A Compound AC1Q3QWB Selectively Disrupts HOTAIR-Mediated Recruitment of PRC2 and Enhances Cancer Therapy of DZNep
A Compound AC1Q3QWB Selectively Disrupts HOTAIR-Mediated Recruitment of PRC2 and Enhances Cancer Therapy of DZNep
复制标题
化合物 AC1Q3QWB 选择性破坏 HOTAIR 介导的 PRC2 募集并增强 DZNep 的癌症治疗
DOI：
10.7150/thno.35188
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发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Kang, Chunsheng
中科院分区：
文献类型：
--
作者：
Li, Yansheng;Ren, Yu;Kang, Chunsheng
超过20%的癌症“驱动”基因编码染色质调节因子。长链非编码rna （lincRNAs）在多种癌症中失调，通过与关键表观遗传调控因子相互作用，在染色质动力学和基因调控中发挥关键作用。此前有报道称，lincRNA HOTAIR介导多梳抑制复合体2 （polycomb suppression complex 2, PRC2）的募集，导致胶质瘤和乳腺癌中肿瘤抑制基因的异常转录沉默。因此，lincRNA HOTAIR可以作为一个有前景的治疗靶点。本文中，我们发现了一种小分子化合物AC1Q3QWB （AQB）作为HOTAIR-EZH2相互作用的选择性和高效干扰物，可阻断PRC2募集并增加肿瘤抑制因子的表达。方法：进行分子对接和高通量筛选，鉴定小分子化合物AQB。采用RIP和ChIRP方法评价AQB对HOTAIR-EZH2相互作用的选择性干扰。在多种肿瘤细胞系和原位乳腺癌模型中评估AQB对肿瘤恶性的影响。AQB与组蛋白甲基转移酶EZH2抑制剂3-Deazaneplanocin A （DZNep）联合治疗用于体外和原位乳腺癌和胶质母细胞瘤患者源异种移植（PDX）模型。结果：高表达HOTAIR和EZH2的肿瘤细胞对AQB敏感。APC2作为靶基因之一，被AQB显著上调，导致β -catenin降解，从而抑制Wnt/ β -catenin信号通路，这可能在体外和原位乳腺癌模型中抑制肿瘤生长和转移。AQB显著增强DZNep的体外毒性。在原位乳腺癌和胶质母细胞瘤患者源异种移植（PDX）模型中，低剂量AQB和DZNep联合治疗比单独DZNep治疗具有更好的杀伤效果。结论：AQB是HOTAIR-EZH2抑制剂，可阻断PRC2的募集，有潜力成为肿瘤靶向治疗的有效药物。
Over 20% of cancer 'driver' genes encode chromatin regulators. Long noncoding RNAs (lincRNAs), which are dysregulated in various cancers, play a critical role in chromatin dynamics and gene regulation by interacting with key epigenetic regulators. It has been previously reported that the lincRNA HOTAIR mediates recruitment of polycomb repressive complex 2 (PRC2) leading to aberrant transcriptional silencing of tumor suppressor genes in glioma and breast cancer. Thus, lincRNA HOTAIR can serve as a promising therapeutic target. Herein, we identified a small-molecule compound AC1Q3QWB (AQB) as a selective and efficient disruptor of HOTAIR-EZH2 interaction, resulting in blocking of PRC2 recruitment and increasing tumor suppressors expression.Methods: Molecular docking and high-throughput screening were performed to identify the small compound, AQB. RIP and ChIRP assays were carried to assess the selective interference of AQB with the HOTAIR-EZH2 interaction. The effects of AQB on tumor malignancy were evaluated in a variety of cancer cell lines and orthotopic breast cancer models. The combination therapy of AQB and 3-Deazaneplanocin A (DZNep), an inhibitor of the histone methyltransferase EZH2 was used in vitro and in orthotopic breast cancer and glioblastoma patient-derived xenograft (PDX) models.Results: Tumor cells highly expressing HOTAIR and EZH2 were sensitive to AQB. APC2, as one of the target genes, was significantly up-regulated by AQB and led to degradation of beta-catenin resulting in suppression of Wnt/beta-catenin signaling which may contribute to inhibition of tumor growth and metastasis in vitro and in orthotopic breast cancer models. Remarkably, AQB enhanced the toxicity of DZNep in vitro. In orthotopic breast cancer and glioblastoma patient-derived xenografts (PDX) models, the combination of low doses of AQB and DZNep realized much better killing than DZNep treatment alone.Conclusion: AQB is a HOTAIR-EZH2 inhibitor, which blocks PRC2 recruitment and has great potential as an effective agent for targeted cancer therapy.