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LincRNA-ROR is activated by H3K27 acetylation and induces EMT in retinoblastoma by acting as a sponge of miR-32 to activate the Notch signaling pathway

Cancer Gene Therapy volume 28, pages 42–54 (2021)Cite this article

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Abstract

Recent studies have suggested that lincRNA-ROR is involved in the tumorigenesis of different types of cancers. However, the role of lincRNA-ROR in retinoblastoma has not been determined. We investigated lincRNA-ROR levels in 58 retinoblastoma and adjacent non-tumor tissues by quantitative reverse transcription PCR. Recurrence-free survival was analyzed using Cox regression analyses. Cell migration and invasion abilities were detected by wound-healing, Transwell invasion, and bioluminescence imaging assays. Western blotting was performed to detect epithelial–mesenchymal transition markers. Interactions between lincRNA-ROR, miR-32-5p, and Notch1 were confirmed by Luciferase, RNA pull-down, and RIP assays. Histone acetylation was detected by chromatin immunoprecipitation assays. We showed that lincRNA-ROR was significantly upregulated in retinoblastoma tissues, and overexpression of lincRNA-ROR was significantly correlated with optic nerve invasion, nodal or distant metastasis, and recurrence. We also showed that lincRNA-ROR is a critical promoter of retinoblastoma cell metastasis, both in vivo and in vitro. Further, we demonstrated that lincRNA-ROR activates the Notch signaling pathway by acting as a sponge of miR-32-5p. Upregulation of lincRNA-ROR was attributed to the CBP-mediated H3K27 acetylation at the promoter region. Our results reveal a potential competing endogenous RNA regulatory pathway, in which lincRNA-ROR modulates the epithelial–mesenchymal transition program by competitively binding to endogenous miR-32-5p and regulating Notch signaling pathway activity in retinoblastoma cells, which may provide new insights into novel molecular therapeutic targets for retinoblastoma.

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Fig. 1: Clinical significance of lincRNA-ROR in retinoblastoma.
Fig. 2: The effects of lincRNA-ROR in metastasis of retinoblastoma in vivo.
Fig. 3: LincRNA-ROR promoted the migration of retinoblastoma cells in vitro.
Fig. 4: LincRNA-ROR promoted the EMT of retinoblastoma cells in vitro.
Fig. 5: MiR-32-5p is negatively regulated by lincRNA-ROR in retinoblastoma.
Fig. 6: MiR-32-5p targeted gene Notch1 in retinoblastoma.
Fig. 7: LincRNA-ROR promotes invasion of retinoblastoma cells by inhibiting the miR-32-5p/Notch1 axis.
Fig. 8: LincRNA-ROR is activated by H3K27 acetylation at the promoter region.

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Funding

The Project Supported by Shenzhen Science and Technology Plan Project (Grant no. JCYJ20170307095222274), Natural Science Foundation of Guangdong Province (Grant no. 2019A1515010412), National Natural Science Foundation of China (Grant no. 81902751).

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  1. Department of Ophthalmology, The Second Clinical Medical College (Shenzhen People’s Hospital), Jinan University, Shenzhen, China

    Yali Gao & Xiaoling Luo

  2. Department of Obstetrics and Gynecology, The Second Clinical Medical College (Shenzhen People’s Hospital), Jinan University, Shenzhen, China

    Jun Zhang

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  1. Yali Gao
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Correspondence to Jun Zhang.

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Gao, Y., Luo, X. & Zhang, J. LincRNA-ROR is activated by H3K27 acetylation and induces EMT in retinoblastoma by acting as a sponge of miR-32 to activate the Notch signaling pathway. Cancer Gene Ther 28, 42–54 (2021). https://doi.org/10.1038/s41417-020-0181-z

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