Targeted design and identification of AC1NOD4Q to block activity of HOTAIR by abrogating the scaffold interaction with EZH2 | Clinical Epigenetics | Full Text

Targeted design and identification of AC1NOD4Q to block activity of HOTAIR by abrogating the scaffold interaction with EZH2 | Clinical Epigenetics | Full Text



Clinical Epigenetics

Targeted design and identification of AC1NOD4Q to block activity of HOTAIR by abrogating the scaffold interaction with EZH2

• Yu Ren†,
• Yun-fei Wang†,
• Jing Zhang,
• Qi-xue Wang,
• Lei Han,
• Mei MeiEmail author and
• Chun-sheng KangEmail authorView ORCID ID profile

†Contributed equally

Clinical Epigenetics201911:29

https://doi.org/10.1186/s13148-019-0624-2

©  The Author(s). 2019

• Received: 12 November 2018
• Accepted: 29 January 2019
• Published: 14 February 2019

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.

Keywords

• AC1NOD4Q
• HOTAIR
• EZH2
• NLK
• High-throughput screening