Kavli Affiliate: Jin Kang
| Authors: Anca Mihalas, Sonali Arora, Samantha O’Connor, Heather Feldman, John Bassett, Kelly Mitchell, Kang Jin, Pia Hoellerbauer, Melissa Ling, Wesley Jenkins, Megan Kufeld, Philip Corrin, Lucas Carter, Bruce J Aronow, Christopher J Plaisier, Anoop Patel and PATRICK PADDISON
| Summary:
In solid tumors, G0-like cell populations likely play important roles in maintaining cellular heterogeneity and promoting recurrence after standard of care. However, little is known about the mechanisms of tumor cell G0 ingress and egress. To discover regulators of G0-like states for glioblastoma (GBM), we performed a genome-wide CRISPR-Cas9 screen in patient-derived GBM stem-like cells (GSCs) for genes that trap cells in G0-like states when inhibited. We identify the protein acetyltransferase KAT5 as a key regulator of G0 and cell cycle dynamics in GSCs and GSC-derived tumors. In primary gliomas, KAT5low cells display G0-like properties, while overall KAT5 activity increases from low to high grade tumors. Further, we find that KAT5 activity suppresses the emergence of non-dividing subpopulations with oligodendrocyte progenitor and radial glial cell characteristics both in vitro and in a GSC tumor model. These results reveal that KAT5 activity regulates transitions between non-dividing/slow cycling, neurodevelopmental, and proliferative states in GBM tumors.