State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangdong 510060, China.
Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangdong 510080, China.
Sci Transl Med. 2024 Oct 2;16(767):eado1573. doi: 10.1126/scitranslmed.ado1573.
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 in promoter-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 of mRNA to the RNA export machinery and transportation of mRNA 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-resistant promoter-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-resistant promoter-methylated GBM.
在维持细胞生理功能和存活的过程中，RNA 受刺激诱导的动态结构重排的机制尚不清楚。在这里，我们表明在启动子甲基化的胶质母细胞瘤（GBM）中，RNA 解旋酶 DEAD 盒解旋酶 46（DDX46）被替莫唑胺（TMZ）激活的检查点激酶 1（CHK1）磷酸化，导致构象由致密变为松散，并增加 DDX46 解旋酶活性。DDX46 介导的 LINC01956 的三级结构重排暴露出 LINC01956 与 O-甲基鸟嘌呤 DNA 甲基转移酶（MGMT）的 3'非翻译区结合的基序。这加速了 mRNA 招募到 RNA 输出机制，并将 mRNA 从细胞核运输到细胞质，导致 MGMT 丰度增加和 TMZ 耐药性。使用患者来源的异种移植（PDX）和肿瘤类器官模型，我们发现 CHK1 抑制剂 SRA737 可消除 TMZ 诱导的 LINC01956 结构重排和随后的 MGMT 上调，使 TMZ 耐药的 启动子甲基化 GBM 对 TMZ 重新敏感。总之，这些发现强调了 TMZ 诱导的 RNA 结构重排的机制，并可能代表了对 TMZ 耐药的 启动子甲基化 GBM 患者的一种潜在治疗策略。
