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

Laporte, Aimée N.; Ji, Jennifer X.; Ma, Limin; Nielsen, Torsten O.; Brodin, Bertha

doi:10.18632/oncotarget.8882

Cited by 13 publications

(15 citation statements)

References 34 publications

(43 reference statements)

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“…In accordance with previous reports [11], the key association of SS18-SSX with TLE1 is lost following treatment with quisinostat, with or without the addition of proteasome inhibitor bortezomib (Fig 2A and 2B). To assess whether there are any superadditive effects in this model, an interaction term between quisinostat and bortezomib was added in a linear regression model (foci per nuclei as the dependent variable, and quisinostat/bortezomib treatment as independent variables).…”

Section: Resultssupporting

confidence: 93%

“…ATF2 binds DNA at CRE/ATF sites, where under normal conditions it functions as a histone acetyltransferase (HAT) to increase gene transcription in response to cellular stress signals [10]. TLE1 has been observed to interact with polycomb-repressor complex 2 (PRC2) and histone deacetylases (HDAC), and has been shown to mediate formation of a complex in which PRC2/HDAC1 represses gene expression at SS18-SSX targeted loci [9, 11]. When this association is disrupted by specific knockdown of TLE1, ATF2 or SS18-SSX, synovial sarcoma cell lines undergo apoptosis, indicating this complex association is important for tumor cell survival [9].…”

Section: Introductionmentioning

confidence: 99%

“…HDAC inhibitors have been shown to disrupt the SS18-SSX/TLE1/ATF2 protein complex [9, 11], providing an explanation for the sensitivity of synovial sarcoma cells to HDAC inhibition [15]. Though no drugs able to specifically target the SS18-SSX fusion oncoprotein are currently available, compounds able to disrupt its partnering interactions might be expected to reactivate normal gene transcription and elicit anti-tumor effects and clinical response.…”

Section: Introductionmentioning

confidence: 99%

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HDAC and Proteasome Inhibitors Synergize to Activate Pro-Apoptotic Factors in Synovial Sarcoma

et al. 2017

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Conventional cytotoxic therapies for synovial sarcoma provide limited benefit, and no drugs specifically targeting its driving SS18-SSX fusion oncoprotein are currently available. Patients remain at high risk for early and late metastasis. A high-throughput drug screen consisting of over 900 tool compounds and epigenetic modifiers, representing over 100 drug classes, was undertaken in a panel of synovial sarcoma cell lines to uncover novel sensitizing agents and targetable pathways. Top scoring drug categories were found to be HDAC inhibitors and proteasomal targeting agents. We find that the HDAC inhibitor quisinostat disrupts the SS18-SSX driving protein complex, thereby reestablishing expression of EGR1 and CDKN2A tumor suppressors. In combination with proteasome inhibition, HDAC inhibitors synergize to decrease cell viability and elicit apoptosis. Quisinostat inhibits aggresome formation in response to proteasome inhibition, and combination treatment leads to elevated endoplasmic reticulum stress, activation of pro-apoptotic effector proteins BIM and BIK, phosphorylation of BCL-2, increased levels of reactive oxygen species, and suppression of tumor growth in a murine model of synovial sarcoma. This study identifies and provides mechanistic support for a particular susceptibility of synovial sarcoma to the combination of quisinostat and proteasome inhibition.

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Section: Resultssupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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HDAC and Proteasome Inhibitors Synergize to Activate Pro-Apoptotic Factors in Synovial Sarcoma

et al. 2017

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“…Histone deacetylase (HDAC) inhibition has been shown to elicit apoptosis in synovial sarcoma models, as well as to disrupt SS18-SSX-mediated repressive complexes (4,7). This inhibition was observed to elicit reactivation of repressed gene targets, including CDKN2A (4,7,8).…”

