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Gong, H.; Xue, B.; Ru, J.; Pei, G.; Li, Y. Targeted Therapy for EWS-FLI1 in Ewing Sarcoma. Encyclopedia. Available online: https://encyclopedia.pub/entry/48154 (accessed on 07 August 2024).
Gong H, Xue B, Ru J, Pei G, Li Y. Targeted Therapy for EWS-FLI1 in Ewing Sarcoma. Encyclopedia. Available at: https://encyclopedia.pub/entry/48154. Accessed August 07, 2024.
Gong, Helong, Busheng Xue, Jinlong Ru, Guoqing Pei, Yan Li. "Targeted Therapy for EWS-FLI1 in Ewing Sarcoma" Encyclopedia, https://encyclopedia.pub/entry/48154 (accessed August 07, 2024).
Gong, H., Xue, B., Ru, J., Pei, G., & Li, Y. (2023, August 17). Targeted Therapy for EWS-FLI1 in Ewing Sarcoma. In Encyclopedia. https://encyclopedia.pub/entry/48154
Gong, Helong, et al. "Targeted Therapy for EWS-FLI1 in Ewing Sarcoma." Encyclopedia. Web. 17 August, 2023.
Targeted Therapy for EWS-FLI1 in Ewing Sarcoma
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This entry is adapted from the peer-reviewed paper 10.3390/cancers15164035

Ewing sarcoma (EwS) is a highly aggressive and metastatic cancer in children and adolescents. Canonical therapy mainly comprises the combination of intensive chemotherapy, radiation, and local surgery, which give rise to acute and chronic adverse effects. Drugs targeting EwS without side effects are in urgent demand. Genetically, EwS is characterized by chromosomal translocations with a low mutation burden. As a result, the chimeric protein EWS-ETS, mainly EWS-FLI1(85%), is critical for the malignancy of EwS. EWS-FLI1 directly binds to GGAA microsatellites in enhancers and promotors of the target genes and recruits multiple transcription factors or epigenetic regulators to reprogramme the epigenome.

ewing sarcoma EWS-FLI1 protein complex targeted therapy

1. Introduction

Ewing sarcoma (EwS) is a poorly differentiated malignancy that mainly arises in bone and soft tissue and is more prevalent among those in the second decade of life [1]. Extraosseous EwS is more common in adults [2]. The cellular origin of EwS remains controversial, although it is speculated that it arises from neuroectodermal cells or primitive mesenchymal stem cells (MSC) [3][4][5]. Despite considerable improvements in overall survival achieved using a multimodal approach, including intensive chemotherapy for localized disease [6], the prognosis of patients who develop metastatic disease or relapse remains dismal [7][8]. Approximately 20–25% of patients are diagnosed with early micro-dissemination [6][9].

