Dependence of PAX3-FOXO1 chromatin occupancy on ETS1 at important disease-promoting genes exposes new targetable vulnerability in Fusion-Positive Rhabdomyosarcoma DOI Creative Commons
Joseph Hsieh, Etienne Danis, Charles R. Owens

et al.

Oncogene, Journal Year: 2024, Volume and Issue: 44(1), P. 19 - 29

Published: Oct. 24, 2024

Abstract Rhabdomyosarcoma (RMS), a malignancy of impaired myogenic differentiation, is the most common soft tissue pediatric cancer. PAX3-FOXO1 oncofusions drive majority clinically more aggressive fusion-positive rhabdomyosarcoma (FP-RMS). Recent studies have established an epigenetic basis for PAX3-FOXO1-driven oncogenic processes. However, details mechanisms, including interactions with, and dependence on, other chromatin transcription factors, are incompletely understood. We previously identified novel disease-promoting axis in RMS, involving histone demethylase KDM3A ETS1 factor, demonstrated that this interfaces with both phenotypically transcriptomically, co-regulation biological processes genes important to FP-RMS progression. In study, we demonstrate colocalize enhancers FP-RMS, FGF8, IL4R, MEST, as well PODXL, which define herein new FP-RMS-promoting gene. show ETS1, induced by KDM3A, exists complex PAX3-FOXO1, augments occupancy. further PAX3-FOXO1/ETS1 can be disrupted relevant small molecule inhibitor YK-4-279. YK-4-279 displaces from interferes PAX3-FOXO1-dependent gene regulation, resulting potent inhibition growth invasive properties along downregulation MEST PODXL expression. additionally that, some also increases levels. Together, our illuminate mechanisms action KDM3A/ETS1 regulatory module, reveal targetable FP-RMS.

Language: Английский

DHX9 helicase impacts on splicing decisions by modulating U2 snRNP recruitment in Ewing sarcoma cells DOI Creative Commons
Valentina Frezza, Lidia Chellini, Veronica Riccioni

et al.

Nucleic Acids Research, Journal Year: 2025, Volume and Issue: 53(4)

Published: Jan. 30, 2025

Ewing sarcomas (ESs) are biologically aggressive tumours of bone and soft tissues caused by chromosomal translocations yielding in-frame fusion proteins driving the neoplastic transformation. The DNA/RNA helicase DHX9 is an important regulator cellular processes often deregulated in cancer. Using transcriptome profiling, our study reveals cancer-relevant genes whose splicing modulated DHX9. Immunodepletion experiments demonstrate that impacts on recruitment U2 small nuclear RNP (snRNP) onto pre-mRNA. Analysis structure sequence features target exons reveal DHX9-sensitive display shorter flanking introns contain HNRNPC TIA1 consensus motifs. A prominent exon 11 Cortactin (CTTN) gene, which alternatively spliced to generate isoforms with different activities cell migration tumour invasion. Alternative inclusion CTTN gene one most recurrent isoform switches multiple cancer types, thus highlighting pivotal role defining phenotype. Biochemical analyses binding promotes U2snRNP, SF3B1, SF3A2 splice sites 11. These findings uncover a new control co-transcriptional ES, may represent druggable counteract ES malignancy.

Language: Английский

Citations

0
Targeting friend leukemia integration 1: A promising approach for prevention and treatment of solid tumors DOI
Moumita Kundu, Ankita Dey, Pradipta Maji

et al.

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: 309, P. 143080 - 143080

Published: April 12, 2025

Language: Английский

Citations

0
Oncogenic Fusions Harboring ETS Genes: Exploring Novel Targetable Opportunities in Prostate Cancer DOI Open Access

Federica De Cecco,

Lidia Chellini, Veronica Riccioni

et al.

Cancers, Journal Year: 2025, Volume and Issue: 17(10), P. 1657 - 1657

Published: May 14, 2025

Chromosomal rearrangements are implicated in the pathogenesis of several human malignancies, but, concurrently, they also represent targetable opportunities, as exemplified by imatinib (Gleevec), which targets BCR-ABL gene fusion myeloid leukemia. In prostate cancer, chromosomal have been identified, most them involving ETS genes, encode key transcription factors. this review, we explore discovery 5′ partners that classify fusions into distinct groups based on specificity and androgen responsiveness. Furthermore, try to address relationship between status patient outcomes discuss possibility using prostate-specific targeting cancer detection, stratification, treatment.

Language: Английский

Citations

0
Targeting the EphA2 pathway: could it be the way for bone sarcomas? DOI Creative Commons
G Giordano,

Cristina Tucciarello,

Alessandra Merlini

et al.

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: Sept. 9, 2024

Language: Английский

Citations

2
Pharmacological targeting of P300/CBP reveals EWS::FLI1-mediated senescence evasion in Ewing sarcoma DOI Creative Commons

Erdong Wei,

Ana Mitanoska,

Quinn O'Brien

et al.

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: Oct. 5, 2024

Language: Английский

Citations

2
Xanthohumol overcomes osimertinib resistance via governing ubiquitination-modulated Ets-1 turnover DOI Creative Commons
Ying Ma, Ruirui Wang, Jinzhuang Liao

et al.

