Cancer-Specific requirement for BUB1B/BUBR1 in human brain tumor isolates and genetically transformed cells

Yu Ding, Christopher G Hubert, Jacob Herman, Philip Corrin, Chad M Toledo, Kyobi Skutt-Kakaria, Julio Vazquez, Ryan Basom, Bin Zhang, Jennifer K Risler, Steven M Pollard, Do-Hyun Nam, Jeffery J Delrow, Jun Zhu, Jeongwu Lee, Jennifer DeLuca, James M Olson, Patrick J Paddison

Research output: Contribution to journalArticlepeer-review

Abstract

To identify new candidate therapeutic targets for glioblastoma multiforme, we combined functional genetics and glioblastoma network modeling to identify kinases required for the growth of patient-derived brain tumor-initiating cells (BTIC) but that are dispensable to proliferating human neural stem cells (NSC). This approach yielded BUB1B/BUBR1, a critical mitotic spindle checkpoint player, as the top-scoring glioblastoma lethal kinase. Knockdown of BUB1B inhibited expansion of BTIC isolates, both in vitro and in vivo, without affecting proliferation of NSCs or astrocytes. Mechanistic studies revealed that BUB1B's GLE2p-binding sequence (GLEBS) domain activity is required to suppress lethal kinetochore-microtubule (KT-MT) attachment defects in glioblastoma isolates and genetically transformed cells with altered sister KT dynamics, which likely favor KT-MT instability. These results indicate that glioblastoma tumors have an added requirement for BUB1B to suppress lethal consequences of altered KT function and further suggest that sister KT measurements may predict cancer-specific sensitivity to BUB1B inhibition and perhaps other mitotic targets that affect KT-MT stability.
Original languageEnglish
Pages (from-to)198-211
Number of pages14
JournalCancer Discovery
Volume3
Issue number2
DOIs
Publication statusPublished - Feb 2013

Keywords

  • Animals
  • Astrocytes
  • Binding Sites
  • Blotting, Western
  • Brain Neoplasms
  • Cell Line
  • Cell Line, Transformed
  • Cell Proliferation
  • Genetic Predisposition to Disease
  • Glioblastoma
  • HeLa Cells
  • Humans
  • Kinetochores
  • Mice
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Neoplastic Stem Cells
  • Neural Stem Cells
  • Protein-Serine-Threonine Kinases
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Spindle Apparatus
  • Transplantation, Heterologous
  • Tumor Cells, Cultured

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