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

Journal of Experimental & Clinical Cancer Research

Oxana Schmidt¹  Carolin Prexler¹  Nadja Nehls¹  Tim Hensel¹  Stefan Burdach²  Kristina von Heyking²  Günther H. S. Richter³  Heathcliff D. Garcia³  Katharina Pardon³  Angelika Eggert³  Anton G. Henssen³  Dennis Gürgen⁴  Tanja Groll⁵  Katja Steiger⁵ 

[1] Children’s Cancer Research Center and Department of Pediatrics, Klinikum rechts der Isar, Technische Universität München, München, Germany;Children’s Cancer Research Center and Department of Pediatrics, Klinikum rechts der Isar, Technische Universität München, München, Germany;German Cancer Research Center (DKFZ), Partner Site Munich, München, Germany;Department of Pediatrics, Division of Oncology and Hematology, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin, Germany;Experimental Pharmacology & Oncology Berlin-Buch GmbH, Berlin, Germany;Institute of Pathology, School of Medicine, Technische Universität München and Comparative Experimental Pathology (CEP), Technische Universität München, München, Germany;

关键词: Ewing sarcoma;    Class I HDACs;    Expression profiles;    Pathogenesis;    Targeted therapy;   

DOI  :  10.1186/s13046-021-02125-z

来源: Springer

【 摘 要 】

BackgroundHistone acetylation and deacetylation seem processes involved in the pathogenesis of Ewing sarcoma (EwS). Here histone deacetylases (HDAC) class I were investigated.MethodsTheir 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.ResultsClass 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.ConclusionsClass 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.

【 授权许可】

CC BY