2. Academic Validation
  3. E2F and STAT3 provide transcriptional synergy for histone variant H2AZ activation to sustain glioblastoma chromatin accessibility and tumorigenicity

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

  • Cell Death Differ. 2022 Jul;29(7):1379-1394. doi: 10.1038/s41418-021-00926-5.
Jeehyun Yoon  # 1 2,  Oleg V Grinchuk  # 1 2,  Roberto Tirado-Magallanes  # 3,  Zhen Kai Ngian 4,  Emmy Xue Yun Tay 1 2,  You Heng Chuah 1 2,  Bernice Woon Li Lee 1 2,  Jia Feng 1 2,  Karen Carmelina Crasta 1 2 5 6,  Chin Tong Ong 4 7,  Touati Benoukraf 3 8,  Derrick Sek Tong Ong 9 10 11 12
Affiliations

Affiliations

  • 1 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117593, Singapore.
  • 2 NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 3 Cancer Science Institute of Singapore, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore.
  • 4 Temasek Life Sciences Laboratory, National University of Singapore, Singapore, 117604, Singapore.
  • 5 Centre for Healthy Longevity, National University Health System, Singapore, 119228, Singapore.
  • 6 Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
  • 7 Department of Biological Sciences, National University of Singapore, Singapore, 117558, Singapore.
  • 8 Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, A1B 3V6, Canada.
  • 9 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117593, Singapore. [email protected].
  • 10 NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. [email protected].
  • 11 Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore. [email protected].
  • 12 National Neuroscience Institute, Singapore, 308433, Singapore. [email protected].
  • # Contributed equally.
PMID: 35058574 DOI: 10.1038/s41418-021-00926-5
Abstract

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.

Figures
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