title: ID4 imparts chemoresistance and cancer stemness to glioma cells by derepressing miR-9*-mediated suppression of SOX2.
abstract: 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 ATP-binding 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.
authors.affiliation: School of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
authors.forename: Hye-Min
authors.initials: HM
authors.lastname: Jeon
authors.forename: Young-Woo
authors.initials: YW
authors.lastname: Sohn
authors.forename: Se-Yeong
authors.initials: SY
authors.lastname: Oh
authors.forename: Se-Young
authors.initials: SY
authors.lastname: Oh
authors.forename: Sung-Hak
authors.initials: SH
authors.lastname: Kim
authors.forename: Samuel
authors.initials: S
authors.lastname: Beck
authors.forename: Soonhag
authors.initials: S
authors.lastname: Kim
authors.forename: Hyunggee
authors.initials: H
authors.lastname: Kim
mesh_terms: D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D055785:Gene Knockdown Techniques; D005910:Glioma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis; D014411:Neoplastic Stem Cells; D055748:SOXB1 Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014161:Transduction, Genetic; D015854:Up-Regulation
chemical_list: D051796:Inhibitor of Differentiation Proteins; D035683:MicroRNAs; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D055748:SOXB1 Transcription Factors; C102029:ABCC6 protein, human; C490128:ID4 protein, human; C541874:MIRN92 microRNA, human; C527782:SOX2 protein, human; C114462:multidrug resistance-associated protein 3