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Nat Commun. 2019 Jan 25;10(1):442. doi: 10.1038/s41467-019-08390-z.

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

Author information

1
Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, 02115, USA.
2
Northeastern University, Boston, MA, 02115, USA.
3
University of Central Florida, Orlando, FL, 32816, USA.
4
Facolta' di medicina e chirurgia, Universita' Cattolica del Sacro Cuore, Rome, 00168, Italy.
5
School of Public Health, University of California, Berkeley, Berkeley, CA, 94720, USA.
6
College of Applied Medical Sciences, Taibah University, Madinah, 42353, Saudi Arabia.
7
Division of Neuro-Pathology, Department of Pathology, Brigham and Women's Hospital, Boston, MA, 02115, USA.
8
Department of Radiation Oncology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.
9
Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, 02115, USA. pperuzzi@bwh.harvard.edu.

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.

PMID:
30683859
PMCID:
PMC6347618
DOI:
10.1038/s41467-019-08390-z
[Indexed for MEDLINE]
Free PMC Article

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