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MiR-584-5p potentiates vincristine and radiation response by inducing spindle defects and DNA damage in medulloblastoma.


ABSTRACT: Despite improvements in overall survival, only a modest percentage of patients survives high-risk medulloblastoma. The devastating side effects of radiation and chemotherapy substantially reduce quality of life for surviving patients. Here, using genomic screens, we identified miR-584-5p as a potent therapeutic adjuvant that potentiates medulloblastoma to radiation and vincristine. MiR-584-5p inhibited medulloblastoma growth and prolonged survival of mice in pre-clinical tumor models. MiR-584-5p overexpression caused cell cycle arrest, DNA damage, and spindle defects in medulloblastoma cells. MiR-584-5p mediated its tumor suppressor and therapy-sensitizing effects by targeting HDAC1 and eIF4E3. MiR-584-5p overexpression or HDAC1/eIF4E3 silencing inhibited medulloblastoma stem cell self-renewal without affecting neural stem cell growth. In medulloblastoma patients, reduced expression of miR-584-5p correlated with increased levels of HDAC1/eIF4E3. These findings identify a previously undefined role for miR-584-5p/HDAC1/eIF4E3 in regulating DNA repair, microtubule dynamics, and stemness in medulloblastoma and set the stage for a new way to treat medulloblastoma using miR-584-5p.

SUBMITTER: Abdelfattah N 

PROVIDER: S-EPMC6208371 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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MiR-584-5p potentiates vincristine and radiation response by inducing spindle defects and DNA damage in medulloblastoma.

Abdelfattah Nourhan N   Rajamanickam Subapriya S   Panneerdoss Subbarayalu S   Timilsina Santosh S   Yadav Pooja P   Onyeagucha Benjamin C BC   Garcia Michael M   Vadlamudi Ratna R   Chen Yidong Y   Brenner Andrew A   Houghton Peter P   Rao Manjeet K MK  

Nature communications 20181031 1


Despite improvements in overall survival, only a modest percentage of patients survives high-risk medulloblastoma. The devastating side effects of radiation and chemotherapy substantially reduce quality of life for surviving patients. Here, using genomic screens, we identified miR-584-5p as a potent therapeutic adjuvant that potentiates medulloblastoma to radiation and vincristine. MiR-584-5p inhibited medulloblastoma growth and prolonged survival of mice in pre-clinical tumor models. MiR-584-5p  ...[more]

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