Targeting the SP/KLF Transcriptional Regulatory Network Synergizes with HDAC Inhibition to Impede Progression of H3K27M Diffuse Intrinsic Pontine Glioma

Résumé fourni par la source

Diffuse intrinsic pontine gliomas (DIPG) are lethal pediatric brain tumors that frequently harbor H3K27M mutations and lack effective treatments. In this study, our epigenomic analyses uncovered an enrichment of specificity protein/Krüppel-like factor (SP/KLF) transcription factors in open chromatin regions specifically in H3K27M-mutated DIPG cells compared with normal pontine neural progenitor cells. SP1 depletion or inhibition of SP/KLF DNA binding with EC-8042, an optimized mithramycin analog, significantly suppressed the proliferation and invasiveness of H3K27M-DIPG cells. A screen of epigenetic drugs showed that histone deacetylase inhibitors (HDACi) synergized with EC-8042 to suppress H3K27M-DIPG cell growth. Unexpectedly, HDACis activated transcriptional programs that enhanced tumor adaptability and invasiveness, an effect counteracted by EC-8042. Mechanistically, HDACi treatment enhanced chromatin accessibility to SP/KLF factors, whereas EC-8042 disrupted both the primary SP/KLF transcription regulatory network and the HDACi-induced secondary network. Consequently, the combination treatment significantly impeded tumor progression in orthotopic xenograft models. Transcriptomic profiling indicated that this combinatorial strategy induced transcriptional changes associated with improved prognosis in patients with DIPG. Thus, this study identifies a therapeutic approach for H3K27M-mutated DIPGs and sheds light on the limitations of HDACis in treating solid tumors. Significance: The SP/KLF transcriptional regulatory network is activated in H3K27M-mutated diffuse intrinsic pontine glioma and represents a promising therapeutic target in combination with HDAC inhibitors for combating these lethal pediatric brain tumors.

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