A Novel miR-146a-POU3F2/SMARCA5 Pathway Regulates Sternness and Therapeutic Response in Glioblastoma
Cui, Tiantian; Bell, Erica H.; McElroy, Joseph; Liu, Kevin; Sebastian, Ebin; Johnson, Benjamin; Gulati, Pooja Manchanda; Becker, Aline Paixao; Gray, Ashley; Geurts, Marjolein; Subedi, Depika; Yang, Linlin; Fleming, Jessica L.; Meng, Wei; Barnholtz-Sloan, Jill S.; Venere, Monica; Wang, Qi En; Robe, Pierre A.; Haque, S. Jaharul; Chakravarti, Arnab
(2021) Molecular Cancer Research, volume 19, issue 1, pp. 48 - 60
(Article)
Abstract
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
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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.
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Keywords: Animals, Apoptosis, Brain Neoplasms/genetics, Cell Line, Tumor, Cell Proliferation, Glioblastoma/genetics, Humans, Mice, Mice, Nude, MicroRNAs/genetics, Signal Transduction, Transfection, Molecular Biology, Oncology, Cancer Research, Research Support, Non-U.S. Gov't, Journal Article, Research Support, N.I.H., Extramural
ISSN: 1541-7786
Publisher: American Association for Cancer Research Inc.
Note: Funding Information: We thank Dr. Jeremy Rich (UC San Diego, USA) for providing primary GBM patient-derived cells. We also thank The Ohio State University (OSU) Comprehensive Cancer Center Small Animal Imaging Core, The Ohio State University (OSU) Genomics Shared Resource (GSR), The Ohio State University (OSU) Target Validation Shared Resource (TVSR), and The Ohio State University (OSU) Comprehensive Cancer Center Pathology Core Facility supported in part by grant no. P30 CA016058, NCI. This work was also supported by NCI [R01CA169368 (to A. Chakravarti), R01CA11522358 (to A. Chakravarti), R01CA1145128 (to A. Chakravarti), R01CA108633 (to A. Chakravarti), R01CA188228 (to A. Chakravarti, K. Liu, and J.S. Barnholtz-Sloan), 1RC2CA148190 (to A. Chakravarti), and U10CA180850-01 (to A. Chakravarti); A Brain Tumor Funders Collaborative Grant (to A. Chakravarti); Ohio State University Comprehensive Cancer Center Award (to A. Chakravarti), and the T&P Bohnenn Fund for Neuro-Oncology Research (grant to P.A. Robe). Publisher Copyright: © 2020 American Association for Cancer Research.
(Peer reviewed)