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  • Otherwise ES cells express high level of histone lysine spec

    2019-11-16

    Otherwise, ES 7867 express high level of histone lysine specific demethylase 1 (LSD1) expression. In this context, it is proposed that LSD1 inhibition may block the function of EWS-ETS proteins [70]. Furthermore, checkpoint kinase 1 (CHK1), a modulator of cell survival under the condition of impaired DNA replication, is a candidate of therapeutic targets in ES [71]. Small-molecule CHK1 inhibitor combined with gemcitabine shows elevated toxicity both in vitro and in vivo models of ES.
    Conclusion EWSR1 participates in various functions which are crucial for the regulation of tissue development and cellular homeostasis. We overviewed that i) genetic mutations of EWSR1 are associated with neurodegeneration, ii) EWSR1 deficiency leads to epigenetic alteration such as miRNA processing, and iii) EWSR1, as if “Jack of all trades, master of none”, plays diverse molecular functions and its deficiency affects many cellular functions including autophagy and mitochondrial activity. Loss of EWSR1 function also contributes to the hypersensitivity of ionizing radiation and premature cellular senescence and aging. Even though several groups have studied in depth about EWSR1, there are still many areas that have not yet been explored. For example, conditional KO or knock-in EWSR1 animal models are necessary to determine the EWSR1\'s multifunctional or undescribed roles in an organ-specific or a cell type-specific manner. For example, to study desmoplastic small round cell tumor characterized by EWSR1‑WT1 translocation, Vanoli et al. developed a strategy using the combination of CRISPR‑Cas9 genome editing and homology-directed repair to select human mesenchymal stem cells containing the EWSR1‑WT1 translocation with fusion transcript expression under the control of the EWSR1 promoter and conditionally using Cre recombinase. A similar strategy was recently applied to generate conditionally inducible EWSR1‑WT1 and EWSR1‑FLI1 fusion genes in a human cell line (HEK293). This approach provides multiple advantages and expected to be a model for studying the tumors driven by chromosomal translocations [72,73]. Another group also developed a mouse model harboring conditional expression of EWS‑FLI1 fusion transcripts under the control of Prx1‑Cre, which is expressed in the primitive mesenchymal cells in the limb bud of embryo. The EWS‑FLI1;Prx1‑Cre mice showed developmental defects of the limbs without tumors. Thus, it was clearly demonstrated that EWS‑FLI1 is not able to initiate sarcoma formation by itself. Nonetheless, conditional deletion of p53 in EWS‑FLI1; p53;Prx1‑Cre triple transgenic mice produced a poorly differentiated sarcoma. These data imply that sarcomagenesis can be induced via the cooperation of EWS‑FLI1 and inactivation of the p53 tumor suppressor pathway [74]. In addition, studies using multiple behavioral and molecular analyses are required to better understand the mechanisms by which EWSR1 regulates brain and motor neuron functions. It is with great anticipation that future studies will further scrutinize and unravel new functions of EWSR1, which could be utilized to fuel new research areas in cancer, neurodegeneration and perhaps open a new field of research.
    Transparency document
    Overview Approximately one-third of soft tissue sarcomas harbor characteristic, recurrent, chromosomal translocations. These translocations are usually balanced and reciprocal and mostly associated with simple karyotypes. Chromosomal translocations involve the exchange of genetic material between 2, usually nonhomologous, chromosomes and lead to tumorigenesis via a variety of mechanisms, generating neoplasms with distinct clinical and pathologic features. Pathogenic translocations are usually initial or early steps in tumor formation; chimeric gene fusions can result in novel, tumor-specific transcription factors that lead to dysregulated gene expression, such as in Ewing sarcoma (ES), or by juxtaposition of promoter regions that drive expression of oncogenes, for example, MYC overexpression in leukemia/lymphoma. Secondary genetic or epigenetic events are required for expression of particular tumoral phenotypes, because there are significant differences in gene expression patterns between different neoplasms harboring the same fusion. Identical gene fusions can generate clinically and pathologically different neoplasms through the instigation of novel differentiation programs characteristic of the properties of their specific target cells. Although the reasons for specific gene rearrangements are not clear, a factor may be the spatial proximity between 2 given genes within the 3-dimensional chromosomal arrangement in the nucleus.2, 3