KAT5 regulates neurodevelopmental states associated with G0-like populations in glioblastoma
Quiescence cancer stem-like cells may play key roles in promoting tumor cell heterogeneity and recurrence for many tumors, including glioblastoma (GBM). Here we show that the protein acetyltransferase KAT5 is a key regulator of transcriptional, epigenetic, and proliferative heterogeneity impacting transitions into G0-like states in GBM. KAT5 activity suppresses the emergence of quiescent subpopulations with neurodevelopmental progenitor characteristics, while promoting GBM stem-like cell (GSC) self-renewal through coordinately regulating E2F- and MYC- transcriptional networks with protein translation. KAT5 inactivation significantly decreases tumor progression and invasive behavior while increasing survival after standard of care. Further, increasing MYC expression in human neural stem cells stimulates KAT5 activity and protein translation, as well as confers sensitivity to homoharringtonine, to similar levels to those found in GSCs and high-grade gliomas. These results suggest that the dynamic behavior of KAT5 plays key roles in G0 ingress/egress, adoption of quasi-neurodevelopmental states, and aggressive tumor growth in gliomas.
Authors
- Melissa Ling
- Kelly Mitchell (ORCID: https://orcid.org/0000-0002-1124-7864)
- Jennifer Delegard
- Pia Hoellerbauer (ORCID: https://orcid.org/0000-0003-3672-5575)
- John Bassett (ORCID: https://orcid.org/0000-0002-9509-0752)
- Patrick J. Paddison (ORCID: https://orcid.org/0000-0002-7144-0228)
- Anoop P. Patel (ORCID: https://orcid.org/0000-0001-7078-9535)
- Samantha O’Connor (ORCID: https://orcid.org/0000-0002-8202-2435)
- Megan Kufeld
- Toshio Tsukiyama (ORCID: https://orcid.org/0000-0001-6478-6207)
- Heather Feldman
- Kang Jin (ORCID: https://orcid.org/0000-0001-5638-040X)
- Bruce J. Aronow (ORCID: https://orcid.org/0000-0001-5109-6514)
- Lucas Carter (ORCID: https://orcid.org/0000-0003-0385-9833)
- Christopher Plaisier (ORCID: https://orcid.org/0000-0003-3273-5717)
- Wesley Jenkins (ORCID: https://orcid.org/0000-0002-7989-4320)
- Anca B. Mihalas
- Christine E. Cucinotta (ORCID: https://orcid.org/0000-0002-9644-3126)
- Philip Corrin
- Sonali Arora (ORCID: https://orcid.org/0000-0002-6661-3024)
- Dayoung Kim (ORCID: https://orcid.org/0000-0002-7221-2446)
Institutions
- Cincinnati Children's Hospital Medical Center (US)
- Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa (ZA)
- Duke University (US)
- University of Washington (US)
- Karolinska Institutet (SE)
- Fred Hutch Cancer Center (US)
- Duke University Hospital (US)
- Pediatric Brain Tumor Foundation (US)
- The Ohio State University (US)
- Arizona State University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-09
- DOI
- https://doi.org/10.1038/s41467-025-59503-w
- Citations
- 4
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 3.22
Funders
- Fred Hutchinson Cancer Research Center
- National Institutes of Health
- National Cancer Institute
- National Institute of General Medical Sciences
- National Institute of Neurological Disorders and Stroke