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

Authors

Chao Wang, Rui Shang, Hua Liang, Meng Zhu, Wujun Chen, Kai Zhao

Published in

Translational oncology. Volume 71. Pages 102912. Jul 14, 2026. Epub Jul 14, 2026.

Abstract

Mesenchymal glioblastoma (MES GBM) is characterized by rapid proliferation, extensive invasion, and formidable treatment resistance. We aimed to find the MES GBM subtype conversion mechanism.
HDAC1 expression was examined across various GBM subtypes through in vitro and in vivo experiments. The impact of HDAC1 inhibitors and bevacizumab on the phenotypic characteristics of MES cells was also 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, followed by the experiments to investigate their effects on MES GBM cells.
Firstly, we observed overexpression of HDAC1 in MES-type cells and its positive correlation with MES representative genes. 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. Additionally, bevacizumab significantly inhibited PN subtype GBM cells, and when combined with RG2833 (an HDAC1/3 inhibitor), it also inhibited the growth and proliferation of MES subtype GBM. RG2833 was found to enhance histone acetylation, promoting the binding of the transcription factor p-SMAD3 (Ser423 and Ser425) 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. Knocking down TP53I11 transformed PN subtype GBM into MES characteristics.
The study indicates that by intervening HDAC1/p-SMAD3-TP53I11, HDAC1 can serve as a promising therapeutic target for the treatment of mesenchymal glioblastoma.

PMID:
42447568
Bibliographic data and abstract were imported from PubMed on 15 Jul 2026.

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