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Cut&Run SU-DIPG13 cells treated Sulfopin/Vorinostat/Sulfopin+Vorinostat or DMSO

ABSTRACT: Diffuse midline gliomas (DMG) are aggressive pediatric tumors of the central nervous system that are highly resistant to treatments and are inevitably fatal. Lysine to methionine substitution of residue 27 on histone H3 (H3-K27M) is a driver mutation in DMGs, reshaping the epigenetic landscape of these cells to promote tumorigenesis. H3-K27M gliomas are characterized by deregulation of histone acetylation and methylation pathways, as well as the oncogenic MYC pathway. In search of effective treatment, we examined the therapeutic potential of dual targeting of histone deacetylases (HDACs) and MYC in these tumors. Treatment of H3-K27M patient-derived cells with Sulfopin, an inhibitor shown to block MYC-driven tumors in vivo, in combination with the HDAC inhibitor Vorinostat, resulted in substantial decrease in cell viability. Moreover, transcriptome and epigenome profiling revealed synergistic effect of this drug combination in downregulation of prominent oncogenic pathways such as mTOR. Finally, in vivo studies of patient-derived orthotopic xenograft models showed significant tumor size reduction in mice treated with the drug combination. These results highlight the combined treatment of Sulfopin and Vorinostat as a promising therapeutic approach for these aggressive tumors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE221611 | GEO | 2024/06/24

REPOSITORIES: GEO

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Project description:Acute myeloid leukaemia (AML) is a highly heterogeneous entity of disorders in haematopoietic progenitors, characterised by an arrest in differentiation and an outgrowth of myeloid blasts in the bone marrow. AML is a disease of the aging, many patients are unable to withstand standard chemotherapy therefore novel approaches for anti-cancer agents has arisen in the understanding of epigenetic regulation in cancer cells, such as chromatin remodelling. Acetylation of histones is a reversible process, whereby acetyl groups are transferred on the ε-amino groups of specific lysine residues by a specific group of enzymes, histone acetyltransferases (HATs) and removed by histone deacetylase complexes (HDACs). HDACs are involved in regulating a number of processes in the cell, such as cell proliferation, differentiation as well as apoptosis. Deregulation of the activity of these enzymes is associated with cancer; therefore it is important that the HAT and HDAC equilibrium is regained. This equilibrium can be improved through the inhibition of HDAC enzymes using HDAC inhibitors. Vorinostat is a HDAC inhibitor, clinically approved for the treatment of CTCL, and is in phase II clinical trials for AML and a number of haematological malignancies. Studies have shown that some patients are non-responsive/resistant to Vorinostat; therefore a fuller characterisation of Vorinostat needs to be made so an adequate combination drug can be identified, as understanding of resistance is crucial to overcoming it. The purpose of this study was to provide a comprehensive analysis of Vorinostat in AML cell lines and to identify potential synergistic therapies that could be used in combination with Vorinostat to provide a better outlook in AML. The global identification of genes associated with Vorinostat induced histone H3 lysine 9 (H3K9) acetylation, investigated using chromatin immunoprecipitation coupled with next generation sequencing (ChIP-SEQ), was integrated with data from gene expression studies to provide a comprehensive approach to understanding Vorinostat. This study has identified the sonic hedgehog homolog (SHH) as a rational and potential therapeutic target for combination therapy with Vorinostat

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Cut&Run SU-DIPG13 cells treated Sulfopin/Vorinostat/Sulfopin+Vorinostat or DMSO

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