Targeted design and identification of AC1NOD4Q to block activity of HOTAIR by abrogating the scaffold interaction with EZH2
Targeted design and identification of AC1NOD4Q to block activity of HOTAIR by abrogating the scaffold interaction with EZH2
复制标题
AC1NOD4Q 的靶向设计和鉴定，通过消除与 EZH2 的支架相互作用来阻断 HOTAIR 的活性
DOI：
10.1186/s13148-019-0624-2
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发表时间：
2019-02-14
影响因子：
5.7
通讯作者：
Kang, Chun-sheng
中科院分区：
文献类型：
--
作者：
Ren, Yu;Wang, Yun-fei;Kang, Chun-sheng
近25%的长基因间非编码rna （lincRNAs）招募染色质修饰蛋白（如EZH2）来沉默靶基因。HOX反义基因间RNA （HOTAIR）在多种癌症中不受调控，可能是最终转移和死亡的独立而有力的预测因子。然而，在短时间内开发出高特异性阻断HOTAIR活性的小分子药物是一个挑战。我们前期的研究通过募集结合EZH2，证实了HOTAIR在胶质母细胞瘤和乳腺癌中负责肿瘤发生和转移的功能域是5′结构域，而不是3′结构域。在这里，我们的目标是建立一种基于结构的方法来识别HOTAIR的先导化合物，通过取消支架与EZH2的相互作用。并通过基于高通量分子对接的PubChem文库虚拟筛选，鉴定出一个小化合物AC1NOD4Q （ADQ）。我们的分析表明，在体外和原位乳腺癌模型中，ADQ充分特异性地干扰HOTAIR/EZH2相互作用，从而破坏h3k27介导的HOTAIR基因靶点NLK的三甲基化，从而通过Wnt/ β -catenin途径抑制肿瘤转移。RIP和EMSA的结果进一步揭示了5′结构域的36G46A是ADQ发挥其抑制作用的必要结合位点，进一步将HOTAIR的结构和功能从5′功能域缩小到微域。我们的发现提示了一种潜在的新策略，即发现靶向lincRNA治疗的先导化合物，并可能为开发ADQ作为更有效的小分子药物的支架铺平道路。
Nearly 25% of long intergenic non-coding RNAs (lincRNAs) recruit chromatin-modifying proteins (e.g., EZH2) to silence target genes. HOX antisense intergenic RNA (HOTAIR) is deregulated in diverse cancers and could be an independent and powerful predictor of eventual metastasis and death. Yet, it is challenging to develop small molecule drugs to block activity of HOTAIR with high specificity in a short time.Our previous study proved that the 5' domain, but not its 3' domain, was the function domain of HOTAIR responsible for tumorigenesis and metastasis in glioblastoma and breast cancer, by recruiting and binding EZH2. Here, we targeted to establish a structure-based methodology to identify lead compounds of HOTAIR, by abrogating scaffold interactions with EZH2. And a small compound AC1NOD4Q (ADQ) was identified by high-throughput molecular docking-based virtual screening of the PubChem library. Our analysis revealed that ADQ was sufficiently and specifically interfering HOTAIR/EZH2 interaction, thereby impairing the H3K27-mediated tri-methylation of NLK, the target of HOTAIR gene, and consequently inhibiting tumor metastasis through Wnt/beta-catenin pathway in vitro and in orthotopic breast cancer models. The results of RIP and EMSA further revealed that 36G46A of 5' domain was the essential binding site for ADQ exerted its inhibitory effect, further narrowed the structure and function of HOTAIR from the 5' functional domain to the micro-domain.Our findings suggest of a potential new strategy to discover the lead compound for targeted lincRNA therapy and potentially pave the way for exploiting ADQ as a scaffold for more effective small molecule drugs.