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miR-490 suppresses telomere maintenance program and associated hallmarks in glioblastoma

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Abstract

Glioblastoma (GBM) is the most aggressive cancer of central nervous system with worst patient outcome. Telomere maintenance is a crucial mechanism governing GBM initiation and progression making it an attractive target. microRNAs (miRNAs) have shown therapeutic potential in GBM. Earlier, we showed miR-490 is downregulated in GBM patients and plays a tumor suppressive role. Here, we show that miR-490 regulates telomere maintenance program in GBM by directly targeting Telomeric Repeat-binding Factor 2 (TERF2) of the shelterin complex, Tankyrase 2 (TNKS2) and Serine/Threonine-protein kinase, SMG1. Overexpression of miR-490 resulted in effects characteristic to hampered telomere maintenance via TERF2 inhibition. These include induction of telomere dysfunction-induced foci and global DNA damage (53BP1 foci), along with an increase in p-γH2AX levels. Further, it led to inhibition of telomere maintenance hallmarks via reduced stemness (SOX2 and SOX4 downregulation) and induction of senescence (H3K9me3 marks gain and SIRT1 downregulation). It also initiated downstream DNA damage response (DDR) leading to p53 pathway activation. Moreover, microarray data analysis highlighted an overlap between miR-490 expression and REST-inhibition responses in GBM. Thus, miR-490-mediated targeting of telomere maintenance could be therapeutically important in GBM.

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Acknowledgements

RK is thankful to the IIT Delhi internal grant for funding this study. OSV thanks the Ministry of Human Resource and Development (MHRD), Govt. of India for Senior Research Fellowship and European Molecular Biology Organization (EMBO) for a Short-Term Fellowship. The authors also thank Miguel Jiménez for help with cell culture and the CNIO histopathology and confocal microscopy cores.

Funding

IIT Delhi Internal Research Grant, Senior Research Fellowship, EMBO Short term fellowship.

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Authors and Affiliations

  1. Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology, Delhi, New Delhi, 110016, India

    Omkar Suhas Vinchure, Deependra Kushwah & Ritu Kulshreshtha

  2. Telomeres and Telomerase Group, Spanish National Cancer Research Centre (CNIO), Melchor Fernandez Almagro 3, 28029, Madrid, Spain

    Kurt Whittemore & Maria A. Blasco

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  1. Omkar Suhas Vinchure
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  2. Kurt Whittemore
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  3. Deependra Kushwah
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  4. Maria A. Blasco
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  5. Ritu Kulshreshtha
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Contributions

RK and MAB conceived the project. RK supervised the whole study. MAB hosted OSV for an EMBO fellowship and supervised the study pertaining to telomere research at CNIO, Spain. OSV and RK designed the experiments. OSV performed all the experiments. DK assisted in preparation of luciferase assay constructs. KW mentored OSV in performing experiments pertaining to telomere research at CNIO, Spain. RK and OSV wrote the manuscript. KW and MAB reviewed the manuscript.

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Correspondence to Ritu Kulshreshtha.

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Vinchure, O.S., Whittemore, K., Kushwah, D. et al. miR-490 suppresses telomere maintenance program and associated hallmarks in glioblastoma. Cell. Mol. Life Sci. 78, 2299–2314 (2021). https://doi.org/10.1007/s00018-020-03644-2

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