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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2021

Open Access 01-12-2021 | Sarcoma | Research

Class I histone deacetylases (HDAC) critically contribute to Ewing sarcoma pathogenesis

Authors: Oxana Schmidt, Nadja Nehls, Carolin Prexler, Kristina von Heyking, Tanja Groll, Katharina Pardon, Heathcliff D. Garcia, Tim Hensel, Dennis Gürgen, Anton G. Henssen, Angelika Eggert, Katja Steiger, Stefan Burdach, Günther H. S. Richter

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

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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.
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Metadata
Title
Class I histone deacetylases (HDAC) critically contribute to Ewing sarcoma pathogenesis
Authors
Oxana Schmidt
Nadja Nehls
Carolin Prexler
Kristina von Heyking
Tanja Groll
Katharina Pardon
Heathcliff D. Garcia
Tim Hensel
Dennis Gürgen
Anton G. Henssen
Angelika Eggert
Katja Steiger
Stefan Burdach
Günther H. S. Richter
Publication date
01-12-2021
Publisher
BioMed Central
Keyword
Sarcoma
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-021-02125-z

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