Статья

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

Vivek BhaskaranHarvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, 02115, USAMichal O. NowickiHarvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, 02115, USAM. Bennani-Baiti IdrissHarvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, 02115, USAMiguel A. JiménezHarvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, 02115, USAGianmarco LugliFacolta' di medicina e chirurgia, Universita' Cattolica del Sacro Cuore, Rome, 00168, ItalyJosie HayesSchool of Public Health, University of California, Berkeley, Berkeley, CA, 94720, USAAhmad Bakur MahmoudCollege of Applied Medical Sciences, Taibah University, Madinah, 42353, Saudi ArabiaRachel ZaneHarvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, 02115, USACarmela PassaroHarvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, 02115, USAKeith L. LigonDivision of Neuro-Pathology, Department of Pathology, Brigham and Women's Hospital, Boston, MA, 02115, USADaphne A. Haas‐KoganDepartment of Radiation Oncology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, 02115, USAAgnieszka BroniszHarvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, 02115, USAJakub GodlewskiHarvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, 02115, USASean LawlerHarvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, 02115, USAE. Antonio ChioccaHarvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, 02115, USAPierpaolo PeruzziHarvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, 02115, USA. [email protected]

2019en

ABI

Аннотация

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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Идентификаторы

DOI: 10.1038/s41467-019-08390-z

Цитирования и источники

Цитирований: 2Использованных источников: 0

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