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EC-8042 reverses the activated transcriptional programs caused by HDACi in H3K27M-DIPG

ABSTRACT: Diffuse intrinsic pontine gliomas (DIPGs) are lethal pediatric brain tumors with limited therapeutic options. Frequently harboring H3K27M mutations, these tumors are resistant to Histone deacetylase inhibitors (HDACi) in clinical trials for yet unclear reasons. Given this, there is a critical need for exploring the reasons of insufficient clinical manifestations of HDACi and identifying effective combinatorial therapeutic strategy for the treatment of DIPG. To explore the possibility of combining HDACi with EC-8042, an analog of Mithramycin that blocks the DNA binding of SP/KLF factors，We performed ChIP-seq of H3K27ac in SU-DIPG-XVII cells after treated with DMSO, vorinostat and combination vorinostat with EC-8042. And discovered that EC-8042 reverses the activated transcriptional programs caused by HDACi.

ORGANISM(S): Homo sapiens

PROVIDER: GSE255011 | GEO | 2024/02/08

REPOSITORIES: GEO

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EC-8042 reverses the increased SP/KLFs chromatin binding caused by HDACi in H3K27M-DIPG

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Project description:Diffuse intrinsic pontine gliomas (DIPGs) are lethal pediatric brain tumors with limited therapeutic options. Frequently harboring H3K27M mutations, these tumors are resistant to Histone deacetylase inhibitors (HDACi) in clinical trials for yet unclear reasons. Given this, there is a critical need for exploring the reasons of insufficient clinical manifestations of HDACi and identifying effective combinatorial therapeutic strategy for the treatment of DIPG. To explore the possibility of combining HDACi with EC-8042, an analog of Mithramycin that blocks the DNA binding of SP/KLF factors, We performed RNA-seq in SU-DIPG-IV and SU-DIPG-XVII cells after treated with DMSO, vorinostat and combination vorinostat with EC-8042. And revealed that HDACi treatment amplifies the expression of hypoxia-responsive genes and promotes tumor invasiveness, which is efficiently counteracted by EC8042. And EC-8042 in combination with HDACi synergistically represses the expression of cell cycle-associated genes and therefore suppresses H3K27M-DIPG cell proliferation, inhibiting tumor progression in orthotopic xenograft models. Transcriptomic analysis further supports that the combination treatment drives transcriptional programs correlating with favorable prognosis in DIPG patients. Therefore, our regulome profiling in H3K27M-DIPGs has provided mechanistic insights into HDACi resistance and a proof-of-concept for novel targeting therapeutics.

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Increased Protein Processing Gene Signature in HDACi-resistant cells predicts response to proteasome inhibitors.

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