EWS-FLI1 regulates and cooperates with core regulatory circuitry in Ewing sarcoma

Shi, Xianping; Zheng, Yueyuan; Jiang, Liling; Zhou, Bo; Yang, Wei; Li, Liyan; Ding, Ling-Wen; Huang, Moli; Gery, Sigal; Lin, De–Chen; Koeffler, H. Phillip

doi:10.1093/nar/gkaa901

Cited by 21 publications

(19 citation statements)

References 73 publications

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“…This model is very plausible as NKX2.2 is a core circuitry complex component and has a proven co-regulatory role in pancreatic cells [ 33 ]. Our findings are further supported by a recent report showing that EWSFLI1 regulates and cooperates with core regulatory circuitry (CRC)-dependent transcriptional networks in ES [ 62 ]. Shi et al in their recent work indicated that NKX2.2, upon upregulation, binds to its own promoter, super-enhancers, and the promoters of KLF15 and TCF4 to form an interconnected autoregulatory loop [ 62 ].…”

Section: Discussionsupporting

confidence: 88%

“…Our findings are further supported by a recent report showing that EWSFLI1 regulates and cooperates with core regulatory circuitry (CRC)-dependent transcriptional networks in ES [ 62 ]. Shi et al in their recent work indicated that NKX2.2, upon upregulation, binds to its own promoter, super-enhancers, and the promoters of KLF15 and TCF4 to form an interconnected autoregulatory loop [ 62 ]. Our work confirms for the first time that NKX2.2 occupies proximal sites on the STEAP1 promoter, known to be regulated by EWSFLI1.…”

Section: Discussionsupporting

confidence: 88%

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Identification of a New Transcriptional Co-Regulator of STEAP1 in Ewing’s Sarcoma

Markey

Romero

Parashar

et al. 2021

Cells

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Ewing’s sarcoma (ES) is caused by a chromosomal translocation leading to the formation of the fused EWSFLI1 gene, which codes for an aberrant transcription factor EWSFLI1. The transcriptional targets of EWSFLI1 have been viewed as promising and novel drug targets in the treatment of ES. One such target is six transmembrane epithelial antigen of the prostate 1 (STEAP1), a transmembrane protein that is upregulated by EWSFLI1 in ES. STEAP1 is a hallmark of tumor invasiveness and an indicator of tumor responsiveness to therapy. EWSFLI1 binds to the STEAP1 promoter region, but the mechanism of action by which it upregulates STEAP1 expression in ES is not entirely understood. Upon analysis of the STEAP1 promoter, we predicted two binding sites for NKX2.2, another crucial transcription factor involved in ES pathogenesis. We confirmed the interaction of NKX2.2 with the STEAP1 promoter using chromatin immunoprecipitation (ChIP) analysis. We used single-molecule RNA imaging, biochemical, and genetic studies to identify the novel role of NKX2.2 in regulating STEAP1 expression in ES. Our results show that NKX2.2 is a co-regulator of STEAP1 expression and functions by interacting with the STEAP1 promoter at sites proximal to the reported EWSFLI1 sites. The co-operative interaction of NKX2.2 with EWSFLI1 in regulating STEAP1 holds potential as a new target for therapeutic interventions for ES.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 88%

Identification of a New Transcriptional Co-Regulator of STEAP1 in Ewing’s Sarcoma

Markey

Romero

Parashar

et al. 2021

Cells

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“…NR0B1 have been associated with the tumor phenotype mediated by EWS/FLI chimera in cell lines [ 38 ]. NKX2–2, a homeodomain transcription factor involved in neuroendocrine/glial differentiation and a downstream target of EWSR1-FLI1, has been reported as an immunohistochemical marker for Ewing sarcoma [ 39 ]. We identified both NR0B1 and NKX2-2 as MRs in our analysis.…”

Section: Discussionmentioning

confidence: 99%

Reverse Engineering of Ewing Sarcoma Regulatory Network Uncovers PAX7 and RUNX3 as Master Regulators Associated with Good Prognosis

