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The functional synergism of microRNA clustering provides therapeutically relevant epigenetic interference in glioblastoma

Bhaskaran, Vivek, Nowicki, Michal O., Idriss, Mahmoud, Jimenez, Miguel A., Lugli, Gianmarco, Hayes, Josie L., Mahmoud, Ahmad Bakur, Zane, Rachel E., Passaro, Carmela, Ligon, Keith L., Haas-Kogan, Daphne, Bronisz, Agnieszka, Godlewski, Jakub, Lawler, Sean E., Chiocca, E. Antonio, Peruzzi, Pierpaolo·2019·Nature Communications
DOI 10.1038/s41467-019-08390-zPMC PMC6347618
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Abstract

MicroRNA deregulation is a consistent feature of glioblastoma, yet the biological effect of each single gene is generally modest, and therapeutically negligible. Here we describe a module of microRNAs, constituted by miR-124, miR-128 and miR-137, which are co-expressed during neuronal differentiation and simultaneously lost in gliomagenesis. Each one of these miRs targets several transcriptional regulators, including the oncogenic chromatin repressors EZH2, BMI1 and LSD1, which are functionally interdependent and involved in glioblastoma recurrence after therapeutic chemoradiation. Synchronizing the expression of these three microRNAs in a gene therapy approach displays significant anticancer synergism, abrogates this epigenetic-mediated, multi-protein tumor survival mechanism and results in a 5-fold increase in survival when combined with chemotherapy in murine glioblastoma models. These transgenic microRNA clusters display intercellular propagation in vivo, via extracellular vesicles, extending their biological effect throughout the whole tumor. Our results support the rationale and feasibility of combinatorial microRNA strategies for anticancer therapies.

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Metadata

Authors
Bhaskaran, V., Nowicki, M. O., Idriss, M., Jimenez, M. A., Lugli, G., Hayes, J. L., Mahmoud, A. B., Zane, R. E., Passaro, C., Ligon, K. L., Haas-Kogan, D., Bronisz, A., Godlewski, J., Lawler, S. E., Chiocca, E. A., & Peruzzi, P.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2019-01-25
Volume
10
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-019-08390-z
PMC
PMC6347618
Cited by
105
References
6
Language
en
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