Abstract
PurposeEpigenetic regulation is crucial in mammalian development and maintenance of tissue-cell specific functions. Perturbation of epigenetic balance may lead to alterations in gene expression, resulting in cellular transformation and malignancy. Previous studies in Ewing sarcoma (ES) have shown that the Nucleosome Remodeling Deacetylase (NuRD) complex binds directly to EWS-FLI1 oncoprotein and modulates its transcriptional activity. The role of EWS-FLI1 as a driver of proliferation and transformation in ES is widely known, but the effect of epigenetic drugs on fusion activity remains poorly described. The present study evaluated the combination effects of the histone deacetylases inhibitor suberoylanilide hydroxamic acid (SAHA) and Lysine-specific demethylase1 inhibitor (HCI-2509) on different biological functions in ES and in comparison to monotherapy treatments.ResultsThe study of proliferation and cell viability showed a synergistic effect in most ES cell lines analyzed. An enhanced effect was also observed in the induction of apoptosis, together with accumulation of cells in G1 phase and a blockage of the migratory capacity of ES cell lines. Treatment, either in monotherapy or in combination, caused a significant decrease of EWS-FLI1 mRNA and protein levels and this effect is mediated in part by fusion gene promoter regulation. The anti-tumor effect of this combination was confirmed in patient-derived xenograft mouse models, in which only the combination treatment led to a statistically significant decrease in tumor volume.ConclusionsThe combination of SAHA and HCI-2509 is proposed as a novel treatment strategy for ES patients to inhibit the essential driver of this sarcoma and tumor growth.
Highlights
Ewing sarcoma (ES) is the second most frequent sarcoma of bone and soft tissues in children and young adults
The combination of suberoylanilide hydroxamic acid (SAHA) and HCI-2509 is proposed as a novel treatment strategy for ES patients to inhibit the essential driver of this sarcoma and tumor growth
This multiprotein complex is formed by different subunits including histone deacetylases (HDACs), lysine-specific demethylase 1 (LSD1) and others, which participate in the transcriptional regulation of EWS-FLI1 target genes [13]
Summary
Ewing sarcoma (ES) is the second most frequent sarcoma of bone and soft tissues in children and young adults. The most frequent gene mutations involve STAG2 and TP53, and copy number alteration events such as gains of chromosome 1q, 2, 8 and 12, and losses of 9p (affecting CDKN2A) and 16q [4,5,6,7]. For this reason, researchers are seeking in the ES epigenome new alternatives to conventional strategies [1]. This multiprotein complex is formed by different subunits including histone deacetylases (HDACs), lysine-specific demethylase 1 (LSD1) and others, which participate in the transcriptional regulation of EWS-FLI1 target genes [13]
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