Abstract
Simple SummaryIn the search of the key factors that differentiate the aggressive glioblastomas from lower-grade gliomas, we determined that the variants of the structural protein of the nucleosome histone H3 show different degrees of expression. In general, high expression of H3.1/H3.2 was associated with clinical features of glioblastomas whereas high expression of H3.3 was linked to molecular alterations found in low-grade gliomas. In fact, those glioblastomas showing low expression levels of H3.1/H3.2 are highly similar to low-grade gliomas, suggesting an association with glioma aggressiveness that deserves further investigation in large cohorts.Glioblastoma (GB) is the most aggressive form of glioma and is characterized by poor prognosis and high recurrence despite intensive clinical interventions. To retrieve the key factors underlying the high malignancy of GB with potential diagnosis utility, we combined the analysis of The Cancer Gene Atlas and the REMBRANDT datasets plus a molecular examination of our own collection of surgical tumor resections. We determined a net reduction in the levels of the non-canonical histone H3 variant H3.3 in GB compared to lower-grade astrocytomas and oligodendrogliomas with a concomitant increase in the levels of the canonical histone H3 variants H3.1/H3.2. This increase can be potentially useful in the clinical diagnosis of high-grade gliomas, as evidenced by an immunohistochemistry screening of our cohort and can be at least partially explained by the induction of multiple histone genes encoding these canonical forms. Moreover, GBs showing low bulk levels of the H3.1/H3.2 proteins were more transcriptionally similar to low-grade gliomas than GBs showing high levels of H3.1/H3.2. In conclusion, this study identifies an imbalanced ratio between the H3 variants associated with glioma malignancy and molecular patterns relevant to the biology of gliomas, and proposes the examination of the H3.3 and H3.1/H3.2 levels to further refine diagnosis of low- and high-grade gliomas in future studies.
Highlights
Gliomas constitute ~70% of primary brain cancers, most of which are aggressive glioblastomas (GBs) [1]
Were superior to H3-3A in all the gliomas (~20-fold, Figure 1A), we predicted a net decrease in the H3.3 protein in GB after inferring the combined contributions of both transcripts to the protein levels
To confirm such protein reduction, we examined the H3.3 levels in Western blotting assays in surgical tumor resections from adult patients (Table S1) who had been diagnosed primarily using histological criteria with astrocytoma, oligodendroglioma, either diffuse or anaplastic, or GB
Summary
Gliomas constitute ~70% of primary brain cancers, most of which are aggressive glioblastomas (GBs) [1]. Clinical management of GBs is challenging due to their cellular and molecular complexity, which explains their high recurrence and poor survival (with the median overall survival of ~15 months after intensive therapies). Both diagnosis and prognosis of GB based entirely on the morphological classification are insufficient [2,3] and further implementation of appropriate molecular criteria is required as predictors of patient outcome during the progression and treatment of gliomas [4,5,6,7,8]. The loss of the ATPase-helicase chromatin remodelling factor ATRX (α-thalassemia/mental retardation syndrome X-linked) disrupts the interaction of multiple epigenetic modulators (including methyl-CpG-binding MECP2, H3K27 methyltransferase EZH2 or histone variants macroH2A and H3.3) in the euchromatin–
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