KAT5 regulates neurodevelopmental states associated with G0-like populations in glioblastoma

Anca B. Mihalas, Sonali Arora, Samantha A. O’Connor, Heather M. Feldman, Christine E. Cucinotta, Kelly Mitchell, John Bassett, Dayoung Kim, Kang Jin, Pia Hoellerbauer, Jennifer Delegard, Melissa Ling, Wesley Jenkins, Megan Kufeld, Philip Corrin, Lucas Carter, Toshio Tsukiyama, Bruce Aronow, Christopher L. Plaisier, Anoop P. Patel () and Patrick J. Paddison ()
Additional contact information
Anca B. Mihalas: Fred Hutchinson Cancer Center
Sonali Arora: Fred Hutchinson Cancer Center
Samantha A. O’Connor: Arizona State University
Heather M. Feldman: Fred Hutchinson Cancer Center
Christine E. Cucinotta: Ohio State University
Kelly Mitchell: Fred Hutchinson Cancer Center
John Bassett: Karolinska Institute
Dayoung Kim: Fred Hutchinson Cancer Center
Kang Jin: Cincinnati Children’s Hospital Medical Center
Pia Hoellerbauer: Fred Hutchinson Cancer Center
Jennifer Delegard: University of Washington
Melissa Ling: University of Washington
Wesley Jenkins: University of Washington
Megan Kufeld: Fred Hutchinson Cancer Center
Philip Corrin: Fred Hutchinson Cancer Center
Lucas Carter: Fred Hutchinson Cancer Center
Toshio Tsukiyama: Fred Hutchinson Cancer Center
Bruce Aronow: Cincinnati Children’s Hospital Medical Center
Christopher L. Plaisier: Arizona State University
Anoop P. Patel: Duke University
Patrick J. Paddison: Fred Hutchinson Cancer Center

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-59503-w

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