Dynamic structural remodeling of LINC01956 enhances temozolomide resistance in-methylated glioblastoma.

in Science translational medicine by Xinyi Liao, Shuxia Zhang, Xincheng Li, Wanying Qian, Man Li, Suwen Chen, Xingui Wu, Xuexin Yu, Ziwen Li, Miaoling Tang, Yingru Xu, Ruyuan Yu, Qiliang Zhang, Geyan Wu, Nu Zhang, Libing Song, Jun Li

TLDR

  • The study investigates how a protein called DEAD-box helicase 46 (DDX46) helps maintain cellular function in glioblastoma (GBM). The study found that when a drug called temozolomide (TMZ) is used to treat GBM, it activates a protein called checkpoint kinase 1 (CHK1) which causes DDX46 to change shape and become more active. This change in shape helps DDX46 bind to a specific RNA molecule called LINC01956, which then gets transported out of the cell's nucleus and into the cytoplasm. This process leads to an increase in the abundance of a protein called MGMT, which helps GBM cells resist the effects of TMZ. The study suggests that targeting CHK1 and DDX46 may be a potential therapeutic strategy for patients with TMZ-resistant GBM.

Abstract

The mechanisms underlying stimuli-induced dynamic structural remodeling of RNAs for the maintenance of cellular physiological function and survival remain unclear. Here, we showed that inpromoter-methylated glioblastoma (GBM), the RNA helicase DEAD-box helicase 46 (DDX46) is phosphorylated by temozolomide (TMZ)-activated checkpoint kinase 1 (CHK1), resulting in a dense-to-loose conformational change and an increase in DDX46 helicase activity. DDX46-mediated tertiary structural remodeling of LINC01956 exposes the binding motifs of LINC01956 to the 3' untranslated region of O-methylguanine DNA methyltransferase (). This accelerates recruitment ofmRNA to the RNA export machinery and transportation ofmRNA from the nucleus to the cytoplasm, leading to increased MGMT abundance and TMZ resistance. Using patient-derived xenograft (PDX) and tumor organoid models, we found that treatment with the CHK1 inhibitor SRA737abolishes TMZ-induced structural remodeling of LINC01956 and subsequent MGMT up-regulation, resensitizing TMZ-resistantpromoter-methylated GBM to TMZ. In conclusion, these findings highlight a mechanism underlying temozolomide-induced RNA structural remodeling and may represent a potential therapeutic strategy for patients with TMZ-resistantpromoter-methylated GBM.

Overview

  • The study investigates the mechanisms underlying stimuli-induced dynamic structural remodeling of RNAs for maintaining cellular physiological function and survival in glioblastoma (GBM).
  • The study focuses on the RNA helicase DEAD-box helicase 46 (DDX46) and its phosphorylation by temozolomide (TMZ)-activated checkpoint kinase 1 (CHK1) in GBM. The study examines the conformational change and increase in DDX46 helicase activity resulting from this phosphorylation. The study also explores the tertiary structural remodeling of LINC01956 and its binding motifs exposed to the 3' untranslated region of O-methylguanine DNA methyltransferase (MGMT) due to this remodeling. The study investigates the impact of this remodeling on mRNA recruitment to the RNA export machinery and transportation of mRNA from the nucleus to the cytoplasm, leading to increased MGMT abundance and TMZ resistance. The study aims to understand the underlying mechanism of temozolomide-induced RNA structural remodeling and its potential therapeutic implications for patients with TMZ-resistant GBM.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions or interventions, specifically the phosphorylation of DDX46 by CHK1 in response to TMZ treatment in GBM. The study identifies a dense-to-loose conformational change and an increase in DDX46 helicase activity resulting from this phosphorylation. The study also identifies the tertiary structural remodeling of LINC01956 and its binding motifs exposed to the 3' untranslated region of MGMT due to this remodeling. The study finds that this remodeling leads to increased MGMT abundance and TMZ resistance. The study also identifies that treatment with the CHK1 inhibitor SRA737 abolishes TMZ-induced structural remodeling of LINC01956 and subsequent MGMT up-regulation, resensitizing TMZ-resistant GBM to TMZ. The study's findings support the hypothesis that temozolomide-induced RNA structural remodeling plays a crucial role in TMZ resistance in GBM.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice. The study identifies a novel mechanism underlying temozolomide-induced RNA structural remodeling and its potential therapeutic implications for patients with TMZ-resistant GBM. The study suggests that targeting CHK1 and DDX46 may be a potential therapeutic strategy for patients with TMZ-resistant GBM. The study also identifies limitations, such as the need for further validation of the findings in larger patient populations and the need to investigate the role of other RNA helicases in this process. The study suggests future research directions, such as investigating the role of other RNA helicases in this process and exploring the potential of combining CHK1 and DDX46 inhibitors with other therapies for TMZ-resistant GBM.
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