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

Author

Listed:
  • Nourhan Abdelfattah

    (University of Texas Health Science Center at San Antonio
    University of Texas Health Science Center at San Antonio
    Faculty of Science, Cairo University)

  • Subapriya Rajamanickam

    (University of Texas Health Science Center at San Antonio
    University of Texas Health Science Center at San Antonio)

  • Subbarayalu Panneerdoss

    (University of Texas Health Science Center at San Antonio
    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
    University of Texas Health Science Center at San Antonio)

  • Benjamin C. Onyeagucha

    (University of Texas Health Science Center at San Antonio
    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
    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
    University of Texas Health Science Center at San Antonio)

  • Manjeet K. Rao

    (University of Texas Health Science Center at San Antonio
    University of Texas Health Science Center at San Antonio)

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.

Suggested Citation

  • Nourhan Abdelfattah & Subapriya Rajamanickam & Subbarayalu Panneerdoss & Santosh Timilsina & Pooja Yadav & Benjamin C. Onyeagucha & Michael Garcia & Ratna Vadlamudi & Yidong Chen & Andrew Brenner & Pe, 2018. "MiR-584-5p potentiates vincristine and radiation response by inducing spindle defects and DNA damage in medulloblastoma," Nature Communications, Nature, vol. 9(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06808-8
    DOI: 10.1038/s41467-018-06808-8
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