Taylor, L, Wade, PK, Johnson, J, Aldighieri, M, Morlando, S, Di Leva, G, Kerr, I and Coyle, B 2023, 'Drug resistance in Medulloblastoma is driven by YB-1, ABCB1 and a seven-gene drug signature' , Cancers, 15 (4) , p. 1086.
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Abstract
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.
| Item Type: | Article |
|---|---|
| Schools: | Schools > School of Health and Society |
| Journal or Publication Title: | Cancers |
| Publisher: | MDPI |
| ISSN: | 2072-6694 |
| Funders: | Biotechnology and Biological Sciences Research Council Doctoral Training Partnership, Stoneygate Trust Career Catalyst Award |
| Depositing User: | USIR Admin |
| Date Deposited: | 16 Mar 2023 09:44 |
| Last Modified: | 16 Mar 2023 09:45 |
| URI: | https://usir.salford.ac.uk/id/eprint/66567 |
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