Co-activation of super-enhancer complex SOX2 and HDAC1 confers temozolomide resistance by promoting PDGFB transcription in glioblastoma
Menée à l'aide d'organoïdes et de xénogreffes de glioblastomes, cette étude met en évidence un mécanisme par lequel la co-activation du complexe SOX2 et de la désacétylase HDAC1 confère aux cellules cancéreuses une résistance au témozolomide en favorisant la transcription de la protéine PDGFB
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 effectively sensitizes GBM cells to TMZ.
Conclusions : Targeting the SE complex enhances TMZ chemosensitivity in GBM, providing a promising therapeutic avenue to overcome drug resistance and improve clinical outcomes.
Neuro-Oncology , résumé, 2025