TY - JOUR
T1 - ID4 imparts chemoresistance and cancer stemness to glioma cells by derepressing miR-9*-mediated suppression of SOX2
AU - Jeon, Hye Min
AU - Sohn, Young Woo
AU - Oh, Se Young
AU - Kim, Sung Hak
AU - Beck, Samuel
AU - Kim, Soonhag
AU - Kim, Hyunggee
N1 - Copyright:
Copyright 2011 Elsevier B.V., All rights reserved.
PY - 2011/5/1
Y1 - 2011/5/1
N2 - Glioma stem cells (GSC) possess tumor-initiating potential and are relatively resistant to conventional chemotherapy and irradiation. Thus, they are considered to be major drivers for glioma initiation, progression, and recurrence. However, the precise mechanism governing acquisition of their drug resistance remains to be elucidated. Our previous study has shown that inhibitor of differentiation 4 (ID4) dedifferentiates Ink4a/Arf-/- mouse astrocytes and human glioma cells to glioma stem-like cells (induced GSCs or iGSCs). In this article, we report that ID4-driven iGSCs exhibit chemoresistant behavior to anticancer drugs through activation of ATPbinding cassette (ABC) transporters. We found that ID4 enhanced SOX2 protein expression by suppressing microRNA-9* (miR-9*), which can repress SOX2 by targeting its 3′-untranslated region. Consequently, ID4-mediated SOX2 induction enhanced ABCC3 and ABCC6 expression through direct transcriptional regulation, indicating that ID4 regulates the chemoresistance of iGSCs by promoting SOX2-mediated induction of ABC transporters. Furthermore, we found that short hairpin RNA-mediated knockdown of SOX2 in ID4-driven iGSCs resulted in loss of cancer stemness. Moreover, ectopic expression of SOX2 could dedifferentiate Ink4a/Arf-/- astrocytes and glioma cells to iGSCs, indicating a crucial role of SOX2 in genesis and maintenance of GSCs. Finally, we found that the significance of the ID4-miR-9*-SOX2-ABCC3/ABCC6 regulatory pathway is recapitulated in GSCs derived from patients with glioma. Together, our results reveal a novel regulatory mechanism by which ID4-driven suppression of miR-9* induces SOX2, which imparts stemness potential and chemoresistance to glioma cells and GSCs.
AB - Glioma stem cells (GSC) possess tumor-initiating potential and are relatively resistant to conventional chemotherapy and irradiation. Thus, they are considered to be major drivers for glioma initiation, progression, and recurrence. However, the precise mechanism governing acquisition of their drug resistance remains to be elucidated. Our previous study has shown that inhibitor of differentiation 4 (ID4) dedifferentiates Ink4a/Arf-/- mouse astrocytes and human glioma cells to glioma stem-like cells (induced GSCs or iGSCs). In this article, we report that ID4-driven iGSCs exhibit chemoresistant behavior to anticancer drugs through activation of ATPbinding cassette (ABC) transporters. We found that ID4 enhanced SOX2 protein expression by suppressing microRNA-9* (miR-9*), which can repress SOX2 by targeting its 3′-untranslated region. Consequently, ID4-mediated SOX2 induction enhanced ABCC3 and ABCC6 expression through direct transcriptional regulation, indicating that ID4 regulates the chemoresistance of iGSCs by promoting SOX2-mediated induction of ABC transporters. Furthermore, we found that short hairpin RNA-mediated knockdown of SOX2 in ID4-driven iGSCs resulted in loss of cancer stemness. Moreover, ectopic expression of SOX2 could dedifferentiate Ink4a/Arf-/- astrocytes and glioma cells to iGSCs, indicating a crucial role of SOX2 in genesis and maintenance of GSCs. Finally, we found that the significance of the ID4-miR-9*-SOX2-ABCC3/ABCC6 regulatory pathway is recapitulated in GSCs derived from patients with glioma. Together, our results reveal a novel regulatory mechanism by which ID4-driven suppression of miR-9* induces SOX2, which imparts stemness potential and chemoresistance to glioma cells and GSCs.
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U2 - 10.1158/0008-5472.CAN-10-3340
DO - 10.1158/0008-5472.CAN-10-3340
M3 - Article
C2 - 21531766
AN - SCOPUS:79955501601
VL - 71
SP - 3410
EP - 3421
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 9
ER -