Inhibition of the oncogenic fusion protein EWS-FLI1 causes G2-M cell cycle arrest and enhanced vincristine sensitivity in Ewings sarcoma

Ewing’s sarcoma (ES) is a rare and highly malignant cancer that grows in the bones or surrounding tissues mostly affecting adolescents and young adults. A chimeric fusion between the RNA binding protein EWS and the ETS family transcription factor FLI1 (EWS-FLI1), which is generated from a chromosomal translocation, is implicated in driving most ES cases by modulation of transcription and alternative splicing. The small-molecule YK-4-279 inhibits EWS-FLI1 function and induces apoptosis in ES cells. We aimed to identify both the underlying mechanism of the drug and potential combination therapies that might enhance its antitumor activity. We tested 69 anticancer drugs in combination with YK-4-279 and found that vinca alkaloids exhibited synergy with YK-4-279 in five ES cell lines. The combination of YK-4-279 and vincristine reduced tumor burden and increased survival in mice bearing ES xenografts. We determined that independent drug-induced events converged to cause this synergistic therapeutic effect. YK-4-279 rapidly induced G2-M arrest, increased the abundance of cyclin B1, and decreased EWS-FLI1–mediated generation of microtubule-associated proteins, which rendered cells more susceptible to microtubule depolymerization by vincristine. YK-4-279 reduced the expression of the EWS-FLI1 target gene encoding the ubiquitin ligase UBE2C, which, in part, contributed to the increase in cyclin B1. YK-4-279 also increased the abundance of proapoptotic isoforms of MCL1 and B...
Source: Signal Transduction Knowledge Environment - Category: Science Authors: Tags: STKE Research Articles Source Type: news

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Source: Asian Pacific Journal of Cancer Prevention - Category: Cancer & Oncology Tags: Asian Pac J Cancer Prev Source Type: research
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Source: Asian Pacific Journal of Cancer Prevention - Category: Cancer & Oncology Tags: Asian Pac J Cancer Prev Source Type: research
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Source: Asian Pacific Journal of Cancer Prevention - Category: Cancer & Oncology Tags: Asian Pac J Cancer Prev Source Type: research
Conclusion Astroblastoma is an extremely rare CNS tumor. Morphological diagnosis is difficult, as the typical astroblastic rosettes may be present also in other CNS tumors, including some gliomas and ependymomas. In fact, AB can be considered as a morphologic pattern, which can be associated with a spectrum of molecular entities. Total resection is the best treatment; the precise role of chemotherapy and radiotherapy is still debated, particularly for high-grade tumors. We believe that DNA-methylation profiles represents an important instrument for confirming diagnosis, predicting prognosis and better defining the molec...
Source: Frontiers in Genetics - Category: Genetics & Stem Cells Source Type: research
tsky JA Abstract Ewing's sarcoma (ES) is a rare and highly malignant cancer that grows in the bones or surrounding tissues mostly affecting adolescents and young adults. A chimeric fusion between the RNA binding protein EWS and the ETS family transcription factor FLI1 (EWS-FLI1), which is generated from a chromosomal translocation, is implicated in driving most ES cases by modulation of transcription and alternative splicing. The small-molecule YK-4-279 inhibits EWS-FLI1 function and induces apoptosis in ES cells. We aimed to identify both the underlying mechanism of the drug and potential combination therapies th...
Source: Science Signaling - Category: Biomedical Science Authors: Tags: Sci Signal Source Type: research
Objective: Ewing sarcoma (ES) is an aggressive and poorly differentiated tumor, commonly arising in adolescents and young adults. It is molecularly defined by a reciprocal translocation resulting in the fusion of EWS to an ETS transcription factor, being EWS-FLI the most common chimera. EWS-FLI1 up-regulates gene expression through the interaction with GGAA repeats, however, data obtained by depleting EWS-FLI1 revealed that more genes are down-regulated than up-regulated. A variety of repressive mechanisms have been described including the polycomb group (PcG) of proteins EZH2 and BMI1 that contribute to the epigenetic rep...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Epigenetics Source Type: research
Authors: Jacques C, Lamoureux F, Baud'huin M, Calleja LR, Quillard T, Amiaud J, Tirode F, Rédini F, Bradner JE, Heymann D, Ory B Abstract Ewing Sarcoma is a rare bone and soft tissue malignancy affecting children and young adults. Chromosomal translocations in this cancer produce fusion oncogenes as characteristic molecular signatures of the disease. The most common case is the translocation t (11; 22) (q24;q12) which yields the EWS-Fli1 chimeric transcription factor. Finding a way to directly target EWS-Fli1 remains a central therapeutic approach to eradicate this aggressive cancer. Here we demonstrate that...
Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research
Conclusion: Our results have identified a specific whole blood miRNA signature that may serve as an independent biomarker for the diagnosis of local recurrence or distant metastasis of synovial sarcoma. It even distinguishes synovial sarcoma from other sarcoma subtypes, thus potentially serving as a specific biomarker for synovial sarcoma.
Source: Molecular Cancer - Category: Cancer & Oncology Authors: Source Type: research
Conclusion: The increased risk of several cancers other than ES in ES cases and in their relatives suggests the possibility of an inherent genetic predisposition to mutagenesis that predisposes both to observed mutations and chromosomal rearrangements seen in ES cases and to additional cancers (primarily brain and prostate) in individuals who do not have ES.Citation Format: Diana Abbott, R. Lor Randall, Joshua Schiffman, Stephen Lessnick, Lisa A. Cannon-Albright. A population-based survey of excess cancers observed in Ewing's sarcoma and in their first-, second-, and third-degree relatives. [abstract]. In: Proceedings of t...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Epidemiology Source Type: research
In conclusion, a tissue engineered preclinical ES model allows scientists a unique opportunity to modulate and control key interactions between tumor cells, their adjacent microenvironment, and even heterotopic cells while simultaneously monitoring the impact of these interactions on cancer cell behavior. At the expense of reduced biological complexity, the more simplified ex vivo system is expected to shed new light on druggable targets tangent to the cells themselves, and in so doing, ultimately yield innovative therapies able to cure ES patients.Citation Format: Joseph A. Ludwig, Salah Lamhamedi Cherradi, Brian Menegaz,...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Tumor Biology Source Type: research
More News: Bone Cancers | Cancer | Cancer & Oncology | Cancer in Adolescents | Cancer in Young Adults | Environmental Health | Ewing's Sarcoma | Genetics | Sarcomas | Translocation