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Title: Identification of a novel SYK/c-MYC/MALAT1 signaling pathway and its potential therapeutic value in Ewing sarcoma
Authors: Sun, H
Lin, D.-C 
Cao, Q
Pang, B 
Gae, D.D
Lee, V.K.M 
Lim, H.J
Doan, N
Said, J.W
Gery, S
Chow, M
Mayakonda, A 
Forscher, C
Tyner, J.W
Koeffler, H.P 
Keywords: entospletinib
long untranslated RNA
Myc protein
protein kinase B
protein kinase Syk
small interfering RNA
unclassified drug
long untranslated RNA
MALAT1 long non-coding RNA, human
Myc protein
MYC protein, human
protein kinase Syk
SYK protein, human
animal experiment
animal model
animal tissue
cell proliferation
chromatin immunoprecipitation
controlled study
DNA microarray
drug targeting
enzyme inhibition
enzyme phosphorylation
enzyme reactivation
Ewing sarcoma
high throughput screening
human cell
luciferase assay
molecular library
polymerase chain reaction system
priority journal
promoter region
signal transduction
SYK cMYC MALAT1 signaling pathway
transcription regulation
administration and dosage
antagonists and inhibitors
drug effect
drug screening
Ewing sarcoma
gene expression regulation
molecularly targeted therapy
signal transduction
tumor cell line
Cell Line, Tumor
Cell Proliferation
Gene Expression Regulation, Neoplastic
High-Throughput Screening Assays
Molecular Targeted Therapy
Oligonucleotide Array Sequence Analysis
Proto-Oncogene Proteins c-myc
RNA, Long Noncoding
RNA, Small Interfering
Sarcoma, Ewing
Signal Transduction
Small Molecule Libraries
Syk Kinase
Xenograft Model Antitumor Assays
Issue Date: 2017
Publisher: American Association for Cancer Research Inc.
Citation: Sun, H, Lin, D.-C, Cao, Q, Pang, B, Gae, D.D, Lee, V.K.M, Lim, H.J, Doan, N, Said, J.W, Gery, S, Chow, M, Mayakonda, A, Forscher, C, Tyner, J.W, Koeffler, H.P (2017). Identification of a novel SYK/c-MYC/MALAT1 signaling pathway and its potential therapeutic value in Ewing sarcoma. Clinical Cancer Research 23 (15) : 4376-4387. ScholarBank@NUS Repository.
Abstract: Purpose: Ewing sarcoma (EWS) is a devastating soft tissue sarcoma affecting predominantly young individuals. Tyrosine kinases (TK) and associated pathways are continuously activated in many malignancies, including EWS; these enzymes provide candidate therapeutic targets. Experimental Design: Two high-throughput screens (a siRNA library and a small-molecule inhibitor library) were performed in EWS cells to establish candidate targets. Spleen tyrosine kinase (SYK) phosphorylation was assessed in EWS patients and cell lines. SYK was inhibited by a variety of genetic and pharmacological approaches, and SYK-regulated pathways were investigated by cDNA microarrays. The transcriptional regulation of MALAT1 was examined by ChIP-qPCR, luciferase reporter, and qRT-PCR assays. Results: SYK was identified as a candidate actionable target through both high-throughput screens. SYK was highly phosphorylated in the majority of EWS cells, and SYK inhibition by a variety of genetic and pharmacologic approaches markedly inhibited EWS cells both in vitro and in vivo. Ectopic expression of SYK rescued the cytotoxicity triggered by SYK-depletion associated with the reactivation of both AKT and c-MYC. A long noncoding RNA, MALAT1, was identified to be dependent on SYK-mediated signaling. Moreover, c-MYC, a SYK-promoted gene, bound to the promoter of MALAT1 and transcriptionally activated MALAT1, which further promoted the proliferation of EWS cells. Conclusions: This study identifies a novel signaling involving SYK/c-MYC/MALAT1 as a promising therapeutic target for the treatment of EWS. ©2017 AACR.
Source Title: Clinical Cancer Research
ISSN: 1078-0432
DOI: 10.1158/1078-0432.CCR-16-2185
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