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Lookup NU author(s): Dr Louisa Taylor
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Therapy resistance represents an unmet challenge in the treatment of medulloblastoma. Accordingly, the identification of targets that mark drug-resistant cell populations, or drive the proliferation of resistant cells, may improve treatment strategies. To address this, we undertook a targeted approach focused on the multi-functional transcription factor YB-1. Genetic knockdown of YB-1 in Group 3 medulloblastoma cell lines diminished cell invasion in 3D in vitro assays and increased sensitivity to standard-of-care chemotherapeutic vincristine and anti-cancer agents panobinostat and JQ1. For vincristine, this occurred in part by YB-1-mediated transcriptional regulation of multi-drug resistance gene ABCB1, as determined by chromatin immunoprecipitation. Whole transcriptome sequencing of YB-1 knockdown cells identified a role for YB-1 in the regulation of tumourigenic processes, including lipid metabolism, cell death and survival and MYC and mTOR pathways. Stable cisplatin- and vincristine-tolerant Group 3 and SHH cell lines were generated to identify additional mechanisms driving resistance to standard-of-care medulloblastoma therapy. Next-generation sequencing revealed a vastly different transcriptomic landscape following chronic drug exposure, including a drug-tolerant seven-gene expression signature, common to all sequenced drug-tolerant cell lines, representing therapeutically targetable genes implicated in the acquisition of drug tolerance. Our findings provide significant insight into mechanisms and genes underlying therapy resistance in medulloblastoma. 36831428
Author(s): Taylor L, Wade P, Johnson J, Aldighieri M, Morlando S, Di Leva G, Kerr I, Coyle B
Publication type: Article
Publication status: Published
Journal: Cancers
Year: 2023
Volume: 15
Issue: 4
Print publication date: 08/02/2023
Online publication date: 08/02/2023
Acceptance date: 04/02/2023
Date deposited: 04/07/2023
ISSN (electronic): 2072-6694
Publisher: MDPI AG
URL: https://doi.org/10.3390/cancers15041086
DOI: 10.3390/cancers15041086
PubMed id: 36831428
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