The fusion protein SS18-SSX1 employs core Wnt pathway transcription factors to induce a partial Wnt signature in synovial sarcoma

Cironi, Luisa; Petricevic, Tanja; Vieira, Víctor Fernandes; Provero, Paolo; Fusco, Carlo; Cornaz, Sandrine; Fregni, Giulia; Letovanec, Igor; Aguet, Michel; Stamenkovic, Ivan

doi:10.1038/srep22113

Cited by 36 publications

(47 citation statements)

References 54 publications

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“…Similar to prior studies [22,25], we observed frequent b-catenin expression in synovial sarcoma. Synovial sarcoma is characterized by translocation t(X; 18)(p11; q11) [26], resulting in SS18 gene rearrangement with one of three SSX gene fusion partners (SSX1, SSX2, or SSX4); SS18-SSX activation of the Wnt signaling pathway has been demonstrated using in vitro and in vivo studies [27][28][29].…”

Section: Discussionmentioning

confidence: 99%

Nuclear β-Catenin Expression is Frequent in Sinonasal Hemangiopericytoma and Its Mimics

Fletcher

2016

Head and Neck Pathol

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Sinonasal hemangiopericytoma (HPC) is a tumor showing pericytic myoid differentiation and which arises in the nasal cavity and paranasal sinuses. CTNNB1 mutations appear to be a consistent aberration in sinonasal HPC, and nuclear expression of b-catenin has been reported. Our aim was to evaluate the frequency of b-catenin expression in sinonasal HPC and its histologic mimics in the upper aerodigestive tract. Cases were retrieved from the surgical pathology and consultation files. Immunohistochemical staining for b-catenin was performed on 50 soft tissue tumors arising in the sinonasal tract or oral cavity, and nuclear staining was recorded semiquantitatively by extent and intensity. Nuclear reactivity for b-catenin was present in 19/20 cases of sinonasal HPC; 17 showed moderate-to-strong multifocal or diffuse staining, and 2 had moderate focal nuclear reactivity. All solitary fibrous tumors (SFT) (10/10) showed focal-to-multifocal nuclear staining, varying from weak to strong in intensity. Most cases of synovial sarcoma (9/10) showed nuclear b-catenin expression in the spindle cell component, ranging from focal-weak to strong-multifocal. No cases of myopericytoma (0/10) showed any nuclear b-catenin expression. bcatenin expression is prevalent in sinonasal HPC, but is also frequent in SFT and synovial sarcoma. Our findings indicate that b-catenin is not a useful diagnostic tool in the evaluation of spindle cell tumors with a prominent hemangiopericytoma-like vasculature in the sinonasal tract and oral cavity, and that definitive diagnosis relies on the use of a broader immunohistochemical panel.

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Section: Discussionmentioning

confidence: 99%

Nuclear β-Catenin Expression is Frequent in Sinonasal Hemangiopericytoma and Its Mimics

Fletcher

2016

Head and Neck Pathol

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“…SS18-SSX while serving as a bridge between activating transcription factor 2 (ATF2) and transducin-like enhancer of split 1 (TLE1), resulted in repression of ATF2 target genes. Besides, the fusion oncoprotein SS18-SSX via TCF/LEF, TLE1 and HDAC interaction leads to an upregulation of AXIN2, which is involved in the WNT pathway but without direction interaction with the pathway 33 . Romidepsin significantly suppressed the growth of synovial sarcoma cells compared with that of osteosarcoma, as it impacted SS18-SSX target gene expression by preventing TLE1 complex recruitment 34, 35 .…”

Section: Molecular Mechanisms Of Hdis In Sarcomamentioning

confidence: 99%

Therapeutic applications of histone deacetylase inhibitors in sarcoma

Tang

Choy

et al. 2017

Cancer Treatment Reviews

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Sarcomas are a rare group of malignant tumors originating from mesenchymal stem cells. Surgery, radiation and chemotherapy are currently the only standard treatments for sarcoma. However, their response rates to chemotherapy are quite low. Toxic side effects and multi-drug chemoresistance make treatment even more challenging. Therefore, better drugs to treat sarcomas are needed. Histone deacetylase inhibitors (HDAC inhibitors, HDACi, HDIs) are epigenetic modifying agents that can inhibit sarcoma growth in vitro and in vivo through a variety of pathways, including inducing tumor cell apoptosis, causing cell cycle arrest, impairing tumor invasion and preventing metastasis. Importantly, preclinical studies have revealed that HDIs can not only sensitize sarcomas to chemotherapy and radiotherapy, but also increase treatment responses when combined with other chemotherapeutic drugs. Several phase I and II clinical trials have been conducted to assess the efficacy of HDIs either as monotherapy or in combination with standard chemotherapeutic agents or targeted therapeutic drugs for sarcomas. Combination regimen for sarcomas appear to be more promising than monotherapy when using HDIs. This review summarizes our current understanding and therapeutic applications of HDIs in sarcomas.

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“…The fusion of SSX to SS18 also recruits interacting proteins involved in epigenetic regulation, including transducin-like enhancer of split 1 (TLE1), activating transcription factor 2 (ATF2), members of the polycomb group and histone deacetylases (HDAC) [5, 6]. Together, this is thought to bring about the abnormal transcriptional pattern that drives malignant transformation in synovial sarcoma [4, 5].…”

Section: Introductionmentioning

confidence: 99%

Identification of cytotoxic agents disrupting synovial sarcoma oncoprotein interactions by proximity ligation assay

Laporte

et al. 2016

Oncotarget

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Conventional cytotoxic therapies for synovial sarcoma provide limited benefit. Drugs specifically targeting the product of its driver translocation are currently unavailable, in part because the SS18-SSX oncoprotein functions via aberrant interactions within multiprotein complexes. Proximity ligation assay is a recently-developed method that assesses protein-protein interactions in situ. Here we report use of the proximity ligation assay to confirm the oncogenic association of SS18-SSX with its co-factor TLE1 in multiple human synovial sarcoma cell lines and in surgically-excised human tumor tissue. SS18-SSX/TLE1 interactions are disrupted by class I HDAC inhibitors and novel small molecule inhibitors. This assay can be applied in a high-throughput format for drug discovery in fusion-oncoprotein associated cancers where key effector partners are known.

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The fusion protein SS18-SSX1 employs core Wnt pathway transcription factors to induce a partial Wnt signature in synovial sarcoma

Cited by 36 publications

References 54 publications

Nuclear β-Catenin Expression is Frequent in Sinonasal Hemangiopericytoma and Its Mimics

Nuclear β-Catenin Expression is Frequent in Sinonasal Hemangiopericytoma and Its Mimics

Therapeutic applications of histone deacetylase inhibitors in sarcoma

Identification of cytotoxic agents disrupting synovial sarcoma oncoprotein interactions by proximity ligation assay

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