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

TitleCancer-Specific requirement for BUB1B/BUBR1 in human brain tumor isolates and genetically transformed cells.
Publication TypeJournal Article
Year of Publication2013
AuthorsDing Y, Hubert CG, Herman J, Corrin P, Toledo CM, Skutt-Kakaria K, Vazquez J, Basom R, Zhang B, Risler JK, Pollard SM, Nam D-H, Delrow JJ, Zhu J, Lee J, DeLuca J, Olson JM, Paddison PJ
JournalCancer Discov
Date Published2013 Feb
KeywordsAnimals, 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, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference, Spindle Apparatus, Transplantation, Heterologous, Tumor Cells, Cultured

UNLABELLED: 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.

SIGNIFICANCE: Currently, no effective therapies are available for glioblastoma, the most frequent and aggressive brain tumor. Our results suggest that targeting the GLEBS domain activity of BUB1B may provide a therapeutic window for glioblastoma, as the GLEBS domain is nonessential in untransformed cells. Moreover, the results further suggest that sister KT distances at metaphase may predict sensitivity to anticancer therapeutics targeting KT function.

Alternate JournalCancer Discov
PubMed ID23154965
PubMed Central IDPMC3632446
Grant ListCA15704 / CA / NCI NIH HHS / United States
CA170722-01 / CA / NCI NIH HHS / United States
P30 CA015704 / CA / NCI NIH HHS / United States
P30 DK056465 / DK / NIDDK NIH HHS / United States
R01 CA155360 / CA / NCI NIH HHS / United States
R01 GM088371 / GM / NIGMS NIH HHS / United States
R21 CA170722 / CA / NCI NIH HHS / United States
T32 CA080416 / CA / NCI NIH HHS / United States
T32CA080416 / CA / NCI NIH HHS / United States
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