title: Identification of FoxM1/Bub1b signaling pathway as a required component for growth and survival of rhabdomyosarcoma.
abstract: We identified Bub1b as an essential element for the growth and survival of rhabdomyosarcoma (RMS) cells using a bar-coded, tetracycline-inducible short hairpin RNA (shRNA) library screen. Knockdown of Bub1b resulted in suppression of tumor growth in vivo, including the regression of established tumors. The mechanism by which this occurs is via postmitotic endoreduplication checkpoint and mitotic catastrophe. Furthermore, using a chromatin immunoprecipitation assay, we found that Bub1b is a direct transcriptional target of Forkhead Box M1 (FoxM1). Suppression of FoxM1 either by shRNA or the inhibitor siomycin A resulted in reduction of Bub1b expression and inhibition of cell growth and survival. These results show the important role of the Bub1b/FoxM1 pathway in RMS and provide potential therapeutic targets.
authors.affiliation: Molecular Oncology Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. xiaolinw@mail.nih.gov
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Wan
authors.forename: Choh
authors.initials: C
authors.lastname: Yeung
authors.forename: Su Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Dolan
authors.forename: Vu N
authors.initials: VN
authors.lastname: Ngo
authors.forename: Sandra
authors.initials: S
authors.lastname: Burkett
authors.forename: Javed
authors.initials: J
authors.lastname: Khan
authors.forename: Louis M
authors.initials: LM
authors.lastname: Staudt
authors.forename: Lee J
authors.initials: LJ
authors.lastname: Helman
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D058893:DNA Barcoding, Taxonomic / Q000379:methods; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D012204:Rh-Hr Blood-Group System / Q000096:biosynthesis; D012208:Rhabdomyosarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D014183:Transplantation, Heterologous
chemical_list: C584278:Bub1b protein, mouse; D018797:Cell Cycle Proteins; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C066468:RHCE protein, human; D034741:RNA, Small Interfering; D012204:Rh-Hr Blood-Group System; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases