A Novel miR-146a-POU3F2/SMARCA5 Pathway Regulates Sternness and Therapeutic Response in Glioblastoma

Tiantian Cui, Erica H. Bell, Joseph McElroy, Kevin Liu, Ebin Sebastian, Benjamin Johnson, Pooja Manchanda Gulati, Aline Paixao Becker, Ashley Gray, Marjolein Geurts, Depika Subedi, Linlin Yang, Jessica L. Fleming, Wei Meng, Jill S. Barnholtz-Sloan, Monica Venere, Qi En Wang, Pierre A. Robe, S. Jaharul Haque, Arnab Chakravarti*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Rapid tumor growth, widespread brain-invasion, and therapeutic resistance critically contribute to glioblastoma (GBM) recurrence and dismal patient outcomes. Although GBM stem cells (GSC) are shown to play key roles in these processes, the molecular pathways governing the GSC phenotype (GBM-stemness) remain poorly defined. Here, we show that epigenetic silencing of miR-146a significantly correlated with worse patient outcome and importantly, miR-146a level was significantly lower in recurrent tumors compared with primary ones. Further, miR-146a overexpression significantly inhibited the proliferation and invasion of GBM patient-derived primary cells and increased their response to temozolomide (TMZ), both in vitro and in vivo. Mechanistically, miR-146a directly silenced POU3F2 and SMARCA5, two transcription factors that mutually regulated each other, significantly compromising GBM-stemness and increasing TMZ response. Collectively, our data show that miR-146a–POU3F2/SMARCA5 pathway plays a critical role in suppressing GBM-stemness and increasing TMZ-response, suggesting that POU3F2 and SMARCA5 may serve as novel therapeutic targets in GBM. Implications: miR-146a predicts favorable prognosis and the miR-146a–POU3F2/SMARCA5 pathway is important for the suppression of stemness in GBM.

Original languageEnglish
Pages (from-to)48-60
Number of pages13
JournalMolecular Cancer Research
Issue number1
Publication statusPublished - 1 Jan 2021


  • Animals
  • Apoptosis
  • Brain Neoplasms/genetics
  • Cell Line, Tumor
  • Cell Proliferation
  • Glioblastoma/genetics
  • Humans
  • Mice
  • Mice, Nude
  • MicroRNAs/genetics
  • Signal Transduction
  • Transfection


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