Upregulation of ERK-EGR1-heparanase axis by HDAC inhibitors provides targets for rational therapeutic intervention in synovial sarcoma

Abstract Background Synovial sarcoma (SS) is an aggressive soft tissue tumor with limited therapeutic options in advanced stage. SS18-SSX fusion oncogenes, which are the hallmarks of SS, cause epigenetic rewiring involving histone deacetylases (HDACs). Promising preclinical studies supporting HDAC t...

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Autores principales:	Cinzia Lanzi, Enrica Favini, Laura Dal Bo, Monica Tortoreto, Noemi Arrighetti, Nadia Zaffaroni, Giuliana Cassinelli
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	EGR1 ERK Heparanase inhibitor Histone deacetylase inhibitor FK228 SAHA Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/258ac722b6dc4231a4a62b0a9178a243
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spelling	oai:doaj.org-article:258ac722b6dc4231a4a62b0a9178a2432021-12-05T12:10:15ZUpregulation of ERK-EGR1-heparanase axis by HDAC inhibitors provides targets for rational therapeutic intervention in synovial sarcoma10.1186/s13046-021-02150-y1756-9966https://doaj.org/article/258ac722b6dc4231a4a62b0a9178a2432021-12-01T00:00:00Zhttps://doi.org/10.1186/s13046-021-02150-yhttps://doaj.org/toc/1756-9966Abstract Background Synovial sarcoma (SS) is an aggressive soft tissue tumor with limited therapeutic options in advanced stage. SS18-SSX fusion oncogenes, which are the hallmarks of SS, cause epigenetic rewiring involving histone deacetylases (HDACs). Promising preclinical studies supporting HDAC targeting for SS treatment were not reflected in clinical trials with HDAC inhibitor (HDACi) monotherapies. We investigated pathways implicated in SS cell response to HDACi to identify vulnerabilities exploitable in combination treatments and improve the therapeutic efficacy of HDACi-based regimens. Methods Antiproliferative and proapoptotic effects of the HDACi SAHA and FK228 were examined in SS cell lines in parallel with biochemical and molecular analyses to bring out cytoprotective pathways. Treatments combining HDACi with drugs targeting HDACi-activated prosurvival pathways were tested in functional assays in vitro and in a SS orthotopic xenograft model. Molecular mechanisms underlying synergisms were investigated in SS cells through pharmacological and gene silencing approaches and validated by qRT-PCR and Western blotting. Results SS cell response to HDACi was consistently characterized by activation of a cytoprotective and auto-sustaining axis involving ERKs, EGR1, and the β-endoglycosidase heparanase, a well recognized pleiotropic player in tumorigenesis and disease progression. HDAC inhibition was shown to upregulate heparanase by inducing expression of the positive regulator EGR1 and by hampering negative regulation by p53 through its acetylation. Interception of HDACi-induced ERK-EGR1-heparanase pathway by cell co-treatment with a MEK inhibitor (trametinib) or a heparanase inhibitor (SST0001/roneparstat) enhanced antiproliferative and pro-apoptotic effects. HDAC and heparanase inhibitors had opposite effects on histone acetylation and nuclear heparanase levels. The combination of SAHA with SST0001 prevented the upregulation of ERK-EGR1-heparanase induced by the HDACi and promoted caspase-dependent cell death. In vivo, the combined treatment with SAHA and SST0001 potentiated the antitumor efficacy against the CME-1 orthotopic SS model as compared to single agent administration. Conclusions The present study provides preclinical rationale and mechanistic insights into drug combinatory strategies based on the use of ERK pathway and heparanase inhibitors to improve the efficacy of HDACi-based antitumor therapies in SS. The involvement of classes of agents already clinically available, or under clinical evaluation, indicates the transferability potential of the proposed approaches.Cinzia LanziEnrica FaviniLaura Dal BoMonica TortoretoNoemi ArrighettiNadia ZaffaroniGiuliana CassinelliBMCarticleEGR1ERKHeparanase inhibitorHistone deacetylase inhibitorFK228SAHANeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENJournal of Experimental & Clinical Cancer Research, Vol 40, Iss 1, Pp 1-25 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	EGR1 ERK Heparanase inhibitor Histone deacetylase inhibitor FK228 SAHA Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	EGR1 ERK Heparanase inhibitor Histone deacetylase inhibitor FK228 SAHA Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Cinzia Lanzi Enrica Favini Laura Dal Bo Monica Tortoreto Noemi Arrighetti Nadia Zaffaroni Giuliana Cassinelli Upregulation of ERK-EGR1-heparanase axis by HDAC inhibitors provides targets for rational therapeutic intervention in synovial sarcoma
