The Synovial Sarcoma–Associated SS18-SSX2 Fusion Protein Induces Epigenetic Gene (De)Regulation

Bruijn, Diederik R.H. de; Allander, Susanne V.; Dijk, Anke H.A. van; Willemse, Marieke; Thijssen, J.P.H.; Groningen, J.J.M. van; Meltzer, Paul S.; Kessel, Ad Geurts van

doi:10.1158/0008-5472.can-05-3726

Cited by 90 publications

(78 citation statements)

References 52 publications

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“…Due to the heterogeneity of sarcoma, >100 distinct subtypes have been described to date, with new subtypes frequently reported (4). Synovial sarcoma, a soft-tissue tumor, is characterized by a reciprocal t(X;18) translocation, in which the SS18 gene on chromosome 18 fuses with the SSX1, SSX2 or, less commonly, SSX4 gene on the X chromosome (5,6). Ewing's sarcoma has a relatively simple genetic signature, consisting of a t(11;22) translocation (7,8).…”

Section: Introductionmentioning

confidence: 99%

The importance of Src signaling in sarcoma

et al. 2015

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Abstract. Src is a tyrosine kinase that is of significance in tumor biology. The present review focuses on Src, its molecular structure, and role in cancer, in addition to its expression and function in sarcoma. In addition, the feasibility of Src as a potential drug target for the treatment of sarcoma is also discussed. Previous studies have suggested that Src has essential functions in cell proliferation, apoptosis, invasion, metastasis and the tumor microenvironment. Thus, it may be a potential target for cancer therapy. Src has been found to enhance proliferation, reduce apoptosis and promote metastasis in certain subtypes of sarcoma, including osteosarcoma, chondrosarcoma and Ewing's sarcoma. Furthermore, a number of novel effective therapeutic agents, such as SI-83, which target Src have been investigated in vitro and in vivo. Bosutinib and dasatinib, which inhibit Src, have been approved by the U.S. Food and Drug Administration for the treatment of chronic myelogenous leukemia. In addition, vandetanib is approved for the treatment of medullary thyroid cancer. Furthermore, the Src inhibitor, saracatinib, is currently in clinical trials for the treatment of a variety of solid tumors, including breast and lung cancers. Thus, Src is considered to be an important factor in sarcoma progression and may present a novel clinical therapeutic target. This review demonstrates the importance and clinical relevance of Src in sarcoma, and discusses a number of small molecular inhibitors of src kinase, such as dasatinib and sarcatinib, which are currently in clinical trials for the treatment of sarcoma patients.

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Section: Introductionmentioning

confidence: 99%

The importance of Src signaling in sarcoma

et al. 2015

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“…The QPGY domain is a transcriptional coactivation domain and mediates multimerization of the SS18 protein (Brett et al, 1997;Thaete et al, 1999;Perani et al, 2003). Together, these findings indicate that the SS18 protein acts as transcriptional co-activator through chromatin modification mechanisms (de Bruijn et al, 2006).…”

Section: Introductionmentioning

confidence: 80%

“…The main body of the SS18 protein, including the SNH domain, is fused to the highly polar C-terminal SSX tail, including the SSX-divergent (SXXDDs) and SSXRDs. This fusion has been associated with neoplastic transformation (Nagai et al, 2001) and changes in the epigenetic makeup of target genes (de Bruijn et al, 2006). Another recent study indicated that the SS18-SSX1 and SS18-SSX2 fusion proteins interact preferentially with the transcription factors Snail and Slug, respectively (Saito et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…The SS18 protein is a modular protein, consisting of two functional domains, the SS18 N-terminal homology (SNH) domain and the glutamine, proline, glycine and tyrosine-rich QPGY domain (Thaete et al, 1999;de Bruijn et al, 2001a). Of these, the SNH domain directly interacts with the acute leukemia-associated transcription factor AF10 (de Bruijn et al, 2001a), the SWI/SNF ATPases BRM and BRG1 (Thaete et al, 1999;Perani et al, 2003;de Bruijn et al, 2006), the histone acetyltransferase p300 (Eid et al, 2000) and the corepressor mSin3A (Ito et al, 2004). Indirectly, the SS18 protein associates with yet another SWI/SNF protein, INI1 (Debernardi et al, 2002;Kato et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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The C terminus of the synovial sarcoma-associated SSX proteins interacts with the LIM homeobox protein LHX4

