title: Isorhapontigenin suppresses growth of patient-derived glioblastoma spheres through regulating miR-145/SOX2/cyclin D1 axis.
abstract: Glioblastoma (GBM) is the most common malignant brain tumor, and glioma stem cells (GSCs) are considered a major source of treatment resistance for glioblastoma. Identifying new compounds that inhibit the growth of GSCs and understanding their underlying molecular mechanisms are therefore important for developing novel therapy for GBM.
  
  
  
  We investigated the potential inhibitory effect of isorhapontigenin (ISO), an anticancer compound identified in our recent investigations, on anchorage-independent growth of patient-derived glioblastoma spheres (PDGS) and its mechanism of action.
  
  
  
  ISO treatment resulted in significant anchorage-independent growth inhibition, accompanied with cell cycle G0-G1 arrest and cyclin D1 protein downregulation in PDGS. Further studies established that cyclin D1 was downregulated by ISO at transcription levels in a SOX2-dependent manner. In addition, ISO attenuated SOX2 expression by specific induction of miR-145, which in turn suppressed 3'UTR activity of SOX2 mRNA without affecting its mRNA stability. Moreover, ectopic expression of exogenous SOX2 rendered D456 cells resistant to induction of cell cycle G0-G1 arrest and anchorage-independent growth inhibition upon ISO treatment, whereas inhibition of miR-145 resulted in D456 cells resistant to ISO inhibition of SOX2 and cyclin D1 expression. In addition, overexpression of miR-145 mimicked ISO treatment in D456 cells.
  
  
  
  ISO induces miR-145 expression, which binds to the SOX2 mRNA 3'UTR region and inhibits SOX2 protein translation. Inhibition of SOX2 leads to cyclin D1 downregulation and PDGS anchorage-independent growth inhibition. The elucidation of the miR-145/SOX2/cyclin D1 axis in PDGS provides a significant insight into understanding the anti-GBM effect of ISO compound.
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York (Z.X., X.Z., J.X., D.X., J.L., H.J., G.J., C.H.); Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China (Z.X.); Division of Neuro-Oncology, Department of Neurology, University of Alabama, Birmingham, Alabama (X.H.).
authors.forename: Zhou
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York (Z.X., X.Z., J.X., D.X., J.L., H.J., G.J., C.H.); Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China (Z.X.); Division of Neuro-Oncology, Department of Neurology, University of Alabama, Birmingham, Alabama (X.H.).
authors.forename: Xingruo
authors.initials: X
authors.lastname: Zeng
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York (Z.X., X.Z., J.X., D.X., J.L., H.J., G.J., C.H.); Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China (Z.X.); Division of Neuro-Oncology, Department of Neurology, University of Alabama, Birmingham, Alabama (X.H.).
authors.forename: Jiawei
authors.initials: J
authors.lastname: Xu
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York (Z.X., X.Z., J.X., D.X., J.L., H.J., G.J., C.H.); Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China (Z.X.); Division of Neuro-Oncology, Department of Neurology, University of Alabama, Birmingham, Alabama (X.H.).
authors.forename: Derek
authors.initials: D
authors.lastname: Xu
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York (Z.X., X.Z., J.X., D.X., J.L., H.J., G.J., C.H.); Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China (Z.X.); Division of Neuro-Oncology, Department of Neurology, University of Alabama, Birmingham, Alabama (X.H.).
authors.forename: Jingxia
authors.initials: J
authors.lastname: Li
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York (Z.X., X.Z., J.X., D.X., J.L., H.J., G.J., C.H.); Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China (Z.X.); Division of Neuro-Oncology, Department of Neurology, University of Alabama, Birmingham, Alabama (X.H.).
authors.forename: Honglei
authors.initials: H
authors.lastname: Jin
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York (Z.X., X.Z., J.X., D.X., J.L., H.J., G.J., C.H.); Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China (Z.X.); Division of Neuro-Oncology, Department of Neurology, University of Alabama, Birmingham, Alabama (X.H.).
authors.forename: Guosong
authors.initials: G
authors.lastname: Jiang
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York (Z.X., X.Z., J.X., D.X., J.L., H.J., G.J., C.H.); Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China (Z.X.); Division of Neuro-Oncology, Department of Neurology, University of Alabama, Birmingham, Alabama (X.H.).
authors.forename: Xiaosi
authors.initials: X
authors.lastname: Han
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York (Z.X., X.Z., J.X., D.X., J.L., H.J., G.J., C.H.); Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China (Z.X.); Division of Neuro-Oncology, Department of Neurology, University of Alabama, Birmingham, Alabama (X.H.).
authors.forename: Chuanshu
authors.initials: C
authors.lastname: Huang
mesh_terms: D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019938:Cyclin D1 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: C530104:CCND1 protein, human; C541010:MIRN145 microRNA, human; D035683:MicroRNAs; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D013267:Stilbenes; C432307:isorhapontigenin; D019938:Cyclin D1
keywords: cell cycle; cyclin D1; glioblastoma sphere; isorhapontigenin; miR-145