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KAT5 activity regulates quiescent-like states in human gliomas.

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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE198524 | GEO | 2023/12/01

REPOSITORIES: GEO

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Project description:The cranial neural crest plays a fundamental role in orofacial development and morphogenesis. As a pluripotent and dynamic cell population, the cranial neural crest is undergoing vast transcriptional alterations throughout embryogenesis and the formation of facial structures. These transcriptional changes are regulated by several transcription factors and remodeling complexes. Previously, we revealed the relevance of the Ep400/Kat5 histone acetyltransferase complex in the cranial neural crest and showed that the knockout of Ep400 causes neural crest-related malformations such as orofacial clefting. Furthermore, a case study identified three patients carrying missense mutations in Kat5 who showed severe mental impairments as well as orofacial clefts.2 The exact molecular causes and mechanisms, however, are still unknown. In this study we selectively knocked out Ep400 or Kat5 in the murine cranial neural crest cell line O9-1 to examine its roles in neural crest biology. To understand the regulatory effects of Ep400 and Kat5, knockout neural crest cells were investigated via bulk RNA sequencing to unravel transcriptomic changes in the affected cells. Bioinformatic analyses hinted at the regulation of major cellular functions such as proliferation, ATP generation and protein synthesis by the Ep400/Kat5 complex. Reduced proliferation was confirmed by crystal violet staining, phospho-histone H3 staining and the determination of mitotic cells with condensed chromatin in vitro. We did not detect increased apoptosis in the knockout cell lines. The energetic profile of the cells was investigated by Seahorse technology. The ATP-rate assay showed a decreased glycolytic activity in Ep400- or Kat5-deficient cells. An O-propargyl-puromycin (OPP) Click-iT assay revealed a significant reduction in protein synthesis. To verify in vivo the discovered in vitro effects, Ep400 and Kat5 were selectively ablated in cranial neural crest using Wnt1-Cre in transgenic mice. The knockout of each of the subunits resulted in severe craniofacial malformations from E12.5 onwards. At E10.5 a significant reduction in neural crest-derived tissue and proliferation rate was evident. The strong defect in orofacial structures of mice lacking Kat5 or Ep400 completely correspond to the milder orofacial malformations in patients carrying heterozygous missense mutations. Our results furthermore argue that changes of metabolism, protein synthesis and proliferation in cranial neural crest cells are responsible for the orofacial defects observed in patients.

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KAT5 activity regulates quiescent-like states in human gliomas.

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