Mizuki Azuma

Mizuki Azuma
  • Associate Professor


The function of Ewing sarcoma proteins in mitosis

Ewing sarcoma is the second most common bone tumor in children. The common molecular abnormality in Ewing sarcoma is the t(11; 22) chromosomal translocation, which results in the expression of a chimeric fusion protein containing EWS-derived sequences at the amino terminus fused to the carboxyl-terminus of the ETS transcription factor FLI1. My research goal is to elucidate the molecular mechanism whereby the Ewing sarcoma fusion protein EWS/FLI1 leads to malignant transformation.

In recent studies we reported that both the knockdown of EWS, and expression of the EWS/FLI1 fusion protein, in zebrafish embryos and HeLa cells leads to mitotic defects. We subsequently demonstrated a biochemical interaction between EWS/FLI1 and wildtype EWS, leads to inhibition of EWS activity by EWS/FLI1 in a dominant negative manner.

The hypothesis of my research is that the EWS/FLI1-EWS interaction in Ewing sarcoma induces mitotic defects leading to malignant transformation. Chromosomal instability is a hallmark of malignancy. Therefore, the functional loss of EWS due to its interaction with EWS/FLI may cause mitotic defects leading to chromosome instability, and ultimately to Ewing Sarcoma. We will analyze both EWS/FLI1 and EWS in human cells and in zebrafish.  Experiments will be carried out in human cell lines to understand the molecular basis of EWS/FLI1 more closely, and to take advantage of the availability of reagents to study the mitotic spindle. These findings will then be assessed in zebrafish by generating transgenic fish expressing EWS/FLI1. The zebrafish will provide an in vivo whole animal model amenable to genetic screening for second hit mutations or suppressor genes.

We will directly address the molecular basis for this interaction and assess the activity of the EWS/FLI1 fusion in vivo in the zebrafish.  Understanding how the fusion proteins resulting from these translocations lead to malignant transformation remains an important biological and clinical problem.

Selected Publications

  • Kim H, Park H, Schulz ET, Azuma Y, Azuma M. EWSR1 prevents the induction of aneuploidy through direct regulation of Aurora B. Front Cell Dev Biol. 2023 Feb 15; 11:987153. PMID: 36875767; PMCID: PMC9975954.
  • Zhao C, Matalonga J, Lancman JJ, Liu L, Xiao C, Kumar S, Gates KP, He J, Graves A, Huisken J, Azuma M, Lu Z, Chen C, Ding BS, Dong PDS Regenerative failure of intrahepatic biliary cells in Alagille syndrome rescued by elevated Jagged/Notch/Sox9 signaling. Proc Natl Acad Sci U S A. 2022 Dec 13; 119(50):e2201097119. Epub 2022 Dec 5. PMID: 36469766; PMCID: PMC9897440.
  • Park H, Kim H, Hassebroek V, Azuma Y, Slawson C, Azuma M, 2021 Chromosomal localization of Ewing sarcoma EWSR1/FLI1 protein promotes the induction of aneuploidy. J Biol Chem 296:100164. PMID: 33293370. PMCID: PMC7857440.
  • So J, Kim M, Lee SH, Ko S, Lee DA, Park H, Azuma M, Parsons MJ, Prober D, Shin D, 2021 Attenuating the Epidermal Growth Factor Receptor-Extracellular Signal-Regulated Kinase-Sex-Determining Region Y-Box 9 Axis Promotes Liver Progenitor Cell-Mediated Liver Regeneration in Zebrafish. Hepatology 73:1494-1508. PMID: 32602149. PMCID: PMC7769917.
  • Huang W, Beer RL, Delaspre F, Wang G, Edelman HE, Park H, Azuma M, Parsons MJ, 2016 Sox9b is a mediator of retinoic acid signaling restricting endocrine progenitor differentiation. Dev Biol 418:28-39. PMID: 27565026. PMCID: PMC5031550.
  • Park H, Galbraith R, Turner T, Mehojah J, Azuma M, 2016 Loss of Ewing sarcoma EWS allele promotes tumorigenesis by inducing chromosomal instability in zebrafish. Sci Rep 6:32297. PMID: 27557633. PMCID: PMC4997631.
  • Lanza C, Tan EP, Zhang Z, Machacek M, Brinker AE, Azuma M, Slawson C, 2016 Reduced O-GlcNAcase expression promotes mitotic errors and spindle defects. Cell Cycle 15:1363-75. PMID: 27070276. PMCID: PMC4889296.
  • Wiley EO, Fuiten AM, Doosey MH, Lohman BK, Merkes C, Azuma M. 2015 The Caudal Skeleton of the Zebrafish, Danio rerio, from a Phylogenetic Perspective: A Polyural Interpretation of Homologous Structures. Copeia 103:740-750. PMID: 28250540. PMCID: PMC5328193.
  • Merkes C, Turkalo TK, Wilder N, Park H, Wenger LW, Lewin SJ, Azuma M, 2015 Ewing sarcoma ewsa protein regulates chondrogenesis of Meckel's cartilage through modulation of Sox9 in zebrafish. PLoS One 10:e0116627. PMID: 25617839. PMCID: PMC4305327.
  • Park H, Turkalo TK, Nelson K, Folmsbee SS, Robb C, Roper B, Azuma M, 2014 Ewing sarcoma EWS protein regulates midzone formation by recruiting Aurora B kinase to the midzone. Cell Cycle 13:2391-9. PMID: 25483190. PMCID: PMC4128884.
  • Shive HR, West RR, Embree LJ, Azuma M, Sood R, Liu P, Hickstein DD, 2010 brca2 in zebrafish ovarian development, spermatogenesis, and tumorigenesis. Proc Natl Acad Sci USA 107:19350-5. PMID: 20974951. PMCID: PMC2984219.
  • Embree LJ, Azuma M, Hickstein DD, 2009 Ewing sarcoma fusion protein EWSR1/FLI1 interacts with EWSR1 leading to mitotic defects in zebrafish embryos and human cell lines. Cancer Res 69:4363-71. PMID: 19417137. PMCID: PMC2766243.
  • Azuma M, Embree LJ, Sabaawy H, Hickstein DD, 2007 Ewing sarcoma protein ewsr1 maintains mitotic integrity and proneural cell survival in the zebrafish embryo. PLoS One 2:e979. PMID: 17912356. PMCID: PMC1991596.

See all papers by Mizuki Azuma on PubMed