title: MEIS2 is essential for neuroblastoma cell survival and proliferation by transcriptional control of M-phase progression.
abstract: MEIS2 has an important role in development and organogenesis, and is implicated in the pathogenesis of human cancer. The molecular basis of MEIS2 action in tumorigenesis is not clear. Here, we show that MEIS2 is highly expressed in human neuroblastoma cell lines and is required for neuroblastoma cell survival and proliferation. Depletion of MEIS2 in neuroblastoma cells leads to M-phase arrest and mitotic catastrophe, whereas ectopic expression of MEIS2 markedly enhances neuroblastoma cell proliferation, anchorage-independent growth, and tumorigenicity. Gene expression profiling reveals an essential role of MEIS2 in maintaining the expression of a large number of late cell-cycle genes, including those required for DNA replication, G2-M checkpoint control and M-phase progression. Importantly, we identify MEIS2 as a transcription activator of the MuvB-BMYB-FOXM1 complex that functions as a master regulator of cell-cycle gene expression. Further, we show that FOXM1 is a direct target gene of MEIS2 and is required for MEIS2 to upregulate mitotic genes. These findings link a developmentally important gene to the control of cell proliferation and suggest that high MEIS2 expression is a molecular mechanism for high expression of mitotic genes that is frequently observed in cancers of poor prognosis.
authors.affiliation: Department of Neurology, The First Hospital of Yichang, Institute of Translational Neuroscience, Three Gorges University College of Medicine, Yichang, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zha
authors.affiliation: 1] Department of Neurology, The First Hospital of Yichang, Institute of Translational Neuroscience, Three Gorges University College of Medicine, Yichang, China [2] Cancer Center, Georgia Regents University, Augusta, GA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Cancer Center, Georgia Regents University, Augusta, GA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Ding
authors.affiliation: 1] Cancer Center, Georgia Regents University, Augusta, GA, USA [2] Department of Biostatistics and Epidemiology, Georgia Regents University, Augusta, GA, USA.
authors.forename: J-H
authors.initials: JH
authors.lastname: Choi
authors.affiliation: State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and System Biology, Southwest University, Chongqing, China.
authors.forename: L
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Cellular Biology and Anatomy, Georgia Regents University, Augusta, GA, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Dong
authors.affiliation: 1] Cancer Center, Georgia Regents University, Augusta, GA, USA [2] Department of Biochemistry and Molecular Biology, Georgia Regents University, Augusta, GA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Yan
authors.affiliation: Department of Biochemistry and Molecular Biology, Georgia Regents University, Augusta, GA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Huang
authors.affiliation: 1] Cancer Center, Georgia Regents University, Augusta, GA, USA [2] Department of Pathology, Medical College of Georgia, Georgia Regents University, Augusta, GA, USA.
authors.forename: H-F
authors.initials: HF
authors.lastname: Ding
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002455:Cell Division; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D018797:Cell Cycle Proteins; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; C491172:MEIS2 protein, human; D014157:Transcription Factors