TY - JOUR
T1 - Identification of a novel SYK/c-MYC/MALAT1 signaling pathway and its potential therapeutic value in Ewing sarcoma
AU - Sun, Haibo
AU - Lin, De Chen
AU - Cao, Qi
AU - Pang, Brendan
AU - Gae, David D.
AU - Lee, Victor Kwan Min
AU - Lim, Huey Jin
AU - Doan, Ngan
AU - Said, Jonathan W.
AU - Gery, Sigal
AU - Chow, Marilynn
AU - Mayakonda, Anand
AU - Forscher, Charles
AU - Tyner, Jeffrey W.
AU - Koeffler, H. Phillip
N1 - Funding Information:
We thank Dr. Kimberly Stegmaier and Dr. Stephen L. Lessnick for their generous help with the reagents and cell lines. This research was supported by the Alan B. Slifka Foundation, the National Research Foundation Singapore and the Singapore Ministry of Education under the Research Centres of Excellence initiative, and the Singapore Ministry of Health's National Medical Research Council under its Singapore Translational Research (STaR) Investigator Award. D.-C. Lin was supported by Donna and Jesse Garber Awards for Cancer Research and the National Center for Advancing Translational Sciences UCLA CTSI Grant UL1TR000124. This research is also partially supported by the RNA Biology Center, Cancer Science Institute of Singapore, NUS (MOE2014-T3-1-006). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
©2017 AACR.
PY - 2017/8/1
Y1 - 2017/8/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-16-2185
DO - 10.1158/1078-0432.CCR-16-2185
M3 - Article
C2 - 28336564
AN - SCOPUS:85026648242
VL - 23
SP - 4376
EP - 4387
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 15
ER -