The tumour-promoting role of ZBTB18 N-terminal short form in glioblastoma progression and initial characterization of ZBTB18 C-terminal short form

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Abstract: Despite extensive and aggressive therapy, the highly malignant glioblastoma continues to be associated with a very poor prognosis and requires more intensive research to understand the multifactorial pathogenesis. Interestingly, the previously discovered tumour suppressor protein ZBTB18 is cleaved by calpain 2 into two short protein fragments, of which the ZBTB18 N terminal fragment was detected in tumorous tissue and identified as tumour-promoting. Therefore, the aim of this work was to investigate pro-oncogenic mechanisms of ZBTB18 SF Nte contributing to glioblastoma progression, as well as the initial characterisation and role of the C-terminal ZBTB18 SF fragment in glioblastoma pathogenesis. Using molecular biology methods, the expression regulation of hypoxic genes by ZBTB18 SF Nte and its role in tumour metabolism, with a particular focus on lipid metabolism, was evaluated. The ZBTB18 SF-Nte-mediated effect on immune metabolism was also investigated. The cloning of ZBTB18 SF-Cte into the pCHMWS vector allowed its overexpression in BTSC and consequently, first investigations regarding its function in glioblastoma progression through different phenotypic assays. In addition, sequence-specific differences between the BTSC with and without ZBTB18 SF expression were investigated in terms of differential protein stability. ZBTB18 SF-Nte was shown to activate HIF1α target genes, which further leads to an increase in lipid uptake, lipid droplet formation and a generally enhanced cell metabolism, which, however, can also be regulated by ZBTB18 SF-Nte in a hypoxia-independent manner. Furthermore, an upregulation of pro-oncogenic immunosuppressive cytokines among ZBTB18 SF-Nte presence was indicated. A stable ZBTB18 SF-Cte protein was detected in the nuclear cell compartment of specific BTSC and showed no relevant alterations in its amino acid sequence compared to BTSC without ZBTB18 SF expression. The assumption that ZBTB18 SF-Cte has a tumour-suppressive effect due to its nuclear localisation was only confirmed by a reduced invasion ability of the tumour cells. Further investigations of the exact mechanisms of gene expression regulation by ZBTB18 SF Nte and confirmation of its activating effect on immunosuppressive cytokines should be performed. In particular, the ZBTB18 SF-Cte product requires further investigation to clarify its exact function in the course of the disease

Standort
Deutsche Nationalbibliothek Frankfurt am Main
Umfang
Online-Ressource
Sprache
Englisch
Anmerkungen
Universität Freiburg, Dissertation, 2024

Schlagwort
Genexpression
Glioblastom
Neurochirurgie
Gliom

Ereignis
Veröffentlichung
(wo)
Freiburg
(wer)
Universität
(wann)
2025
Urheber
Beteiligte Personen und Organisationen

DOI
10.6094/UNIFR/262072
URN
urn:nbn:de:bsz:25-freidok-2620729
Rechteinformation
Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
Letzte Aktualisierung
15.08.2025, 07:29 MESZ

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  • 2025

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