et al. 2007

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As a result of the synovial sarcoma-associated t(X;18) translocation, the SS18 gene on chromosome 18 is fused to either one of the three closely related SSX genes on the X chromosome. The SS18 protein is thought to act as a transcriptional co-activator, whereas the SSX proteins are thought to act as transcriptional corepressors. The main SSX-repression domain is located in its C terminus, a domain that is retained in the respective SS18-SSX fusion proteins. Both the SS18 and SSX proteins lack DNAbinding domains. Previously, we found that the SS18 and SS18-SSX fusion proteins may be tethered to DNA targets via the SS18-interacting protein AF10. Here, we set out to isolate proteins that interact with the SSX C-terminal repression domain using a yeast two-hybrid interaction trap. Of the positive clones isolated, two corresponded to the LIM homeobox protein LHX4, a DNA-binding protein that is involved in transcription regulation. An endogenous interaction was subsequently established in mammalian cells via colocalization and coimmunoprecipitation of the respective proteins. Interestingly, the LHX4 gene was previously found to be deregulated in various human leukemias. In addition, it was previously found that LIM homeobox proteins may bind to and activate the glycoprotein-a (CGA) promoter. Using LHX4 chromatin immunoprecipitation and CGApromoter assays, we found that endogenous LHX4 binds to the CGA promoter and that LHX4-mediated CGA activation is enhanced by the SS18-SSX protein, but not by the SSX protein. Taken together, we conclude that this novel protein -protein interaction may have direct consequences for the (de)regulation of SSX and/or SS18-SSX target genes and, thus, for the development of human synovial sarcomas.

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“…This could In synovial sarcoma, in vitro studies have found that the SS18-SSX oncogene induces IGF2 expression which seems critical to convey tumorigenic properties. [48][49][50] IGF2 expression was associated with both the ÀSSX1 and ÀSSX2 translocation subtypes. 48 In this study, we present evidence that in primary synovial sarcoma tumor specimens, IGF2 is highly expressed at the protein level, supporting translational relevance to patients of these experimental findings, and attempts to target this pathway in patients using IGF signaling inhibitors.…”

Section: Discussionmentioning

confidence: 98%

Expression of insulin-like growth factor 2 in mesenchymal neoplasms

et al. 2009

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The insulin-like growth factor (IGF) system plays an important role in the growth and development of cells and has been implicated in oncogenesis and tumor progression. Gene expression profiling studies on limited numbers of specimens have shown high expression of IGF2, encoding the activating ligand for this system, in gastrointestinal stromal tumors (GISTs) and in synovial sarcomas. This data may have concrete clinical implications, as several reports exist of patients with GISTs suffering from severe hypoglycemia, a predicted effect of IGF2. Furthermore, new drugs targeting IGF signaling are entering clinical trials. The purpose of this study is to survey IGF2 expression at the protein level on a broad number of mesenchymal tumors representing all major diagnostic classes. By immunostaining tissue microarrays, results were obtained for 51 diagnostic categories of bone and soft-tissue tumors representing 1288 cases. Distinct membranous and/or cytoplasmic IGF2 immunoreactivity was assessed according to published criteria. Solitary fibrous tumors had the highest expression. Of 20 tumor types represented by more than 10 cases, synovial sarcomas, myxoid liposarcomas, GISTs, malignant peripheral nerve sheath tumors, chondrosarcomas, undifferentiated pleomorphic sarcomas (MFH), Ewing's sarcomas and tenosynovial giant cell tumors showed high levels of expression in more than 20% of cases. Of the 445 GIST cases with clinical information, those with high expression of IGF2 had a significantly worse outcome than those with low or no expression. IGF2 protein expression among mesenchymal tumors is largely consistent with gene expression studies and suggests a potential for molecular therapy targeting the IGF signaling pathway system in these neoplasms.

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The Synovial Sarcoma–Associated SS18-SSX2 Fusion Protein Induces Epigenetic Gene (De)Regulation

Cited by 90 publications

References 52 publications

The importance of Src signaling in sarcoma

The importance of Src signaling in sarcoma

The C terminus of the synovial sarcoma-associated SSX proteins interacts with the LIM homeobox protein LHX4

Expression of insulin-like growth factor 2 in mesenchymal neoplasms

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