Co-activation of the super-enhancer complex SOX2 and HDAC1 confers temozolomide resistance by promoting PDGFB transcription in glioblastoma

作者：Han Xie, Tongjie Ji, Chunyu Zhang, Meng Cheng, Rui Wang, Yueyao Wu, Jingzhe Wang, Honghao Wang, Junyu Yang, Siyi Xu, Min Liu, Jing Zhang, Chunlong Zhong · 发表于：Neuro-Oncology · 年份：2025 · DOI：10.1093/neuonc/noaf219 · 被引用次数：4 · 研究领域：Glioma Diagnosis and Treatment、Histone Deacetylase Inhibitors Research、Angiogenesis and VEGF in Cancer

BACKGROUND: Temozolomide (TMZ) resistance remains the major obstacle in the treatment of glioblastoma (GBM). We previously found that the super-enhancer (SE) complex is involved in the regulation of genes related to tumor biology, but its mechanisms in mediating TMZ resistance in GBM remain poorly characterized. METHODS: Comprehensive in vitro and in vivo functional experiments were conducted using patient-derived cells (PDCs), patient-derived organoids, and PDCs xenograft models. Cleavage Under Targets and Tagmentation, chromatin immunoprecipitation, co-immunoprecipitation, mass spectrometry, protein fragment complementation assay, dual-luciferase reporter assay, fluorescence polarization assay, and surface plasmon resonance assay were employed to unravel the molecular mechanisms. RESULTS: We found that SOX2 is significantly upregulated in TMZ-resistant PDCs and associated with the poor prognosis of recurrent GBM patients. Moreover, inhibition of SOX2 enhanced TMZ-induced apoptosis and DNA damage response, thereby promoting TMZ chemosensitivity. Mechanically, we identified PDGFB as a novel SE-associated oncogene mediated by SOX2. SE complex SOX2 and HDAC1 were recruited together to the SE region of PDGFB, synergistically triggering the PDGFB-MAPK/PI3K signaling axis and ultimately promoting TMZ resistance. Notably, virtual screening targeting the critical interaction domain between SOX2 and HDAC1 identified the FDA-approved drug fluvastatin as a potent SOX2 inhibitor that ef...