Unveiling the conversion mechanism of glioblastoma from the mesenchymal to the proneural subtype driven by HDAC1/p-SMAD3-TP53I11 axis

Mesenchymal glioblastoma (MES GBM) is characterized by rapid proliferation, extensive invasion, and formidable treatment resistance. Addressing these characteristics in MES cells is crucial for improving patient prognosis. Here, we discovered the MES GBM subtype conversion mechanism driven by HDAC1/p-SMAD3-TP53I11 in this study. First, the impact of HDAC1 inhibitors and bevacizumab on the phenotypic characteristics of MES cells was assessed. Co-immunoprecipitation (Co-IP) and immunofluorescence techniques elucidated the epigenetic mechanism of HDAC1. Chromatin immunoprecipitation sequencing (ChIP-seq) and RNA-seq identified downstream transcribed genes. We found Inhibition or knockdown of HDAC1 transformed MES characteristics into proneural (PN) characteristics, prolonged survival in patient-derived xenograft (PDX) models, and suppressed in vitro cell proliferation and invasion. RG2833 (an HDAC1 inhibitor) was found to enhance histone acetylation, promoting the binding of the transcription factor p-SMAD3 to the genome. Immunoprecipitation experiments revealed an interaction between p-SMAD3 and HDAC1. RNA-seq and ChIP-seq data analysis from MES cell lines before and after RG2833 treatment identified Tumor Protein P53 Inducible Protein 11 (TP53I11) as a downstream gene. The study indicates that by intervening HDAC1/p-SMAD3-TP53I11, HDAC1 can serve as a promising therapeutic target for the treatment of MES GBM.