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  • UVRAG is a mammalian ortholog of yeast Vps


    UVRAG is a mammalian ortholog of yeast Vps38 and a promoter of autophagy [51,60,61]. It forms distinct complexes with BECN1 (mammalian ortholog of yeast Vps30/Atg6) and the class III phosphatidylinositol 3-kinase (whose catalytic subunit [PIK3C3] is the mammalian ortholog of yeast Vps34) and contributes to both autophagosome formation and maturation [60,62]. UVRAG suppresses cancer cell growth by promoting autophagy, its deficiency leads to decrease in autophagy and uncontrolled cell proliferation [60]. Based on the previous finding that DROSHA level is elevated by Ewsr1 deficiency, it is hypothesized that DROSHA-miRNA dependent pathway may be involved in UVRAG expression [43]. Our group found that Uvrag mRNA is inversely correlated with elevated DROSHA levels in the cytoplasm of Ewsr1 null (−/−) MEFs [59]. In addition, miRNA microarray analysis verified that mir125a and miR351 are significantly increased in Ewsr1 MEFs. Indeed, miR125a and miR351 directly target and degrade Uvrag mRNA. Moreover, Ewsr1 KO mice show that the levels of miR125a and miR351 are significantly increased, whereas the levels of UVRAG and LC3‑II (autophagy marker) are significantly reduced compared with littermate control mice. Together, the previous study suggests that EWSR1 indirectly regulates autophagy via an epigenetic modulation of UVRAG level (Fig. 4). Thus, EWSR1-mediated regulation of UVRAG and autophagy may be a potential therapeutic target for restoration of the cellular function.
    The role of EWSR1 in regulating stem cells The EWSR1 gene plays a crucial role in the regulation of stem WDR5 0103 mg and the development of a number of different tumors. During early development, Oct-4 (octamer-binding transcription factor 4), also known as POU5F1 (POU domain, class 5, transcription factor 1), that encodes a key regulator of stem cell pluripotency, is expressed to maintain the totipotent status of embryonic stem and germ cells. EWSR1 is fused to POU5F1 in hidradenoma of the skin and mucoepidermoid carcinoma of salivary glands [63]. POU5F1-mediated transactivation is stimulated by EWSR1 protein in mouse and human embryonic stem cells [6]. In 85–90% of cases, Ewing's sarcoma (ES) is characterized by the expression of the EWSR1‑FLI1 chimeric protein resulting from the chromosomal translocation, which links the transcription regulating domain of EWSR1 to the ETS DNA-binding domain of FLI1 [64]. This EWSR1‑FLI‑1 fusion oncoprotein is responsible for the transcriptional deregulation of target genes, such as the CD99 membrane receptor. Expression of CD99 contributes to the ES oncogenesis by modulating the growth and differentiation of tumor cells [65]. Also, EWSR1 is chimerically fused to DDIT3 (DNA Damage Inducible Transcript 3) by the myxoid liposarcoma-specific chromosomal translocation. Suzuki K et al. investigated the molecular mechanisms underlying EWSR1‑DDIT3 fusion protein-mediated phenotypic selection of putative target multipotent mesenchymal cells during myxoid liposarcoma development [66]. A better understanding of this mechanism is pivotal to elucidate the direct lineage reprogramming process in oncogenic sarcoma transformation mediated by EWSR1-fusion proteins [66].
    Therapeutic approaches to target EWSR1 EWSR1, EWSR1-fusion protein, EWSR1-interacting molecules, and its downstream pathways can be ideal therapeutic targets to treat ES or EWSR1-related disorders. Interestingly, transcriptional activation of protein kinase PKC‑ß (PRKCB) is directly regulated by the chimeric EWSR1‑FLI1 protein in EWS. PRKCB loss induces apoptosis in vitro and prevents tumor growth in vivo. PRKCB possesses an enzymatic activity that can be directly targeted by small compounds. Accordingly, in the perspective of therapeutic strategy, blocking PRKCB activity in EWS is a new promising approach [67]. Poly (ADP-ribose) polymerase‑1 (PARP) protein plays a role in the regulation of the cell cycle, apoptosis, and etc. It has shown that EWSR1‑ETS fusion protein could be sensitive to PARP inhibitors such as Olaparib, Veliparib, and Iniparib [68]. Trabectedin is an antitumoral agent that modulates EWSR1‑FLI1 transcriptional functions, causing DNA damage. The combination of a PARP inhibitor and Trabectedin highly inhibits proliferation and induces apoptosis in EWS cells [68]. Sanker et al. described that the Nucleosome Remodeling Deacetylase (NuRD) complex directly binds to EWS‑FLI1 oncoprotein and regulates transcriptional activity of EWS‑FLI1 target genes [68]. It has been widely known that the EWS‑FLI1 plays a driver of proliferation and transformation in ES. Daniel et al. investigated that the combination effects of the histone deacetylases inhibitor suberoylanilide hydroxamic acid (SAHA) and Lysine-specific demethylase1 inhibitor (HCI‑2509) on different biological functions in ES. The combination of SAHA and HCI‑2509 inhibits the essential driver of this sarcoma and tumor growth and is proposed as a novel treatment strategy for ES patients [69].