dc.contributor.author
Schmidt, Oxana
dc.contributor.author
Nehls, Nadja
dc.contributor.author
Prexler, Carolin
dc.contributor.author
Heyking, Kristina von
dc.contributor.author
Groll, Tanja
dc.contributor.author
Pardon, Katharina
dc.contributor.author
Garcia, Heathcliff D.
dc.contributor.author
Hensel, Tim
dc.contributor.author
Gürgen, Dennis
dc.contributor.author
Henssen, Anton G.
dc.contributor.author
Eggert, Angelika
dc.contributor.author
Steiger, Katja
dc.contributor.author
Burdach, Stefan
dc.contributor.author
Richter, Günther H. S.
dc.date.accessioned
2023-03-10T14:10:34Z
dc.date.available
2023-03-10T14:10:34Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/38309
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-38028
dc.description.abstract
Background: Histone acetylation and deacetylation seem processes involved in the pathogenesis of Ewing sarcoma (EwS). Here histone deacetylases (HDAC) class I were investigated.
Methods: Their role was determined using different inhibitors including TSA, Romidepsin, Entinostat and PCI-34051 as well as CRISPR/Cas9 class I HDAC knockouts and HDAC RNAi. To analyze resulting changes microarray analysis, qRT-PCR, western blotting, Co-IP, proliferation, apoptosis, differentiation, invasion assays and xenograft-mouse models were used.
Results: Class I HDACs are constitutively expressed in EwS. Patients with high levels of individual class I HDAC expression show decreased overall survival. CRISPR/Cas9 class I HDAC knockout of individual HDACs such as HDAC1 and HDAC2 inhibited invasiveness, and blocked local tumor growth in xenograft mice. Microarray analysis demonstrated that treatment with individual HDAC inhibitors (HDACi) blocked an EWS-FLI1 specific expression profile, while Entinostat in addition suppressed metastasis relevant genes. EwS cells demonstrated increased susceptibility to treatment with chemotherapeutics including Doxorubicin in the presence of HDACi. Furthermore, HDACi treatment mimicked RNAi of EZH2 in EwS. Treated cells showed diminished growth capacity, but an increased endothelial as well as neuronal differentiation ability. HDACi synergizes with EED inhibitor (EEDi) in vitro and together inhibited tumor growth in xenograft mice. Co-IP experiments identified HDAC class I family members as part of a regulatory complex together with PRC2.
Conclusions: Class I HDAC proteins seem to be important mediators of the pathognomonic EWS-ETS-mediated transcription program in EwS and in combination therapy, co-treatment with HDACi is an interesting new treatment opportunity for this malignant disease.
en
dc.rights.uri
https://creativecommons.org/licenses/by/4.0/
dc.subject
Ewing sarcoma
en
dc.subject
Class I HDACs
en
dc.subject
Expression profiles
en
dc.subject
Pathogenesis
en
dc.subject
Targeted therapy
en
dc.subject.ddc
600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit
dc.title
Class I histone deacetylases (HDAC) critically contribute to Ewing sarcoma pathogenesis
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation.articlenumber
322
dcterms.bibliographicCitation.doi
10.1186/s13046-021-02125-z
dcterms.bibliographicCitation.journaltitle
Journal of Experimental & Clinical Cancer Research
dcterms.bibliographicCitation.originalpublishername
Springer Nature
dcterms.bibliographicCitation.volume
40
refubium.affiliation
Charité - Universitätsmedizin Berlin
refubium.funding
Springer Nature DEAL
refubium.resourceType.isindependentpub
no
dcterms.accessRights.openaire
open access
dcterms.bibliographicCitation.pmid
34654445
dcterms.isPartOf.eissn
1756-9966