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

Vivek Bhaskaran, Michal O. Nowicki, Mahmoud Idriss, Miguel A. Jimenez, Gianmarco Lugli, Josie L. Hayes, Ahmad Bakur Mahmoud, Rachel E. Zane, Carmela Passaro, Keith L. Ligon, Daphne Haas-Kogan, Agnieszka Bronisz, Jakub Godlewski, Sean E. Lawler, E. Antonio Chiocca and Pierpaolo Peruzzi ()
Additional contact information
Vivek Bhaskaran: Harvard Medical School and Brigham and Women’s Hospital
Michal O. Nowicki: Harvard Medical School and Brigham and Women’s Hospital
Mahmoud Idriss: Harvard Medical School and Brigham and Women’s Hospital
Miguel A. Jimenez: Harvard Medical School and Brigham and Women’s Hospital
Gianmarco Lugli: Harvard Medical School and Brigham and Women’s Hospital
Josie L. Hayes: University of California, Berkeley
Ahmad Bakur Mahmoud: Harvard Medical School and Brigham and Women’s Hospital
Rachel E. Zane: Harvard Medical School and Brigham and Women’s Hospital
Carmela Passaro: Harvard Medical School and Brigham and Women’s Hospital
Keith L. Ligon: Brigham and Women’s Hospital
Daphne Haas-Kogan: Dana-Farber Cancer Institute
Agnieszka Bronisz: Harvard Medical School and Brigham and Women’s Hospital
Jakub Godlewski: Harvard Medical School and Brigham and Women’s Hospital
Sean E. Lawler: Harvard Medical School and Brigham and Women’s Hospital
E. Antonio Chiocca: Harvard Medical School and Brigham and Women’s Hospital
Pierpaolo Peruzzi: Harvard Medical School and Brigham and Women’s Hospital

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-08390-z

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