P300 promotes tumor recurrence by regulating radiation-induced conversion of glioma stem cells to vascular-like cells

Sree Deepthi Muthukrishnan, Riki Kawaguchi, Pooja Nair, Rachna Prasad, Yue Qin, Maverick Johnson, Qing Wang, Nathan VanderVeer-Harris, Amy Pham, Alvaro G. Alvarado, Michael C. Condro, Fuying Gao, Raymond Gau, Maria G. Castro, Pedro R. Lowenstein, Arjun Deb, Jason D. Hinman, Frank Pajonk, Terry C. Burns, Steven A. Goldman, Daniel H. Geschwind and Harley I. Kornblum ()
Additional contact information
Sree Deepthi Muthukrishnan: The UCLA Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, UCLA
Riki Kawaguchi: The UCLA Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, UCLA
Pooja Nair: The UCLA Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, UCLA
Rachna Prasad: The UCLA Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, UCLA
Yue Qin: The UCLA Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, UCLA
Maverick Johnson: The UCLA Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, UCLA
Qing Wang: The UCLA Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, UCLA
Nathan VanderVeer-Harris: The UCLA Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, UCLA
Amy Pham: The UCLA Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, UCLA
Alvaro G. Alvarado: The UCLA Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, UCLA
Michael C. Condro: The UCLA Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, UCLA
Fuying Gao: The UCLA Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, UCLA
Raymond Gau: The UCLA Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, UCLA
Maria G. Castro: University of Michigan Medical School
Pedro R. Lowenstein: University of Michigan Medical School
Arjun Deb: David Geffen School of Medicine, UCLA
Jason D. Hinman: David Geffen School of Medicine, UCLA
Frank Pajonk: David Geffen School of Medicine, UCLA
Terry C. Burns: Mayo Clinic
Steven A. Goldman: University of Rochester Medical Center
Daniel H. Geschwind: The UCLA Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, UCLA
Harley I. Kornblum: The UCLA Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, UCLA

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract Glioma stem cells (GSC) exhibit plasticity in response to environmental and therapeutic stress leading to tumor recurrence, but the underlying mechanisms remain largely unknown. Here, we employ single-cell and whole transcriptomic analyses to uncover that radiation induces a dynamic shift in functional states of glioma cells allowing for acquisition of vascular endothelial-like and pericyte-like cell phenotypes. These vascular-like cells provide trophic support to promote proliferation of tumor cells, and their selective depletion results in reduced tumor growth post-treatment in vivo. Mechanistically, the acquisition of vascular-like phenotype is driven by increased chromatin accessibility and H3K27 acetylation in specific vascular genes allowing for their increased expression post-treatment. Blocking P300 histone acetyltransferase activity reverses the epigenetic changes induced by radiation and inhibits the adaptive conversion of GSC into vascular-like cells and tumor growth. Our findings highlight a role for P300 in radiation-induced stress response, suggesting a therapeutic approach to prevent glioma recurrence.

Date: 2022
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DOI: 10.1038/s41467-022-33943-0

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