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

Nourhan Abdelfattah, Subapriya Rajamanickam, Subbarayalu Panneerdoss, Santosh Timilsina, Pooja Yadav, Benjamin C. Onyeagucha, Michael Garcia, Ratna Vadlamudi, Yidong Chen, Andrew Brenner, Peter Houghton and Manjeet K. Rao ()
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Nourhan Abdelfattah: University of Texas Health Science Center at San Antonio
Subapriya Rajamanickam: University of Texas Health Science Center at San Antonio
Subbarayalu Panneerdoss: University of Texas Health Science Center at San Antonio
Santosh Timilsina: University of Texas Health Science Center at San Antonio
Pooja Yadav: University of Texas Health Science Center at San Antonio
Benjamin C. Onyeagucha: University of Texas Health Science Center at San Antonio
Michael Garcia: University of Texas Health Science Center at San Antonio
Ratna Vadlamudi: University of Texas Health Science Center at San Antonio
Yidong Chen: University of Texas Health Science Center at San Antonio
Andrew Brenner: University of Texas Health Science Center at San Antonio
Peter Houghton: University of Texas Health Science Center at San Antonio
Manjeet K. Rao: University of Texas Health Science Center at San Antonio

Nature Communications, 2018, vol. 9, issue 1, 1-19

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06808-8

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