E2F and STAT3 provide transcriptional synergy for histone variant H2AZ activation to sustain glioblastoma chromatin accessibility and tumorigenicity

• DOI: 10.1038/s41418-021-00926-5
• Publication Date: 2022-01-20T12:07:40Z
• Authors: Jeehyun Yoon; Oleg V. Grinchuk; Roberto Tirado-Ma...; Zhen Kai Ngian; Emmy Xue Yun Tay; You Heng Chuah; Bernice Woon Li Lee; Jia Feng; Karen Carmelina C...; Chin Tong Ong; Touati Benoukraf; Derrick Sek Tong Ong
• Keywords: E2F; E2F1; Chromatin immunoprecipitation

Abstract The histone variant H2AZ is overexpressed in diverse cancer types where it facilitates the accessibility of transcriptional regulators to promoters cell cycle genes. However, molecular basis for its dysregulation remains unknown. Here, we report that glioblastomas (GBM) and glioma stem cells (GSCs) preferentially overexpress their proliferation, stemness tumorigenicity. Chromatin analysis H2AZ2 depleted GSC revealed E2F1 occupies enhancer region within gene promoter, thereby activating transcription. Exploration other activators using a customized “anti- ” query signature connectivity map identified STAT3. Co-targeting E2F STAT3 synergistically reduced levels H2AZ, 3 lysine 27 acetylation (H3K27ac) transcription, indicating synergize activate transcription GSCs. Remarkably, an E2F/STAT3 inhibitor combination durably suppresses tumorigenicity orthotopic GBM xenograft model. In patients, high signaling associated with expression. Thus, has uniquely opted use E2F1- STAT3-containing “enhanceosomes” integrate multiple pathways achieve activation, supporting translational path be applied treatment.