Targeted design and identification of AC1NOD4Q to block activity of HOTAIR by abrogating the scaffold interaction with EZH2
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 an...
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| Format: | Article |
| Language: | English |
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BMC
2019-02-01
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| Series: | Clinical Epigenetics |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13148-019-0624-2 |
| _version_ | 1818543816244723712 |
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| author | Yu Ren Yun-fei Wang Jing Zhang Qi-xue Wang Lei Han Mei Mei Chun-sheng Kang |
| author_facet | Yu Ren Yun-fei Wang Jing Zhang Qi-xue Wang Lei Han Mei Mei Chun-sheng Kang |
| author_sort | Yu Ren |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T22:40:20Z |
| format | Article |
| id | doaj.art-3ce952da2d0845c68b4ead6021b1f511 |
| institution | Directory Open Access Journal |
| issn | 1868-7075 1868-7083 |
| language | English |
| last_indexed | 2024-12-11T22:40:20Z |
| publishDate | 2019-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Clinical Epigenetics |
| spelling | doaj.art-3ce952da2d0845c68b4ead6021b1f5112022-12-22T00:47:49ZengBMCClinical Epigenetics1868-70751868-70832019-02-0111111610.1186/s13148-019-0624-2Targeted design and identification of AC1NOD4Q to block activity of HOTAIR by abrogating the scaffold interaction with EZH2Yu Ren0Yun-fei Wang1Jing Zhang2Qi-xue Wang3Lei Han4Mei Mei5Chun-sheng Kang6Department of Neurosurgery, Tianjin Medical University General Hospital, Lab of Neuro-oncology, Tianjin Neurological Institute, Key Laboratory of Post-Neuro injury Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin CityDepartment of Neurosurgery, Tianjin Medical University General Hospital, Lab of Neuro-oncology, Tianjin Neurological Institute, Key Laboratory of Post-Neuro injury Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin CityIrving Cancer Research Center, Columba UniversityDepartment of Neurosurgery, Tianjin Medical University General Hospital, Lab of Neuro-oncology, Tianjin Neurological Institute, Key Laboratory of Post-Neuro injury Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin CityDepartment of Neurosurgery, Tianjin Medical University General Hospital, Lab of Neuro-oncology, Tianjin Neurological Institute, Key Laboratory of Post-Neuro injury Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin CityDepartment of Cell Biology, School of Basic Medical Sciences, Tianjin Medical UniversityDepartment of Neurosurgery, Tianjin Medical University General Hospital, Lab of Neuro-oncology, Tianjin Neurological Institute, Key Laboratory of Post-Neuro injury Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin CityAbstract 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.http://link.springer.com/article/10.1186/s13148-019-0624-2AC1NOD4QHOTAIREZH2NLKHigh-throughput screening |
| spellingShingle | Yu Ren Yun-fei Wang Jing Zhang Qi-xue Wang Lei Han Mei Mei Chun-sheng Kang Targeted design and identification of AC1NOD4Q to block activity of HOTAIR by abrogating the scaffold interaction with EZH2 Clinical Epigenetics AC1NOD4Q HOTAIR EZH2 NLK High-throughput screening |
| title | Targeted design and identification of AC1NOD4Q to block activity of HOTAIR by abrogating the scaffold interaction with EZH2 |
| title_full | Targeted design and identification of AC1NOD4Q to block activity of HOTAIR by abrogating the scaffold interaction with EZH2 |
| title_fullStr | Targeted design and identification of AC1NOD4Q to block activity of HOTAIR by abrogating the scaffold interaction with EZH2 |
| title_full_unstemmed | Targeted design and identification of AC1NOD4Q to block activity of HOTAIR by abrogating the scaffold interaction with EZH2 |
| title_short | Targeted design and identification of AC1NOD4Q to block activity of HOTAIR by abrogating the scaffold interaction with EZH2 |
| title_sort | targeted design and identification of ac1nod4q to block activity of hotair by abrogating the scaffold interaction with ezh2 |
| topic | AC1NOD4Q HOTAIR EZH2 NLK High-throughput screening |
| url | http://link.springer.com/article/10.1186/s13148-019-0624-2 |
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