Journal of Neuro-Oncology, Volume (169), No (1), Year (2024-5) , Pages (129-135)

Title : ( Enhancing Temozolomide (TMZ) chemosensitivity using CRISPR-dCas9-mediated downregulation of O6-methylguanine DNA methyltransferase (MGMT) )

Authors: Yasamin yousefi , Reza Nejati , Atiye Eslahi , Farzaneh Alizadeh , Shima Farrokhi , Ahmad Asoodeh , Majid Mojarrad ,

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Abstract

Purpose Glioblastoma (GBM) stands out as the most prevalent and aggressive intracranial tumor, notorious for its poor prognosis. The current standard-of-care for GBM patients involves surgical resection followed by radiotherapy, combined with concurrent and adjuvant chemotherapy using Temozolomide (TMZ). The effectiveness of TMZ primarily relies on the activity of O6-methylguanine DNA methyltransferase (MGMT), which removes alkyl adducts from the O6 position of gua- nine at the DNA level, thereby counteracting the toxic effects of TMZ. Method In this study, we employed fusions of catalytically-inactive Cas9 (dCas9) to DNA methyltransferases (dCas9- DNMT3A) to selectively downregulation MGMT transcription by inducing methylation at MGMT promoter and K-M enhancer. Result Our findings demonstrate a significant reduction in MGMT expression, leading to intensified TMZ sensitivity in the HEK293T cell line. Conclusion This study serves as a proof of concept for the utilization of CRISPR-based gene suppression to overcome TMZ resistance and enhance the lethal effect of TMZ in glioblastoma tumor cells.

Keywords

, MGMT · CRISPR, dCas9 · TMZ · Glioblastoma
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@article{paperid:1098896,
author = {Yousefi, Yasamin and رضا نجاتی and عطیه اصلاحی and فرزانه علیزاده and شیما فرخی and Asoodeh, Ahmad and مجید مجرد},
title = {Enhancing Temozolomide (TMZ) chemosensitivity using CRISPR-dCas9-mediated downregulation of O6-methylguanine DNA methyltransferase (MGMT)},
journal = {Journal of Neuro-Oncology},
year = {2024},
volume = {169},
number = {1},
month = {May},
issn = {0167-594X},
pages = {129--135},
numpages = {6},
keywords = {MGMT · CRISPR-dCas9 · TMZ · Glioblastoma},
}

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%0 Journal Article
%T Enhancing Temozolomide (TMZ) chemosensitivity using CRISPR-dCas9-mediated downregulation of O6-methylguanine DNA methyltransferase (MGMT)
%A Yousefi, Yasamin
%A رضا نجاتی
%A عطیه اصلاحی
%A فرزانه علیزاده
%A شیما فرخی
%A Asoodeh, Ahmad
%A مجید مجرد
%J Journal of Neuro-Oncology
%@ 0167-594X
%D 2024

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