description	Abstract Background Synovial sarcoma (SS) is an aggressive soft tissue tumor with limited therapeutic options in advanced stage. SS18-SSX fusion oncogenes, which are the hallmarks of SS, cause epigenetic rewiring involving histone deacetylases (HDACs). Promising preclinical studies supporting HDAC targeting for SS treatment were not reflected in clinical trials with HDAC inhibitor (HDACi) monotherapies. We investigated pathways implicated in SS cell response to HDACi to identify vulnerabilities exploitable in combination treatments and improve the therapeutic efficacy of HDACi-based regimens. Methods Antiproliferative and proapoptotic effects of the HDACi SAHA and FK228 were examined in SS cell lines in parallel with biochemical and molecular analyses to bring out cytoprotective pathways. Treatments combining HDACi with drugs targeting HDACi-activated prosurvival pathways were tested in functional assays in vitro and in a SS orthotopic xenograft model. Molecular mechanisms underlying synergisms were investigated in SS cells through pharmacological and gene silencing approaches and validated by qRT-PCR and Western blotting. Results SS cell response to HDACi was consistently characterized by activation of a cytoprotective and auto-sustaining axis involving ERKs, EGR1, and the β-endoglycosidase heparanase, a well recognized pleiotropic player in tumorigenesis and disease progression. HDAC inhibition was shown to upregulate heparanase by inducing expression of the positive regulator EGR1 and by hampering negative regulation by p53 through its acetylation. Interception of HDACi-induced ERK-EGR1-heparanase pathway by cell co-treatment with a MEK inhibitor (trametinib) or a heparanase inhibitor (SST0001/roneparstat) enhanced antiproliferative and pro-apoptotic effects. HDAC and heparanase inhibitors had opposite effects on histone acetylation and nuclear heparanase levels. The combination of SAHA with SST0001 prevented the upregulation of ERK-EGR1-heparanase induced by the HDACi and promoted caspase-dependent cell death. In vivo, the combined treatment with SAHA and SST0001 potentiated the antitumor efficacy against the CME-1 orthotopic SS model as compared to single agent administration. Conclusions The present study provides preclinical rationale and mechanistic insights into drug combinatory strategies based on the use of ERK pathway and heparanase inhibitors to improve the efficacy of HDACi-based antitumor therapies in SS. The involvement of classes of agents already clinically available, or under clinical evaluation, indicates the transferability potential of the proposed approaches.
format	article
author	Cinzia Lanzi Enrica Favini Laura Dal Bo Monica Tortoreto Noemi Arrighetti Nadia Zaffaroni Giuliana Cassinelli
author_facet	Cinzia Lanzi Enrica Favini Laura Dal Bo Monica Tortoreto Noemi Arrighetti Nadia Zaffaroni Giuliana Cassinelli
author_sort	Cinzia Lanzi
title	Upregulation of ERK-EGR1-heparanase axis by HDAC inhibitors provides targets for rational therapeutic intervention in synovial sarcoma
title_short	Upregulation of ERK-EGR1-heparanase axis by HDAC inhibitors provides targets for rational therapeutic intervention in synovial sarcoma
title_full	Upregulation of ERK-EGR1-heparanase axis by HDAC inhibitors provides targets for rational therapeutic intervention in synovial sarcoma
title_fullStr	Upregulation of ERK-EGR1-heparanase axis by HDAC inhibitors provides targets for rational therapeutic intervention in synovial sarcoma
title_full_unstemmed	Upregulation of ERK-EGR1-heparanase axis by HDAC inhibitors provides targets for rational therapeutic intervention in synovial sarcoma
title_sort	upregulation of erk-egr1-heparanase axis by hdac inhibitors provides targets for rational therapeutic intervention in synovial sarcoma
publisher	BMC
publishDate	2021
url	https://doaj.org/article/258ac722b6dc4231a4a62b0a9178a243
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Upregulation of ERK-EGR1-heparanase axis by HDAC inhibitors provides targets for rational therapeutic intervention in synovial sarcoma

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