Small molecule inhibition of lysine-specific demethylase 1 (LSD1) and histone deacetylase (HDAC) alone and in combination in Ewing sarcoma cell lines

Welch, Darcy; Kahen, Elliot; Fridley, Brooke L.; Brohl, Andrew S.; Cubitt, Christopher L.; Reed, Damon R.

doi:10.1371/journal.pone.0222228

Cited by 34 publications

(22 citation statements)

References 43 publications

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“…Welch et al selected clinically utilized chemotherapy agents and active metabolites including HDAC inhibitor Romidepsin and the reversible LSD1 inhibitor SP2509, both part of the nucleosome remodeling and deactylase (NuRD) co-repressor complex, for tests in EwS cell lines. In two drug experiments, synergy was observed with several combinations, including when SP2509 was paired with topoisomerase inhibitors or Romidepsin [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

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

Schmidt

Nehls

Prexler

et al. 2021

J Exp Clin Cancer Res

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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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Section: Introductionmentioning

confidence: 99%

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

Schmidt

Nehls

Prexler

et al. 2021

J Exp Clin Cancer Res

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“…The effect has been shown to be secondary to reversal of LSD1 activity at GGAA microsatellite and non-microsatellite sites co-occupied with EWS/FLI with some preference for the non-microsatellite sites [129] . Importantly, combining SP2509 with an HDAC inhibitor leads to marked synergy in various Ewing sarcoma cell lines and patient-derived xenografts [130] , [131] .…”

Section: Manipulating Ews/fli Induced Epigenetic Changesmentioning

confidence: 99%

One oncogene, several vulnerabilities: EWS/FLI targeted therapies for Ewing sarcoma

Flores

Grohar

2021

Journal of Bone Oncology

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Highlights EWS/FLI is the driver oncogene of Ewing sarcoma. EWS-FLI driven transcription yields numerous therapeutic vulnerabilities. The intrinsic cellular stress of dysregulated transcription leads to additional therapeutic vulnerabilities. A number of compounds targeting various steps in EWS/FLI driven transcription are in various stages of clinical development including those that are now in the clinic. The future of EWS/FLI targeting will likely focus on molecularly targeted combination therapies.

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“…Using the single agent SP2509, reversible inhibition of lysine-specific demethylase 1 (LSD1), a subunit of the Mi-2/nucleosome remodeling and deacetylase (NuRD) complex, induces apoptosis and reduces xenograft tumor growth in EwS [144]. Interestingly, this LSD1 inhibitor has a synergistic effect with the HDAC inhibitors suberoylanilide hydroxamic acid (SAHA) or romidepsin in vivo [145,146]. Based on these preclinical studies, more investigations focusing on this and other combinations with HDAC inhibitors are justified.…”

Section: Targeting Protein-dna Interactions Of Fusion Oncoproteins Inmentioning

confidence: 99%

Targeting the undruggable: exploiting neomorphic features of fusion oncoproteins in childhood sarcomas for innovative therapies

Knott

Hölting²,

Ohmura³

et al. 2019

Cancer Metastasis Rev

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While sarcomas account for approximately 1% of malignant tumors of adults, they are particularly more common in children and adolescents affected by cancer. In contrast to malignancies that occur in later stages of life, childhood tumors, including sarcoma, are characterized by a striking paucity of somatic mutations. However, entity-defining fusion oncogenes acting as the main oncogenic driver mutations are frequently found in pediatric bone and soft-tissue sarcomas such as Ewing sarcoma (EWSR1-FLI1), alveolar rhabdomyosarcoma (PAX3/7-FOXO1), and synovial sarcoma (SS18-SSX1/2/4). Since strong oncogene-dependency has been demonstrated in these entities, direct pharmacological targeting of these fusion oncogenes has been excessively attempted, thus far, with limited success. Despite apparent challenges, our increasing understanding of the neomorphic features of these fusion oncogenes in conjunction with rapid technological advances will likely enable the development of new strategies to therapeutically exploit these neomorphic features and to ultimately turn the "undruggable" into first-line target structures. In this review, we provide a broad overview of the current literature on targeting neomorphic features of fusion oncogenes found in Ewing sarcoma, alveolar rhabdomyosarcoma, and synovial sarcoma, and give a perspective for future developments.

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Small molecule inhibition of lysine-specific demethylase 1 (LSD1) and histone deacetylase (HDAC) alone and in combination in Ewing sarcoma cell lines

Cited by 34 publications

References 43 publications

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

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

One oncogene, several vulnerabilities: EWS/FLI targeted therapies for Ewing sarcoma

Targeting the undruggable: exploiting neomorphic features of fusion oncoproteins in childhood sarcomas for innovative therapies

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