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Review
. 2023 Mar 16;24(6):5665.
doi: 10.3390/ijms24065665.

Regulation of Cell Plasticity by Bromodomain and Extraterminal Domain (BET) Proteins: A New Perspective in Glioblastoma Therapy

Deborah Gargano  1 , Marco Segatto  1 , Sabrina Di Bartolomeo  1
Affiliations
Review

Regulation of Cell Plasticity by Bromodomain and Extraterminal Domain (BET) Proteins: A New Perspective in Glioblastoma Therapy

Deborah Gargano et al. Int J Mol Sci. .

Abstract

BET proteins are a family of multifunctional epigenetic readers, mainly involved in transcriptional regulation through chromatin modelling. Transcriptome handling ability of BET proteins suggests a key role in the modulation of cell plasticity, both in fate decision and in lineage commitment during embryonic development and in pathogenic conditions, including cancerogenesis. Glioblastoma is the most aggressive form of glioma, characterized by a very poor prognosis despite the application of a multimodal therapy. Recently, new insights are emerging about the glioblastoma cellular origin, leading to the hypothesis that several putative mechanisms occur during gliomagenesis. Interestingly, epigenome dysregulation associated with loss of cellular identity and functions are emerging as crucial features of glioblastoma pathogenesis. Therefore, the emerging roles of BET protein in glioblastoma onco-biology and the compelling demand for more effective therapeutic strategies suggest that BET family members could be promising targets for translational breakthroughs in glioblastoma treatment. Primarily, "Reprogramming Therapy", which is aimed at reverting the malignant phenotype, is now considered a promising strategy for GBM therapy.

Keywords: BET proteins; cell plasticity; differentiation; epigenome; glioblastoma; reprogramming therapy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Putative mechanisms of GBM onset. During the embryonic development, neural stem cells (NSC) are able to differentiate in a broad phenotypic spectrum, gradually acquiring specialized cellular identities. Three main models have been proposed to explain the loss of cellular identity occurring during gliomagenesis: (i) De-differentiation model, in which de-differentiated cortical astrocytes represent the GBM cells-of-origin; (ii) Arrested Differentiation model, according to which the glioma-initiating cells are multipotent progenitor cells whose proper differentiation is blocked; (iii) Circumvented differentiation model, where a pool of quiescent embryonic progenitors which is dormient in the adult brain re-assume a proliferative expansion originating a tumoral mass.
Figure 2
Figure 2
GBM Epigenome. H3K27M mutation results in global genomic decrease in H3 trimethylation (H3K27Mme3) and a concomitant increase in H3 acetylation (H3K27Mac), coupled to enhanced BRD2 and BRD4 recruitment and aberrant induction of gene expression. Tumor-suppressors hypermethylation also occurs.
Figure 3
Figure 3
Oncogenic pathways regulated by BET proteins in GBM. BET proteins positively regulate some oncogenes involved in the main GBM dysregulated signaling pathways promoting survival, death evasion and stemness maintenance. The numbers in the caption indicate the temporal sequence of the events.
See this image and copyright information in PMC

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