PT  - JOURNAL ARTICLE
AU  - Cui, Tiantian
AU  - Bell, Erica H.
AU  - McElroy, Joseph
AU  - Liu, Kevin
AU  - Sebastian, Ebin
AU  - Johnson, Benjamin
AU  - Gulati, Pooja Manchanda
AU  - Becker, Aline Paixao
AU  - Gray, Ashley
AU  - Geurts, Marjolein
AU  - Subedi, Depika
AU  - Yang, Linlin
AU  - Fleming, Jessica L.
AU  - Meng, Wei
AU  - Barnholtz-Sloan, Jill S.
AU  - Venere, Monica
AU  - Wang, Qi-En
AU  - Robe, Pierre A.
AU  - Haque, S. Jaharul
AU  - Chakravarti, Arnab
TI  - A Novel miR-146a-POU3F2/SMARCA5 Pathway Regulates Stemness and Therapeutic Response in Glioblastoma
AID  - 10.1158/1541-7786.MCR-20-0353
DP  - 2020 Sep 24
TA  - Molecular Cancer Research
4099  - http://mcr.aacrjournals.org/content/early/2020/10/28/1541-7786.MCR-20-0353.short
4100  - http://mcr.aacrjournals.org/content/early/2020/10/28/1541-7786.MCR-20-0353.full
AB  - 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.