Targeting the ubiquitin system in glioblastoma

Scholz, Nico, Kurian, Kathreena M., Siebzehnrubl, Florian A. ORCID: https://orcid.org/0000-0001-8411-8775 and Licchesi, Julien D. F. 2020. Targeting the ubiquitin system in glioblastoma. Frontiers in Oncology 10 , 574011. 10.3389/fonc.2020.574011

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Abstract

Glioblastoma is the most common primary brain tumor in adults with poor overall outcome and 5-year survival of less than 5%. Treatment has not changed much in the last decade or so, with surgical resection and radio/chemotherapy being the main options. Glioblastoma is highly heterogeneous and frequently becomes treatment-resistant due to the ability of glioblastoma cells to adopt stem cell states facilitating tumor recurrence. Therefore, there is an urgent need for novel therapeutic strategies. The ubiquitin system, in particular E3 ubiquitin ligases and deubiquitinating enzymes, have emerged as a promising source of novel drug targets. In addition to conventional small molecule drug discovery approaches aimed at modulating enzyme activity, several new and exciting strategies are also being explored. Among these, PROteolysis TArgeting Chimeras (PROTACs) aim to harness the endogenous protein turnover machinery to direct therapeutically relevant targets, including previously considered “undruggable” ones, for proteasomal degradation. PROTAC and other strategies targeting the ubiquitin proteasome system offer new therapeutic avenues which will expand the drug development toolboxes for glioblastoma. This review will provide a comprehensive overview of E3 ubiquitin ligases and deubiquitinating enzymes in the context of glioblastoma and their involvement in core signaling pathways including EGFR, TGF-β, p53 and stemness-related pathways. Finally, we offer new insights into how these ubiquitin-dependent mechanisms could be exploited therapeutically for glioblastoma.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences European Cancer Stem Cell Research Institute (ECSCRI)
Publisher:	Frontiers Media
ISSN:	2234-943X
Date of First Compliant Deposit:	6 January 2021
Date of Acceptance:	7 October 2020
Last Modified:	29 Jun 2023 17:09
URI:	https://orca.cardiff.ac.uk/id/eprint/137360

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