Section: Introductionmentioning

confidence: 99%

Death by HDAC Inhibition in Synovial Sarcoma Cells

Laporte

Poulin

Barrott

et al. 2017

Molecular Cancer Therapeutics

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Conventional cytotoxic therapies for synovial sarcoma provide limited benefit, and no drugs specifically targeting the causative SS18-SSX fusion oncoprotein are currently available. Histone deacetylase (HDAC) inhibition has been shown in previous studies to disrupt the synovial sarcoma oncoprotein complex, resulting in apoptosis. To understand the molecular effects of HDAC inhibition, RNA-seq transcriptome analysis was undertaken in six human synovial sarcoma cell lines. HDAC inhibition induced pathways of cell-cycle arrest, neuronal differentiation, and response to oxygen-containing species, effects also observed in other cancers treated with this class of drugs. More specific to synovial sarcoma, polycomb group targets were reactivated, including tumor suppressor , and proapoptotic transcriptional patterns were induced. Functional analyses revealed that ROS-mediated FOXO activation and proapoptotic factors BIK, BIM, and BMF were important to apoptosis induction following HDAC inhibition in synovial sarcoma. HDAC inhibitor pathway activation results in apoptosis and decreased tumor burden following a 7-day quisinostat treatment in the mouse model of synovial sarcoma. This study provides mechanistic support for a particular susceptibility of synovial sarcoma to HDAC inhibition as a means of clinical treatment. .

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“…Knockdown of TLE1 in fibroblasts and synovial cells enhances the cytotoxic effect of chemotherapy, which suggests that TLE1 could be a promising therapeutic target for selectively treating synovial sarcoma without damaging healthy tissue [14]. A recent study used a proximity ligation assay to show that class I histone deacetylases inhibitors, which are cytotoxic, disrupt the oncogenic association of SS18-SSX and TLE1 in synovial sarcoma [15]. More information is needed to determine the biological and potential therapeutic roles of TLE1.…”

Section: Introductionmentioning

confidence: 99%

Clinicopathologic and Prognostic Significance of Transducin-Like Enhancer of Split 1 Protein Expression in Invasive Breast Cancer

Lee

Bae

et al. 2017

J Breast Cancer

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PurposeTransducin-like enhancer of split 1 (TLE1) is a member of the TLE family of transcriptional co-repressors that control the transcription of a wide range of genes. We investigated the prognostic significance of TLE1 protein expression in breast cancers by using immunohistochemistry and explored the relationship of TLE1 with clinicopathological parameters.MethodsImmunohistochemistry was performed on 456 cases of breast cancer tiled on tissue microarrays. The relationship between TLE1 expression in normal breast specimens and ductal carcinoma in situ (DCIS) was also analyzed.ResultsTLE1 was highly expressed in 57 of 456 (12.5%) carcinoma samples. TLE1 was more frequently expressed in DCIS and invasive breast cancers than in normal breast tissue (p=0.002). High expression of TLE1 significantly correlated with negative lymph node (LN) metastasis (p=0.007), high histologic grade (p<0.001), estrogen receptor negativity (p<0.001), progesterone receptor negativity (p<0.001), human epidermal growth factor receptor 2 (HER2) positivity (p<0.001), and high Ki-67 proliferation index (p<0.001). Based on intrinsic subtypes, high TLE1 expression was strongly associated with HER2+ and triple-negative breast cancers (TNBC) (p<0.001). Survival analysis demonstrated no significant association between TLE1 expression and disease-free survival (DFS) (p=0.167) or overall survival (OS) (p=0.286). In subgroup analyses, no correlation was found between TLE1 expression and DFS or OS according to LN status or intrinsic subtype.ConclusionHigh TLE1 expression is significantly associated with the HER2+ and TNBC subtypes. This is the first study documenting immunohistochemical expression of TLE1 in invasive breast cancer and its association with clinicopathological parameters, prognosis, and intrinsic subtype.

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

Cited by 13 publications

References 34 publications

HDAC and Proteasome Inhibitors Synergize to Activate Pro-Apoptotic Factors in Synovial Sarcoma

HDAC and Proteasome Inhibitors Synergize to Activate Pro-Apoptotic Factors in Synovial Sarcoma

Death by HDAC Inhibition in Synovial Sarcoma Cells

Clinicopathologic and Prognostic Significance of Transducin-Like Enhancer of Split 1 Protein Expression in Invasive Breast Cancer

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