CHD4 regulates platinum sensitivity through MDR1 expression in ovarian cancer: A potential role of CHD4 inhibition as a combination therapy with platinum agents.
CHD4 regulates platinum sensitivity through MDR1 expression in ovarian cancer: A potential role of CHD4 inhibition as a combination therapy with platinum agents.
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DOI：
10.1371/journal.pone.0251079
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Yaegashi N
中科院分区：
文献类型：
--
作者：
Oyama Y;Shigeta S;Tokunaga H;Tsuji K;Ishibashi M;Shibuya Y;Shimada M;Yasuda J;Yaegashi N
铂敏感性是卵巢癌患者的重要预后因素。染色体结构域-解旋酶-DNA结合蛋白4（Chromodomain-helicase-DNA-binding protein 4，CHD 4）是核小体重塑和脱乙酰酶复合体的核心成员，其功能是染色质重塑剂。新的证据表明，CHD 4可能是癌症治疗的潜在治疗靶点。本研究的目的是阐明CHD 4在卵巢癌中的作用，并研究其治疗潜力，重点关注铂类药物的敏感性。在对癌症基因组图谱卵巢癌数据集的分析中，CHD 4基因扩增与总生存率较差相关。在随后的临床样本分析中，铂类耐药样本中CHD 4 mRNA表达显著更高，表明CHD 4过表达赋予卵巢癌细胞铂类耐药，导致患者生存率差。与这些发现一致，CHD 4敲低增强了卵巢癌细胞TOV 21 G中顺铂介导的凋亡诱导，并增加了来自不同亚型的多种卵巢癌细胞中顺铂的敏感性。然而，CHD 4敲低并不影响RAD 51或p21的表达，RAD 51或p21是其他癌症类型中CHD 4的已知靶点，可以调节铂敏感性。敲低和过表达实验表明，CHD 4正调控多药转运蛋白MDR 1及其编码蛋白P-糖蛋白的表达。此外，一流的CHD 4/SMARCA 5抑制剂ED 2-AD 101显示出与顺铂的协同相互作用。我们的研究结果表明，CHD 4介导铂类药物的敏感性，通过调节MDR 1在卵巢癌的表达。此外，CHD 4抑制具有成为与铂剂组合的新型治疗策略的潜力。
Platinum sensitivity is an important prognostic factor in patients with ovarian cancer. Chromodomain-helicase-DNA-binding protein 4 (CHD4) is a core member of the nucleosome remodeling and deacetylase complex, which functions as a chromatin remodeler. Emerging evidence indicates that CHD4 could be a potential therapeutic target for cancer therapy. The purpose of this study was to clarify the role of CHD4 in ovarian cancer and investigate its therapeutic potential focusing on platinum sensitivity. In an analysis of the Cancer Genome Atlas ovarian cancer dataset, CHD4 gene amplification was associated with worse overall survival. CHD4 mRNA expression was significantly higher in platinum-resistant samples in a subsequent clinical sample analysis, suggesting that CHD4 overexpression conferred platinum resistance to ovarian cancer cells, resulting in poor patient survival. In concordance with these findings, CHD4 knockdown enhanced the induction of apoptosis mediated by cisplatin in ovarian cancer cells TOV21G and increased cisplatin sensitivity in multiple ovarian cancer cells derived from different subtypes. However, CHD4 knockdown did not affect the expression of RAD51 or p21, the known targets of CHD4 in other cancer types that can modulate platinum sensitivity. Knockdown and overexpression assays revealed that CHD4 positively regulated the expression of multi-drug transporter MDR1 and its coding protein p-glycoprotein. In addition, a first-in-class CHD4/SMARCA5 inhibitor ED2-AD101 showed synergistic interactions with cisplatin. Our findings suggest that CHD4 mediates platinum sensitivity by modulating MDR1 expression in ovarian cancer. Further, CHD4 suppression has a potential to be a novel therapeutic strategy in combination with platinum agents.
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影响因子：
16.6
作者：
Domcke, Silvia;Sinha, Rileen;Levine, Douglas A.;Sander, Chris;Schultz, Nikolaus
通讯作者：
Schultz, Nikolaus
影响因子：
4.7
作者：
Chang, Suk-Joon;Hodeib, Melissa;Bristow, Robert E.
通讯作者：
Bristow, Robert E.
影响因子：
10.3
作者：
du Bois, A;Lück, HJ;Pfisterer, J
通讯作者：
Pfisterer, J
影响因子：
3.7
作者：
Beaufort CM;Helmijr JC;Piskorz AM;Hoogstraat M;Ruigrok-Ritstier K;Besselink N;Murtaza M;van IJcken WF;Heine AA;Smid M;Koudijs MJ;Brenton JD;Berns EM;Helleman J
通讯作者：
Helleman J
DOI：
10.1016/s0020-7292(03)90118-4
发表时间：
2003-10-01
影响因子：
3.8
作者：
Heintz, APM;Odicino, F;Pecorelli, S
通讯作者：
Pecorelli, S