E2F and STAT3 provide transcriptional synergy for histone variant H2AZ activation to sustain glioblastoma chromatin accessibility and tumorigenicity.
Jeehyun YoonOleg V GrinchukRoberto Tirado-MagallanesZhen Kai NgianEmmy Xue Yun TayYou Heng ChuahBernice Woon Li LeeJia FengKaren Carmelina CrastaChin Tong OngTouati BenoukrafDerrick Sek Tong OngPublished in: Cell death and differentiation (2022)
The histone variant H2AZ is overexpressed in diverse cancer types where it facilitates the accessibility of transcriptional regulators to the promoters of cell cycle genes. However, the molecular basis for its dysregulation in cancer remains unknown. Here, we report that glioblastomas (GBM) and glioma stem cells (GSCs) preferentially overexpress H2AZ for their proliferation, stemness and tumorigenicity. Chromatin accessibility analysis of H2AZ2 depleted GSC revealed that E2F1 occupies the enhancer region within H2AZ2 gene promoter, thereby activating H2AZ2 transcription. Exploration of other H2AZ2 transcriptional activators using a customized "anti-H2AZ2" query signature for connectivity map analysis identified STAT3. Co-targeting E2F and STAT3 synergistically reduced the levels of H2AZ, histone 3 lysine 27 acetylation (H3K27ac) and cell cycle gene transcription, indicating that E2F1 and STAT3 synergize to activate H2AZ gene transcription in GSCs. Remarkably, an E2F/STAT3 inhibitor combination durably suppresses GSC tumorigenicity in an orthotopic GBM xenograft model. In glioma patients, high STAT3 signaling is associated with high E2F1 and H2AZ2 expression. Thus, GBM has uniquely opted the use of E2F1- and STAT3-containing "enhanceosomes" that integrate multiple signaling pathways to achieve H2AZ gene activation, supporting a translational path for the E2F/STAT3 inhibitor combination to be applied in GBM treatment.
Keyphrases
- cell cycle
- cell proliferation
- transcription factor
- genome wide
- stem cells
- genome wide identification
- gene expression
- dna methylation
- signaling pathway
- copy number
- dna damage
- end stage renal disease
- poor prognosis
- young adults
- long non coding rna
- white matter
- multiple sclerosis
- newly diagnosed
- single cell
- peritoneal dialysis
- cancer therapy
- oxidative stress
- smoking cessation
- lymph node metastasis
- replacement therapy
- amino acid