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

被引：1

作者：

Liao, Xinyi ^{[1
,2
]}

Zhang, Shuxia ^{[2
]}

Li, Xincheng ^{[2
]}

Qian, Wanying ^{[2
]}

Li, Man ^{[2
]}

Chen, Suwen ^{[2
]}

Wu, Xingui ^{[2
]}

Yu, Xuexin ^{[2
]}

Li, Ziwen ^{[2
]}

Tang, Miaoling ^{[2
]}

Xu, Yingru ^{[2
]}

Yu, Ruyuan ^{[2
]}

Zhang, Qiliang ^{[2
]}

Wu, Geyan ^{[2
]}

Zhang, Nu ^{[3
]}

Song, Libing ^{[1
]}

Li, Jun ^{[1
,2
]}

机构：

[1] Sun Yat Sen Univ, Canc Ctr, Collaborat Innovat Ctr Canc Med, State Key Lab Oncol South China, Guangzhou 510060, Guangdong, Peoples R China

[2] Sun Yat Sen Univ, Zhongshan Sch Med, Dept Biochem, Guangzhou 510080, Guangdong, Peoples R China

[3] Sun Yat Sen Univ, Affiliated Hosp 1, Dept Neurosurg, Guangzhou 510080, Guangdong, Peoples R China

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2024年 / 16卷 / 767期

基金：

中国国家自然科学基金;

关键词：

RNA SECONDARY STRUCTURE; PROMOTER METHYLATION; DNA-DAMAGE; PROTEIN EXPRESSION; CELLS; ASSOCIATION; REPAIR; GENE; MECHANISM; LNCRNA;

D O I：

10.1126/scitranslmed.ado1573

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 MGMT 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-6-methylguanine DNA methyltransferase (MGMT). This accelerates recruitment of MGMT mRNA to the RNA export machinery and transportation of MGMT 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 MGMT 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 MGMT promoter-methylated GBM.

引用

页数：17

共 21 条

[21] REGORAFENIB IN COMBINATION WITH TEMOZOLOMIDE WITH OR WITHOUT RADIOTHERAPY IN PATIENTS WITH NEWLY DIAGNOSED MGMT-METHYLATED, IDH WILDTYPE GLIOBLASTOMA: A PHASE I DOSE-FINDING STUDY (REGOMA-2, EUDRA CT N° 2021-001604-15)
Padovan, M.
De Salvo, G.
Cerretti, G.
Krengli, M.
Caccese, M.
Maccari, M.
Farina, M.
Bergo, E.
Zabeo, C.
Grosso, D.
Caumo, F.
Coppola, M.
D'Avolio, A.
Zagonel, V.
Lombardi, G.
NEURO-ONCOLOGY, 2023, 25

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