RT Journal Article
SR Electronic
T1 A Novel miR-146a-POU3F2/SMARCA5 Pathway Regulates Stemness and Therapeutic Response in Glioblastoma
JF Molecular Cancer Research
JO Mol Cancer Res
FD American Association for Cancer Research
DO 10.1158/1541-7786.MCR-20-0353
A1 Cui, Tiantian
A1 Bell, Erica H.
A1 McElroy, Joseph
A1 Liu, Kevin
A1 Sebastian, Ebin
A1 Johnson, Benjamin
A1 Gulati, Pooja Manchanda
A1 Becker, Aline Paixao
A1 Gray, Ashley
A1 Geurts, Marjolein
A1 Subedi, Depika
A1 Yang, Linlin
A1 Fleming, Jessica L.
A1 Meng, Wei
A1 Barnholtz-Sloan, Jill S.
A1 Venere, Monica
A1 Wang, Qi-En
A1 Robe, Pierre A.
A1 Haque, S. Jaharul
A1 Chakravarti, Arnab
YR 2020
UL http://mcr.aacrjournals.org/content/early/2020/10/28/1541-7786.MCR-20-0353.abstract
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.