Down regulation of Akirin-2 increases chemosensitivity in human glioblastomas more efficiently than Twist-1

Oncotarget. 2015 Aug 28;6(25):21029-45. doi: 10.18632/oncotarget.3763.


The Twist-1 transcription factor and its interacting protein Akirin-2 regulate apoptosis. We found that in glioblastomas, highly malignant brain tumors, Akirin-2 and Twist-1 were expressed in glial fibrillary acidic protein positive tumor regions as well as in tumor endothelial cells and infiltrating macrophages / microglia. Temozolomide (TMZ) induced the expression of both molecules, partly shifting their nuclear to cytosolic localization. The knock-down (kd) of Akirin-2 increased the activity of cleaved (c)Caspase-3/-7, the amounts of cCaspases-3, -7 and cPARP-1 and resulted in an increased number of apoptotic cells after TMZ exposure. Glioblastoma cells containing decreased amounts of Akirin-2 after kd contained increased amounts of cCaspase-3 as determined by the ImageStreamx Mark II technology. For Twist-1, similar results were obtained with the exception that the combination of TMZ treatment and Twist-1 kd failed to significantly reduce chemoresistance compared with controls. This could be attributed to a cell population containing only slightly increased cCaspase-3 together with decreased Twist-1 levels, which was clearly larger than the respective population observed under Akirin-2 kd. Our results showed that, compared with Twist-1, Akirin-2 is the more promising target for RNAi strategies antagonizing Twist-1/Akirin-2 facilitated glioblastoma cell survival.

Keywords: Akirin-2; Twist-1; chemoresistance; glioblastoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Alkylating / chemistry
  • Apoptosis*
  • Brain Neoplasms / metabolism*
  • CD11b Antigen / metabolism
  • Caspase 3 / metabolism
  • Caspase 7 / metabolism
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cytosol / metabolism
  • DNA-Binding Proteins / metabolism*
  • Dacarbazine / analogs & derivatives
  • Dacarbazine / chemistry
  • Down-Regulation
  • Drug Resistance, Neoplasm
  • Gene Expression Profiling*
  • Gene Expression Regulation, Neoplastic*
  • Glial Fibrillary Acidic Protein / metabolism
  • Glioblastoma / metabolism
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Microscopy, Fluorescence
  • Nuclear Proteins / metabolism*
  • RNA Interference
  • Temozolomide
  • Transcription Factors / metabolism*
  • Twist-Related Protein 1 / metabolism*
  • von Willebrand Factor / metabolism


  • Antineoplastic Agents, Alkylating
  • CD11b Antigen
  • DNA-Binding Proteins
  • Glial Fibrillary Acidic Protein
  • ITGAM protein, human
  • Nuclear Proteins
  • TWIST1 protein, human
  • Transcription Factors
  • Twist-Related Protein 1
  • ZBTB7A protein, human
  • von Willebrand Factor
  • Dacarbazine
  • CASP3 protein, human
  • CASP7 protein, human
  • Caspase 3
  • Caspase 7
  • Temozolomide