Abstract | BACKGROUND: 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. RESULTS: 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/β- 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. CONCLUSIONS: 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.
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Authors | Yu Ren, Yun-Fei Wang, Jing Zhang, Qi-Xue Wang, Lei Han, Mei Mei, Chun-Sheng Kang |
Journal | Clinical epigenetics
(Clin Epigenetics)
Vol. 11
Issue 1
Pg. 29
(02 14 2019)
ISSN: 1868-7083 [Electronic] Germany |
PMID | 30764859
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- HOTAIR long untranslated RNA, human
- RNA, Long Noncoding
- Small Molecule Libraries
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Topics |
- Animals
- Binding Sites
- Breast Neoplasms
(drug therapy, genetics)
- Cell Line, Tumor
- DNA Methylation
- Drug Design
- Drug Screening Assays, Antitumor
- Epigenesis, Genetic
- Female
- Gene Expression Regulation, Neoplastic
(drug effects)
- Humans
- Mice
- Molecular Docking Simulation
- RNA, Long Noncoding
(antagonists & inhibitors, chemistry)
- Small Molecule Libraries
(administration & dosage, chemistry, pharmacology)
- Structure-Activity Relationship
- Wnt Signaling Pathway
(drug effects)
- Xenograft Model Antitumor Assays
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