Defining a Correlative Transcriptional Signature Associated with Bulk Histone H3 Acetylation Levels in Adult Glioblastomas

Cells. 2023 Jan 19;12(3):374. doi: 10.3390/cells12030374.

Abstract

Glioblastoma (GB) is the most prevalent primary brain cancer and the most aggressive form of glioma because of its poor prognosis and high recurrence. To confirm the importance of epigenetics in glioma, we explored The Cancer Gene Atlas (TCGA) database and we found that several histone/DNA modifications and chromatin remodeling factors were affected at transcriptional and genetic levels in GB compared to lower-grade gliomas. We associated these alterations in our own cohort of study with a significant reduction in the bulk levels of acetylated lysines 9 and 14 of histone H3 in high-grade compared to low-grade tumors. Within GB, we performed an RNA-seq analysis between samples exhibiting the lowest and highest levels of acetylated H3 in the cohort; these results are in general concordance with the transcriptional changes obtained after histone deacetylase (HDAC) inhibition of GB-derived cultures that affected relevant genes in glioma biology and treatment (e.g., A2ML1, CD83, SLC17A7, TNFSF18). Overall, we identified a transcriptional signature linked to histone acetylation that was potentially associated with good prognosis, i.e., high overall survival and low rate of somatic mutations in epigenetically related genes in GB. Our study identifies lysine acetylation as a key defective histone modification in adult high-grade glioma, and offers novel insights regarding the use of HDAC inhibitors in therapy.

Keywords: HDACi; RNA-seq; TSA; acetylation; epigenetics; glioma; histone.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Adult
  • Glioblastoma* / genetics
  • Glioma* / genetics
  • Histone Deacetylase Inhibitors / pharmacology
  • Histones / metabolism
  • Humans
  • Vesicular Glutamate Transport Protein 1

Substances

  • Histones
  • Histone Deacetylase Inhibitors
  • SLC17A7 protein, human
  • Vesicular Glutamate Transport Protein 1

Grants and funding

L.M.V.’s research is supported by Programa Estatal de Generación de Conocimiento y Fortalecimiento del Sistema Español de I+D+i and financed by Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional 2014–2020 (grants CP15/00180, PI16/00722, PI19/00125), Plan Propio INiBICA (grant LI19-07IN-CO07) and Ayudas para el Apoyo y Fomento de la Investigación de ISABIAL (grant 2021-0406). C.C.’s research is supported by the Integrated Territorial Investment Operational Programme of the European Commission and by the Department of Health and Families (Consejería de Salud y Familias) of the Regional Government of Andalusia (project reference: ITI-0042-2019 ITI CÁDIZ 2019). L.M.V. is the recipient of a Miguel Servet II contract (CPII20/00025), financed by Instituto de Salud Carlos III and Fondo Social Europeo 2014–2020, Programa Estatal de Promoción del Talento y su empleabilidad en I+D+i.