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

Author

Listed:
  • 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
    Fred Hutchinson Cancer Center)

  • 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
    Duke University
    Duke University)

  • Patrick J. Paddison

    (Fred Hutchinson Cancer Center
    University of Washington)

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.

Suggested Citation

  • 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 & Me, 2025. "KAT5 regulates neurodevelopmental states associated with G0-like populations in glioblastoma," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59503-w
    DOI: 10.1038/s41467-025-59503-w
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