Abstract
BackgroundNearly 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.ResultsOur 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.ConclusionsOur 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.
Highlights
25% of long intergenic non-coding RNAs recruit chromatin-modifying proteins (e.g., EZH2) to silence target genes
Our previous study proved that the 5′ domain, but not its 3′ domain, which was the function domain of HOX antisense intergenic RNA (HOTAIR) is responsible for tumorigenesis and metastasis in glioblastoma and breast cancer, by recruiting and binding EZH2, the catalytic subunit of polycomb repressive complex 2 (PRC2), to silence target genes nemo-like kinase (NLK) [12,13,14]
Based on deep understanding of the structure and function of HOTAIR, here, we aimed to establish a structurebased method by performing in silico high-throughput screening to identify a lead compound for molecular inference in the HOTAIR/EZH2 scaffold interaction and targeted HOTAIR therapy (Fig. 1)
Summary
25% of long intergenic non-coding RNAs (lincRNAs) recruit chromatin-modifying proteins (e.g., EZH2) to silence target genes. Our previous study proved that the 5′ domain, but not its 3′ domain, which was the function domain of HOTAIR is responsible for tumorigenesis and metastasis in glioblastoma and breast cancer, by recruiting and binding EZH2, the catalytic subunit of PRC2, to silence target genes nemo-like kinase (NLK) [12,13,14]. Based on deep understanding of the structure and function of HOTAIR, here, we aimed to establish a structurebased method by performing in silico high-throughput screening to identify a lead compound for molecular inference in the HOTAIR/EZH2 scaffold interaction and targeted HOTAIR therapy (Fig. 1). Our findings established a novel methodology to develop new classes of small molecule drugs by screening libraries of synthetic compounds and natural products, with different binding sites and higher binding affinities, potentially paving the way for exploiting ADQ as a scaffold for more effective small molecule drugs
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
