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Targeting Ewing sarcoma cells via small molecule YK-4-279 treatment and downregulation of DHX9 helicase

ABSTRACT: Targeting Ewing sarcoma cells via small molecule YK-4-279 treatment and downregulation of DHX9 helicase

PROVIDER: PRJNA884647 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21722256_1.fastq.gz	Fastqsanger.gz
	SRR21722256_2.fastq.gz	Fastqsanger.gz
	SRR21722257_1.fastq.gz	Fastqsanger.gz
	SRR21722257_2.fastq.gz	Fastqsanger.gz
	SRR21722258_1.fastq.gz	Fastqsanger.gz

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Targeting Ewing sarcoma cells via small molecule YK-4-279 treatment and downregulation of DHX9 helicase

Project description:To investigate the function of DHX9 in Ewing sarcoma cell growth and proliferation, we targeted DHX9 gene by shRNA or EWS_FLI1/DHX9 interaction by YK-4-279 treatment.

2025-02-19 | GSE214257 | GEO

Characterization of Ewing sarcoma resistance to the EWS-FLI1 inhibitor YK-4-279

Project description:Ewing sarcoma (ES) is the second most common pediatric malignancy of the bones and soft tissue, but few advances in therapeutic options have been made over the past several decades. A characteristic feature of ES that and an attractive therapeutic targets is the EWS-FLI1 fusion protein. A small molecule inhibitor of EWS-FLI1, YK-4-279 was as a targeted therapy option for Ewing sarcoma patients. A YK-4-279 analog, TK216, is currently in clinical trial. With any targeted therapy, there is always the risk that tumors will become resistant and stop responding to treatment. Here, we investigated resistance mechanisms to YK-4-279 (YK) by developing ES cell lines specifically resistant to YK. We found that expression of the cell surface protein CD99 was elevated in YK-resistant cells. Increased CD99 expression occurs within five days of YK treatment in vivo. When CD99 expression is reduced by shRNA, resistant cells regain sensitivity to YK but reducing CD99 expression in non-resistant cells does not affect sensitivity. Little is known about CD99 function in the context of Ewing sarcoma, but the data presented here indicates the function of CD99 is altered upon acquisition of YK resistance, and that CD99 serves a critical function in developed resistance to YK-4-279. RNA sequencing analysis yielded candidate genes that may also be involved in the YK resistance mechanism. We identified a potential modulator of CD99 function, ANO1, a member of the ANO family and a participant in membrane-bound ion channel activity. CD99 has previously been linked with membrane-associated ion channels. A functional association between the two proteins remains to be investigated.

2020-03-21 | GSE132762 | GEO

The ETS inhibitor YK-4-279 suppresses thyroid cancer progression independent of TERT promoter mutations

Project description:Hotspot mutations in the core promoter region of the telomerase reverse transcriptase (TERT) gene have been well established to associate with aggressive clinical characteristics, radioiodine refractory, tumor recurrence and mortality in thyroid cancer. Several E-twenty-six (ETS) transcription factors were reported to selectively bound to the mutant TERT promoter and activated TERT expression. In this study we aimed to investigate whether TERT promoter mutations confer sensitivity to ETS inhibitor YK-4-279 in thyroid cancer cells and whether this inhibitor could be served as a potential therapeutic agent for thyroid cancer. In vitro assays showed that YK-4-279 treatment sharply suppressed cell viability, colony formation, migration and invasion, as well as induced cell cycle arrest and apoptosis in a panel of thyroid cancer cells. The cell viability after YK-4-279 treatment were similar between cell lines harboring mutant and wild-type TERT promoter. Furthermore, YK-4-279 treatment reduced both luciferase activity and mRNA expression of TERT independent of TERT promoter mutation status. Data from RNA-seq further revealed that YK-4-279 significantly affected biological processes including DNA replication and cell cycle. Reduced DNA helicase activity and decreased expression of several helicase genes were observed after YK-4-279 treatment. Moreover, YK-4-279 significantly inhibited tumor growth and induced apoptosis in a xenograft mice model. Thus, ETS inhibitor YK-4-279 suppressed TERT expression and conferred anti-tumor activity in a TERT promoter mutation-independent manner, and it could be a potential agent for the treatment of advanced thyroid cancers.

