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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 4376-4387 |
| Number of pages | 12 |
| Journal | Clinical Cancer Research |
| Volume | 23 |
| Issue number | 15 |
| DOIs | |
| State | Published - Aug 1 2017 |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
Identification of a novel SYK/c-MYC/MALAT1 signaling pathway and its potential therapeutic value in Ewing sarcoma. / Sun, Haibo; Lin, De Chen; Cao, Qi; Pang, Brendan; Gae, David D.; Lee, Victor Kwan Min; Lim, Huey Jin; Doan, Ngan; Said, Jonathan W.; Gery, Sigal; Chow, Marilynn; Mayakonda, Anand; Forscher, Charles; Tyner, Jeffrey; Koeffler, H. Phillip.
In: Clinical Cancer Research, Vol. 23, No. 15, 01.08.2017, p. 4376-4387.Research output: Contribution to journal › Article
}
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
AU - Koeffler, H. Phillip
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.
UR - http://www.scopus.com/inward/record.url?scp=85026648242&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85026648242&partnerID=8YFLogxK
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 -