Cell Death Discovery, Journal Year: 2024, Volume and Issue: 10(1)

Published: Oct. 28, 2024

Abstract Non-small cell lung cancer (NSCLC) is a prevalent and fatal malignancy with significant global impact. Recent advancements have introduced targeted therapies like tyrosine kinase inhibitors (TKIs) such as osimertinib, which improved patient outcomes, particularly in those EGFR mutations. Despite these advancements, acquired resistance to TKIs remains challenge. Hence, one of the current research priorities understanding mechanisms identifying new therapeutic targets improve efficacy. Herein, we identified high expression c-Met osimertinib-resistant NSCLC cells, depletion significantly inhibited proliferation cells prolonged survival mice, suggesting an attractive target. To identify effective anti-tumor agents targeting c-Met, screened compound library containing 641 natural products found that only xanthohumol exhibited potent inhibitory effects against cells. Moreover, combination treatment osimertinib sensitized both vitro vivo. Mechanistically, disrupted interaction between USP9X Ets-1, phosphorylation Ets-1 at Thr38, promoting its degradation, thereby Ets-1/c-Met signaling axis inducing intrinsic apoptosis Overall, highlights critical role address NSCLC. By demonstrating efficacy overcoming enhancing this study provides valuable insights potential strategies for improving clinical management

Language: Английский

Citations

1
A novel combination of CDK4/6 and PI3K inhibitors exhibits highly synergistic activity and translational potential in Ewing sarcoma. DOI

Maria Ana Isabel C. De Los Santos,

Helen F. Gloege,

Min Shen

et al.

Published: Oct. 17, 2024

Abstract Ewing sarcoma is a highly aggressive solid malignancy affecting children and young adults. driven primarily by EWSR1::FLI1, fusion oncoprotein that has been notoriously difficult to target with traditional pharmacologic agents. There are numerous examples of preclinical promising combinations small molecules never tested in pediatric clinical trials because agents fail reach the market due limited efficacy for common adult cancers. Moreover, effectiveness single-agent therapies cancer treatment often limited. To address these limitations, we selected 28 compounds were largely FDA approved or late stages development known regulate important pathways sarcoma. We performed drug screen cell lines 180 tyrosine kinase inhibitors, cycle conventional chemotherapy. The results revealed PI3K inhibitor, copanlisib, combined CDK4/6 ribociclib, exhibited strong synergistic anti-Ewing activity. Using proteomic methods such as reverse-phase protein array western immunoblotting, demonstrated this combination induced downregulation PI3K/AKT pathway well proteins involved regulation. further confirmed vitro data using bulk RNA-sequencing. evaluate phenotypic effect PI3K/CDK4/6 inhibition lines, apoptosis analyses flow cytometry ribociclib G0/G1 arrest minimal on viability but significantly enhanced apoptotic copanlisib treatment. In xenograft model sarcoma, therapy prolonged survival compared either vehicle alone. Our findings identify new candidate FDA-approved drugs provide resource additional potential future validation. Statement translational relevance Treatment patients newly diagnosed involves intensive multi- agent chemotherapy, radiation, surgery, leading long-term toxicities. Children relapsed metastatic disease experience poor outcomes five-year overall rates only 15 30 percent. Therefore, therapeutic approaches urgently needed. several activity including inhibitor ribociclib. This also improved mouse Pre-clinical validation composed two FDA- nominates early phase refractory group greatly need opportunities. generated our may be used other therapies.

Language: Английский

Citations

0
Dependence of PAX3-FOXO1 chromatin occupancy on ETS1 at important disease-promoting genes exposes new targetable vulnerability in Fusion-Positive Rhabdomyosarcoma DOI Creative Commons
Joseph Hsieh, Etienne Danis, Charles R. Owens

et al.

Oncogene, Journal Year: 2024, Volume and Issue: 44(1), P. 19 - 29

Published: Oct. 24, 2024

Abstract Rhabdomyosarcoma (RMS), a malignancy of impaired myogenic differentiation, is the most common soft tissue pediatric cancer. PAX3-FOXO1 oncofusions drive majority clinically more aggressive fusion-positive rhabdomyosarcoma (FP-RMS). Recent studies have established an epigenetic basis for PAX3-FOXO1-driven oncogenic processes. However, details mechanisms, including interactions with, and dependence on, other chromatin transcription factors, are incompletely understood. We previously identified novel disease-promoting axis in RMS, involving histone demethylase KDM3A ETS1 factor, demonstrated that this interfaces with both phenotypically transcriptomically, co-regulation biological processes genes important to FP-RMS progression. In study, we demonstrate colocalize enhancers FP-RMS, FGF8, IL4R, MEST, as well PODXL, which define herein new FP-RMS-promoting gene. show ETS1, induced by KDM3A, exists complex PAX3-FOXO1, augments occupancy. further PAX3-FOXO1/ETS1 can be disrupted relevant small molecule inhibitor YK-4-279. YK-4-279 displaces from interferes PAX3-FOXO1-dependent gene regulation, resulting potent inhibition growth invasive properties along downregulation MEST PODXL expression. additionally that, some also increases levels. Together, our illuminate mechanisms action KDM3A/ETS1 regulatory module, reveal targetable FP-RMS.

Language: Английский

Citations

0