2. Involvement of EWS-FLI1 in Transcription, Epigenetic Reprogramming, and Alternative Splicing in EwS

2.1. EWS-FLI1 in Transcription and Epigenetic Reprogramming

EWS-FLI1 is an aberrant transcription factor that drives cellular transformation by rewiring the epigenome to induce a large number of oncogenes. The N-terminus of EWSR1 contains a prion-like domain, characterized by an intrinsically disordered structure and low complexity. This domain has phase transition properties and manipulates multiple proteins involved in epigenome reprogramming and epigenetic alterations [10][11][12][13][14][15][16][17]. In addition to the canonical ETS-binding sites, EWS-FLI1 binds to DNA sequences at the GGAA/T core motif [18][19][20] via a conserved ETS domain. It regulates multiple proteins through its prion-like domain to tumor-specific enhancers and promotors, recruiting acetyltransferases and establishing de novo enhancers by generating H3K27ac, thus opening the chromosomal architecture, which contributes to the activation of target genes [10][11][18][20]. The EWS-FLI1 protein complex includes RNA polymerase II [21][22], the core subunit hsRBP7 (human RNA polymerase II) [23][24], E2F3 [25][26], EWSR1 [27], CBP/p300 [28], WDR5, ASH2, MLL [11], and the BAF complex (mammalian SWI/SNF complex) [10][29]. The threshold of GGAA motifs optimal for maximal expression is 20–26 [30], which differs from that in wild-type FLI1. Super-enhancer-associated MEIS1 and RING1B also contribute to the chromatin reprogramming through co-localization with EWS-FLI1 at the active enhancers to drive the malignancy of EwS [31][32]. This specific coupling results in the activation of many genes (Figure 1), such as NKX2.2 [33], NROB1 [34][35][36], IGF1R [37], BCL11B [38], EZH2 [17], VRK1 [11], GLI1 [39], PTPL1 [40], PPPR1A [41], ERG2 [42], GSTM4 [43], PAX7 [44], CHM1 [45], REST [46], PHF19 [13], STEAP1 [47][48], SLFN11(Schlafen 11) [49], HDAC3 [50], TNC [51], APCDD1 [31], IL1RAP [52][53], MYC [54], and PRC1 (protein regulator of cytokinesis 1) [55].
Figure 1. The EWS-FLI1 protein complex drives the specific transcription profile of EwS. EWS-FLI1 recruits E2F3, hsRBP7, BAF, RING1B, RHA, P300, and MEIS1, among others, to GGAA repeats and further activates CHM1, EZH2, PAX7, NKX2.2, NROB1, and STEAP1, among others. EWS-FLI1 functions as a protein complex with ERG, BAF, RHA, DDX5, and U1C to drive alternative splicing. Among the genes, the purple ones, such as CHM1, could serve as TCR-based immunotherapy targets; the red ones, such as NKX2-2, serve as diagnostic markers in clinic diagnosis. EWS/FLI1 recruits LSD1 and unknown transcription factors (?) to repress TGFBR1 and IGFBP3, which still needs further research.
Among the direct targets of EWS-FLI1, NKX2-2 mediates oncogenic transformation via transcriptional repression and is necessary and sufficient for the oncogenic phenotype of EwS [56]. Further work demonstrates that NKX2-2, KLF15, and TCF4 occupy similar super-enhancers and promoters, forming an inter-connected auto-regulatory loop and occupying 77.2% of promoters and 55.6% of enhancers shared with EWS-FLI1 [57], such as STEAP1 [58]; this kind of coordinate regulation drives the proliferation of EwS. NROB1 directly interacts with EWS-FLI1 to modulate multiple gene expressions and mediate the oncogenic phenotype of EwS [59]. SLFN11 is a putative DNA/RNA helicase that recruits to the stressed replication fork and irreversibly triggers replication block and cell death. Overexpression of SLFN11 is associated with resistance to topoisomerase I inhibitors and poly (ADP-ribose) polymerase (PARP) inhibitor combinations [49][60]. STEAP1 and IL1RAP are vital for the redox homeostasis of EwS [47][52]. APCDD1, PHF19, GSTM4, and PTPL1 are genes that are involved in the proliferation of EwS.
EWS-FLI1 is also involved in transcriptional repression of tumor suppressors such as IGFBP3 [61] and PHLDA1 [35] to drive oncogenic transformation [12][62]. The nucleosome remodeling and deacetylase (NuRD) complex is a typical ATP-dependent chromatin remodeling complex [63] that plays a critical role in transcription and determines differentiation and development [64]. EWS-FLI1 recruits the NuRD-LSD1 complex to repress LOX and TGFBR2 [62][65]. It also affects the transcriptional activation of AP-1 [14] and MRTFB [66] and binds to the promotor of FOXO1 to repress its expression, thereby increasing tumor growth [67]. EWS-FLI1 promotes the phosphorylation of cyclin-dependent kinase-2 and AKT to inhibit the activity of FOXO1, thus rewiring transcriptional repression [67]. EWS-FLI1 is also involved in the regulation of microRNAs (miRNAs) [68]. It downregulates miRNA-145 to initiate mesenchymal stem-cell reprogramming toward EwS stem cells [69] and represses miR-708, which induces the overexpression of EYA3 and contributes to the chemoresistance to etoposide and doxorubicin [70].
The histone methyltransferase EZH2 exhibits silencing activity via methylation of H3K27 [71]. In EwS, EWS-FLI1 upregulates EZH2 expression by interacting with the EZH2 promoter, thereby promoting tumor growth/metastasis and blocking endothelial/neuro-ectodermal differentiation [17].
MiR-34a inhibits the proliferation and increases the sensitivity of EwS to doxorubicin and vincristine and is a strong predictor of a favorable prognosis in EwS [72]. However, the exact mechanism underlying its downregulation remains elusive. Exportin 5 (XPO5), which mediates the nuclear export of pre-miRNAs and short hairpin RNAs [73][74][75], interacts with EWS-FLI1 based on mass spectrometry [76]. XPO5 is highly expressed in various cancers including EwS. Furthermore, the phosphorylation of XPO5 alters the nucleus and cytoplasm shift [77]. Investigating XPO5 and its relationship with EWS-FLI1 may offer new insights into the therapy of EwS. Post-translational modifications of EWS-FLI1 modulate its transcriptional activity. Phosphorylation and O-GlcNAcylation of the N-terminus of EWSR1 [78][79][80], as well as acetylation of the C-terminal FLI1 domain by PCAF (KAT2B, lysine acetyltransferase 2B), enhance the transcriptional activity of EWS-FLI1 [81]. However, PCAF expression is lower in EwS tissues, which is a common feature of cancer.

2.2. EWS-FLI1 in Alternative Splicing

Pre-mRNA splicing is critical for gene expression, and most protein-encoding transcripts are alternatively spliced to provide diverse functions [82][83]. The N-terminus of EWSR1 interacts with the hyperphosphorylated RNA polymerase II and recruits serine-arginine (SR) through its C-terminus. After chromosome translocation, the C-terminus of wild-type EWSR1 is replaced by FLI1, which hinders the recruitment of SR-splicing factors and interferes with mRNA splicing [21], thus demonstrating the negative property of this chimeric protein [84]. This leads to comprehensive alternative splicing of numerous genes. Meanwhile, EWS-FLI1 interacts with the splicing components (snRNP) U1C and SF1 to modulate pre-mRNA splicing [85]. It also recruits the BAF complex to drive the alternative splicing of ARID1A and the preferential splicing of ARID1A-L, which is necessary for tumor growth [86]. Work by Selvanathan [76] demonstrates that EWS-FLI1 is involved in the alternative splicing of CLK1, CASP3, PPFIBP1, and TERT, which potentially regulate the oncogenesis of EwS.