Dantas

Imparato

Dalmolin³

et al. 2021

Cancers

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Ewing Sarcoma (ES) is a rare malignant tumor occurring most frequently in adolescents and young adults. The ES hallmark is a chromosomal translocation between the chromosomes 11 and 22 that results in an aberrant transcription factor (TF) through the fusion of genes from the FET and ETS families, commonly EWSR1 and FLI1. The regulatory mechanisms behind the ES transcriptional alterations remain poorly understood. Here, we reconstruct the ES regulatory network using public available transcriptional data. Seven TFs were identified as potential MRs and clustered into two groups: one composed by PAX7 and RUNX3, and another composed by ARNT2, CREB3L1, GLI3, MEF2C, and PBX3. The MRs within each cluster act as reciprocal agonists regarding the regulation of shared genes, regulon activity, and implications in clinical outcome, while the clusters counteract each other. The regulons of all the seven MRs were differentially methylated. PAX7 and RUNX3 regulon activity were associated with good prognosis while ARNT2, CREB3L1, GLI3, and PBX3 were associated with bad prognosis. PAX7 and RUNX3 appear as highly expressed in ES biopsies and ES cell lines. This work contributes to the understanding of the ES regulome, identifying candidate MRs, analyzing their methilome and pointing to potential prognostic factors.

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“…Zhang was recently the first to study SE-associated CRC transcriptional control in lung adenocarcinoma: master TFs ELF3 , EHF , and TGIF1 were found to co-occupy the SE region and promote each other’s expression through the formation of CRC, which induces the malignant progression of lung adenocarcinoma [ 109 ]. Similarly, in Ewing sarcoma, KLF15 , TCF4 , and NKX2–2 have been identified as the master TFs containing both EWS-FLI1 binding motif and SE peaks [ 110 ]. Importantly, these three CRC TFs co-regulate the PI3K/AKT and MAPK signaling pathways to promote the aggressiveness of Ewing sarcoma [ 110 ].…”

Section: Structures and Functions Of Sesmentioning

confidence: 99%

“…Similarly, in Ewing sarcoma, KLF15 , TCF4 , and NKX2–2 have been identified as the master TFs containing both EWS-FLI1 binding motif and SE peaks [ 110 ]. Importantly, these three CRC TFs co-regulate the PI3K/AKT and MAPK signaling pathways to promote the aggressiveness of Ewing sarcoma [ 110 ].…”

Section: Structures and Functions Of Sesmentioning

confidence: 99%

Super-enhancers: a new frontier for epigenetic modifiers in cancer chemoresistance

et al. 2021

J Exp Clin Cancer Res

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Although new developments of surgery, chemotherapy, radiotherapy, and immunotherapy treatments for cancer have improved patient survival, the emergence of chemoresistance in cancer has significant impacts on treatment effects. The development of chemoresistance involves several polygenic, progressive mechanisms at the molecular and cellular levels, as well as both genetic and epigenetic heterogeneities. Chemotherapeutics induce epigenetic reprogramming in cancer cells, converting a transient transcriptional state into a stably resistant one. Super-enhancers (SEs) are central to the maintenance of identity of cancer cells and promote SE-driven-oncogenic transcriptions to which cancer cells become highly addicted. This dependence on SE-driven transcription to maintain chemoresistance offers an Achilles’ heel for chemoresistance. Indeed, the inhibition of SE components dampens oncogenic transcription and inhibits tumor growth to ultimately achieve combined sensitization and reverse the effects of drug resistance. No reviews have been published on SE-related mechanisms in the cancer chemoresistance. In this review, we investigated the structure, function, and regulation of chemoresistance-related SEs and their contributions to the chemotherapy via regulation of the formation of cancer stem cells, cellular plasticity, the microenvironment, genes associated with chemoresistance, noncoding RNAs, and tumor immunity. The discovery of these mechanisms may aid in the development of new drugs to improve the sensitivity and specificity of cancer cells to chemotherapy drugs.

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EWS-FLI1 regulates and cooperates with core regulatory circuitry in Ewing sarcoma

Cited by 21 publications

References 73 publications

Identification of a New Transcriptional Co-Regulator of STEAP1 in Ewing’s Sarcoma

Identification of a New Transcriptional Co-Regulator of STEAP1 in Ewing’s Sarcoma

Reverse Engineering of Ewing Sarcoma Regulatory Network Uncovers PAX7 and RUNX3 as Master Regulators Associated with Good Prognosis

Super-enhancers: a new frontier for epigenetic modifiers in cancer chemoresistance

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