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  • miRNAs are known to regulate the autophagy related


    miRNAs are known to regulate the autophagy-related genes and their activities. Also, miRNAs modulate autophagy at different stages such as autophagic induction, vesicle nucleation, vesicle elongation and completion, by targeting autophagy complexes via different miRNAs [[56], [57], [58]]. Recently, although there has been plenty of evidence that miRNAs modulate autophagy, their target genes and precise roles in the autophagy pathways have not been fully defined yet. In this context, our group previously investigated whether EWSR1 plays a role in the autophagy pathway or not using Ewsr1 null (−/−) MEFs. Two novel findings were identified as follows: First, Ewsr1 deficiency up regulates microprocessor complexes and miR125a and miR351. Interestingly, EWSR1 indirectly regulates UVRAG expression at the post-transcriptional level via miR125a and miR351 [59]. Second, UVRAG dysfunction subsequently leads to an aberrant deregulation of autophagy pathway. Decreased expression levels of Uvrag mRNA and protein are correlated with the altered autophagy pathway in Ewsr1 KO (−/−) mice. 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 Anisomycin 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 cells 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].