Identification of a novel SYK/c-MYC/MALAT1 signaling pathway and its potential therapeutic value in Ewing sarcoma

Haibo Sun, De Chen Lin, Qi Cao, Brendan Pang, David D. Gae, Victor Kwan Min Lee, Huey Jin Lim, Ngan Doan, Jonathan W. Said, Sigal Gery, Marilynn Chow, Anand Mayakonda, Charles Forscher, Jeffrey Tyner, H. Phillip Koeffler

Research output: Contribution to journalArticle

16 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)4376-4387
Number of pages12
JournalClinical Cancer Research
Volume23
Issue number15
DOIs
StatePublished - Aug 1 2017

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Ewing's Sarcoma
Therapeutics
Syk Kinase
Long Noncoding RNA
Small Molecule Libraries
Oligonucleotide Array Sequence Analysis
Luciferases
Sarcoma
Protein-Tyrosine Kinases
Small Interfering RNA
Research Design
Phosphorylation
Pharmacology

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 journalArticle

Sun, H, Lin, DC, Cao, Q, Pang, B, Gae, DD, Lee, VKM, Lim, HJ, Doan, N, Said, JW, Gery, S, Chow, M, Mayakonda, A, Forscher, C, Tyner, J & Koeffler, HP 2017, 'Identification of a novel SYK/c-MYC/MALAT1 signaling pathway and its potential therapeutic value in Ewing sarcoma', Clinical Cancer Research, vol. 23, no. 15, pp. 4376-4387. https://doi.org/10.1158/1078-0432.CCR-16-2185
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. / Identification of a novel SYK/c-MYC/MALAT1 signaling pathway and its potential therapeutic value in Ewing sarcoma. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 15. pp. 4376-4387.
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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.",
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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.

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