y
通讯作者：
Shi Y
影响因子：
64.5
作者：
Klose, Robert J.;Yan, Qin;Kaelin, William G., Jr.
通讯作者：
Kaelin, William G., Jr.
组蛋白去甲基化酶 KDM5B 是基因组稳定性的关键调节因子
DOI：
10.1073/pnas.1324036111
发表时间：
2014-05-13
影响因子：
11.1
作者：
Li, Xin;Liu, Ling;Shi, Lei
通讯作者：
Shi, Lei
影响因子：
4.3
作者：
Lee, Suk-young;Oh, Sang Cheul
通讯作者：
Oh, Sang Cheul
影响因子：
--
作者：
Lu W;Liu S;Li B;Xie Y;Adhiambo C;Yang Q;Ballard BR;Nakayama KI;Matusik RJ;Chen Z
通讯作者：
Chen Z