Introduction: Diffuse intrinsic pontine gliomas (DIPGs) pose significant challenges in pediatric oncology with limited treatment options. Frequently harboring H3K27M mutations, these tumors are insensitive to histone deacetylase inhibitors (HDACi) in clinical trials for yet unclear reasons.
Methods: In this study, we conducted in vitro functional assays, in vivo animal model experiments, tumor tissue pathology analysis, western blotting and immunofluorescence, as well as multi-omics joint analysis including RNA-Seq, ATAC-Seq, and ChIP-Seq.
Results: Here we find that HDACi induce histone hyperacetylation including H3K27 acetylation, and increased accessibility at genomic regions linked to tumor microenvironment adaptation and invasiveness. And these regions gain occupancy of the SP/KLF family of transcription factors. Encouragingly, targeted intervention with EC-8042 effectively reverses this activated regulatory network by HDACi, thereby mitigating tumor adaptation and invasiveness. Furthermore, the combination of EC-8042 with HDACi enhances the repression of transcription in cell cycle-associated genes, leading to the inhibition of H3K27M-DIPG cell proliferation and impeding tumor progression in orthotopic xenograft models. Transcriptomic analysis further supports that the combination treatment drives transcriptional programs correlating with favorable prognosis in DIPG patients.
Conclusion : Therefore, employing DIPG models, this study provides critical mechanistic understanding of the limited responsiveness to HDACi in solid tumors, thereby laying the groundwork for the innovation of novel combination strategies.
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