GLI1 Is a Central Mediator of EWS/FLI1 Signaling in Ewing Tumors

Abstract

The Ewing Sarcoma Family Tumors (ESFT) consist of the classical pathologic entities of Ewing Sarcoma and peripheral Primitive Neuroectodermal Tumor. Occurring largely in the childhood through young adult years, these tumors have an unsurpassed propensity for metastasis and have no defined cell of origin. The biology of these aggressive malignancies centers around EWS/FLI1 and related EWS/ETS chimeric transcription factors, which are largely limited to this tumor class. Much progress has been made in the identification of a network of loci whose expression is modulated by EWS/FLI1 and its congeners. To date, little progress has been made in reconstructing the sequence of direct and indirect events that produce this network of modulated loci. The recent identification of GLI1 as an upregulated target of EWS/ETS transcription factors suggests a target which may be a more central mediator in the ESFT signaling network. In this paper, we further define the relationship of EWS/FLI1 expression and GLI1 upregulation in ESFT. This relationship is supported with data from primary tumor specimens. It is consistently observed across multiple ESFT cell lines and with multiple means of EWS/FLI1 inhibition. GLI1 inhibition affects tumor cell line phenotype whether shRNA or endogenous or pharmacologic inhibitors are employed. As is seen in model transformation systems, GLI1 upregulation by EWS/FLI1 appears to be independent of Hedgehog stimulation. Consistent with a more central role in ESFT pathogenesis, several known EWS/FLI1 targets appear to be targeted through GLI1. These findings further establish a central role for GLI1 in the pathogenesis of Ewing Tumors.

Arsenic trioxide inhibits human cancer cell growth and tumor development in mice by blocking Hedgehog/GLI pathway

“…Our prior investigations, along with publications by other groups, have established GLI1 as an important transcription factor for ESFT tumorigenesis (15)(16)(17). GLI activation as a downstream target of the Hh pathway has been actively studied in tumors with constitutively activated Smoothened (caused by PTCH1 mutation or loss), such as BCC and medulloblastoma.…”

“…Additionally, we and others have previously shown that GLI1 modulates Ewing sarcoma family of tumors (ESFT) carcinogenesis as a direct transcriptional target of Ewing sarcoma breakpoint region 1-Friend leukemia virus integration 1 (EWS-FLI1; refs. [15][16][17]. Therefore, a novel therapy targeted to GLI would be beneficial for a wide spectrum of patients whose tumors have high GLI protein levels with an intact Patched/Smoothened axis.…”

Ewing sarcoma EWS protein regulates midzone formation by recruiting Aurora B kinase to the midzone

“…1,[3][4][5][6][7] The most well defined function of EWS/FLI1 is the transcriptional misregulation of target genes. 2,[8][9][10][11][12][13][14] The interaction between RNA helicase A and EWS/ FLI1 enhances EWS/FLI1-dependent transcriptional activity. 15,16 EWS/FLI1 also regulates a subgroup of miRNAs that specifically regulate the IGF pathway.…”

Englerin A Inhibits EWS-FLI1 DNA Binding in Ewing Sarcoma Cells

“…4A). This activity profile was suggestive of changes in Ca 2ϩ homeostasis and/or signaling (23)(24)(25)(26). Interestingly, previous high throughput screens aimed at identifying inhibitors of Fli-1 in leukemia led to the identification of calcium ionophores including calcimycin and thapsigargin as hits (27).…”