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Epigenomic perturbation of novel EGFR enhancers reduces the proliferative and invasive capacity of glioblastoma and increases sensitivity to temozolomide
Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).ORCID iD: 0000-0003-1283-0784
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2023 (English)In: BMC Cancer, E-ISSN 1471-2407, Vol. 23, no 1, article id 945Article in journal (Refereed) Published
Abstract [en]

Background: Glioblastoma (GB) is the most aggressive of all primary brain tumours and due to its highly invasive nature, surgical resection is nearly impossible. Patients typically rely on radiotherapy with concurrent temozolomide (TMZ) treatment and face a median survival of ~ 14 months. Alterations in the Epidermal Growth Factor Receptor gene (EGFR) are common in GB tumours, but therapies targeting EGFR have not shown significant clinical efficacy.

Methods: Here, we investigated the influence of the EGFR regulatory genome on GB cells and identified novel EGFR enhancers located near the GB-associated SNP rs723527. We used CRISPR/Cas9-based approaches to target the EGFR enhancer regions, generating multiple modified GB cell lines, which enabled us to study the functional response to enhancer perturbation.

Results: Epigenomic perturbation of the EGFR regulatory region decreases EGFR expression and reduces the proliferative and invasive capacity of glioblastoma cells, which also undergo a metabolic reprogramming in favour of mitochondrial respiration and present increased apoptosis. Moreover, EGFR enhancer-perturbation increases the sensitivity of GB cells to TMZ, the first-choice chemotherapeutic agent to treat glioblastoma.

Conclusions: Our findings demonstrate how epigenomic perturbation of EGFR enhancers can ameliorate the aggressiveness of glioblastoma cells and enhance the efficacy of TMZ treatment. This study demonstrates how CRISPR/Cas9-based perturbation of enhancers can be used to modulate the expression of key cancer genes, which can help improve the effectiveness of existing cancer treatments and potentially the prognosis of difficult-to-treat cancers such as glioblastoma.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2023. Vol. 23, no 1, article id 945
Keywords [en]
CRISPR/Cas9, EGFR, Enhancer, Epigenomic perturbation, Glioblastoma
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:umu:diva-215716DOI: 10.1186/s12885-023-11418-9ISI: 001082654500001PubMedID: 37803333Scopus ID: 2-s2.0-85173760974OAI: oai:DiVA.org:umu-215716DiVA, id: diva2:1811064
Funder
Umeå UniversitySwedish Research Council, 2019–01960Swedish Cancer Society, 21 1720Knut and Alice Wallenberg FoundationThe Kempe Foundations, SMK-1964.2Available from: 2023-11-10 Created: 2023-11-10 Last updated: 2024-07-04Bibliographically approved

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Vincent, Craig A.Nissen, ItzelDakhel, SoranHörnblad, AndreasRemeseiro, Silvia

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