2021-04-06 | GSE171473 | GEO

Gene expression changes between sensitive and YK-4-279-resistant Ewing's Sarcoma cell lines

2014-09-04 | GSE61042 | GEO

Tumor Cell Survival Dependence on the DExH-Box Helicase DHX9

Project description:The ATP-dependent DExH/D-box helicase DHX9 is a key participant in a number of gene regulatory steps, including transcriptional, translational, microRNA-mediated control, DNA replication, and maintenance of genomic stability. DHX9 has also been implicated in maintenance of the tumorigenic process and in drug response. Here, we report that inhibition of DHX9 expression is lethal to multiple human and mouse cancer cell lines. In contrast, using a novel conditional shDHX9 mouse model, we demonstrate that sustained and prolonged suppression of DHX9 is well tolerated at the organismal level. Our results demonstrate a robust tolerance for DHX9 knockdown in non-transformed cells and supports the targeting of DHX9 as an effective and specific chemotherapeutic approach. Comparison of gene expression in large intestine of mice with or without reduced expression of DHX9.

2016-05-19 | E-GEOD-76765 | biostudies-arrayexpress

Gene expression changes between sensitive and YK-4-279-resistant Ewing's Sarcoma cell lines

Project description:Microarray gene expression analysis conducted from cell lines in each of three cohorts: (1) Resistant ES cell lines, (2) Sensitive parental ES cell lines treated with YK-4-279 for 72 hours, and (3) untreated sensitive parental ES cell lines (Three replicates from TC32 & TC71 original parental cell lines) We used microarrays to detail the global programme of gene expression underlying mechanism of resistance to YK-4-279 within parental sensitive and resistant selected Ewing's Sarcoma cell lines. We identified distinct classes of up-regulated genes during this process. Total RNA was extracted from the cell lines using the Qiagen miRNeasy Mini kit. RNA quality was assessed to have an RNA integrity number before amplification and labeling using AffymetrixM-bM-^@M-^Ys GeneChip GeneChipM-BM-.3M-bM-^@M-^Y IVT Express Kit following manufacturerM-bM-^@M-^Ys instructions. Amplified and biotinylated cRNAs were hybridized onto Affymetrix GeneChip Human Genome U133A 2.0 cartridge arrays, Washed, and Stained with kit following manufacturerM-bM-^@M-^Ys instructions. Arrays were scanned using Affymetrix GeneChip Scanner 3000 and the initial raw data were extracted using Affymetrix GeneChip Command Console-Expression software. The statistical analyses of scanned data were performed using default setting on GeneSpring GX 12.1 software (Agilent).

2014-09-04 | E-GEOD-61042 | biostudies-arrayexpress

The ETS inhibitors YK-4-279 and TK-216 have anti-tumor activity in lymphomas and interfere with SPIB in activated B cell-like type diffuse large B cell lymphoma

Project description:TMD8 and U2932 were treated with YK-4-279 for 4 and 8 hours.

2021-05-01 | GSE114022 | GEO

Inhibition of ERG Activity in Patient Derived Prostate Cancer Xenografts using the Small Molecule Inhibitor YK-4-279

Project description:ERG activity was blocked using YK-4-279 in three subcutaneously implanted ERG+ (LuCaP 23.1, 86.2, and 35) and one ERG- (LuCaP 96) PDX. Tumor volume (TV), body weight (BW), serum prostate specific antigen (PSA), and overall survival (OS) were compared to vehicle treated controls. Changes in gene expression were assessed by RNASeq and tissue microarrays were constructed to assess necrosis, proliferation, apoptosis, microvessel density, and ERG expression.

2017-11-16 | GSE86387 | GEO

Tumor Cell Survival Dependence on the DExH-Box Helicase DHX9

2016-05-19 | GSE76765 | GEO

Characterization of Ewing sarcoma resistance to the EWS-FLI1 inhibitor YK-4-279

Project description:Characterization of Ewing sarcoma resistance to the EWS-FLI1 inhibitor YK-4-279

| PRJNA548934 | ENA