3. The Regulation of EWS-FLI1

Transcription and post-transcriptional modifications are involved in the regulation of expression and activity of EWS-FLI1. Although the transcriptional regulation of EWS-FLI1 remains elusive, the BRD4 inhibitor JQ1 suppresses this activity [13][15][87]. HDAC6 deacetylates specificity protein 1 (SP1), thereby inhibiting the recruitment of the SP1/P300 complex to the promoters of EWSR1 and EWS-FLI1 and downregulating EWS-FLI1 [88]. MiR-145 and let-7 repress EWS-FLI1 by targeting its mRNA [69][89][90][91] and inhibit the proliferation of EwS. The RNA-binding protein LIN28B interacts with EWS-FLI1 transcripts to maintain the stability and ensure the expression of EWS-FLI1 to enhance the tumorigenicity of the self-renewal of EwS [90]. At the post-transcriptional level, EWS-FLI1 degradation is proteasome dependent, and the protein has a half-life of 2–4 h [92]. This process can be protected by the action of ubiquitin-specific protease 19 (USP19) at the N-terminus [93] and accelerated by tripartite-motif-containing 8 (TRIM8) at K334 [94]; however, USP19 is expressed at low levels in EwS. Casein kinase 1 (CK1)-mediated phosphorylation of the VTSSS degron in the FLI1 domain activates speckle-type POZ protein (SPOP) activity, which degrades EWS-FLI1. In contrast, OTU-domain-containing protein 7A (OTUD7A) participates in the deubiquitination of the C-terminus and stabilizes EWS-FLI1 [95]. The inhibitor of chromosomal maintenance 1 (CRM1 and XPO1), KPT-330 [96], and IFN-γ [97] suppress expression of EWS-FLI1 at the protein level. FOXM1, a downstream factor of EWS-FLI1, upregulates its expression [98]. Cytosine arabinoside (ARA-C) downregulates EWS-FLI1 at the protein level and inhibits tumor growth [99]; however, it shows hematologic toxicity and minimal activity in patients [100].
STAG2 (stromal antigen 2) is a core subunit of the cohesion complex and is frequently mutated in multiple cancers [101] including EwS [102][103]. Mutation of STAG2 in EwS is associated with poor outcomes by improving metastasis [102]. Mechanically, in addition to the disruption of PRC2-mediated regulation of gene expression in EwS [104], the inactivation of STAG2 strongly altered CTCF-anchored loop extrusion and decreases promotor-enhancer interactions. As a result, the cis-mediated EWS-FLI1 activity at GGAA microsatellite neo-enhancers is downregulated and the cells are enhanced in their migration and invasion properties [104][105].
Unlike STAG2, there was no evidence showing mutations of the ETS transcription factor ETV6 in EwS [106]. ETV6 does not change the expression of EWS-FLI1 but co-occupy loci genome wide at the short consecutive GGAA repeats and constrains the transcriptional activity of EWS-FLI1 [107][108]. Upon inactivating ETV6, EWS-FLI1 overtakes and activates these cis-elements to promote mesenchymal differentiation by upregulating the expression of SOX11 [108].

4. CAR-T Therapy

Unlike TCR-based T-cell therapy, which is limited to specific HLA restriction and deficient HLA expression in EwS [109] because of the presence of myeloid-derived suppressor cells, F2 fibrocytes, and M2-like macrophages in the microenvironment [110], CAR-engineered T-cell therapy can target specific cell-surface antigens in tumors, independent of HLA. VEGFR2 is a potential target for CAR-T-cell therapy in EwS [111]. In addition to TCR-T-cells, CAR-T-cells [112] can target STEAP1, which is involved in the malignant phenotype of EwS [47].
CAR-T targeting GPR64, ROR1, and IGF1R, which are highly expressed in EwS [113][114], leads to a selective killing of EwS in vivo [115]. LINGO1, which is highly expressed in EwS [116], is a direct target of EWS-FLI1. EZH2 inhibition by GSK-126 induces GD2 surface expression in EwS [117], and the combination of CAR-T therapy targeting GD2 and EZH2 inhibitors have synthetic cytotoxic in the treatment of EwS; this kind of combination provides new options for the clinical application. IL1RAP, a direct target of EWS-FLI1, is highly expressed in EwS, but minimally expressed in normal tissues, which makes it a promising surface target for EwS [52] and a potential candidate for advanced CAR-T therapy. ICAM-1 can promote tumor cell/T-cell interaction and T-cell activation, and the knockdown of EWS-FLI1 upregulates ICAM-1 expression and leads to the upregulation of PD-L1 and PD-L2, both proteins that inhibit the activity of T-cells [97]. Blocking PD-1 with a checkpoint inhibitor could increase the T-cell-mediated killing of EwS cells with low expression of EWS-FLI1.

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Helong Gong
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Busheng Xue
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Guoqing Pei
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Yan Li
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