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LC-MS/MS analysis of LINC01956-binding protein in GBM cells

ABSTRACT: LncRNAs interact with other cellular molecules, such as DNA, RNA and proteins, to regulate various biological processes. In our study, we demonstrated that LINC01956 promoted MGMT mRNA nuclear export and led to TMZ resistance. In order to elucidate the potential molecular mechanism of LINC01956 promoting MGMT mRNA nuclear export, RNA pulldown experiments and quantitative proteomics mass-spectrometry (MS) analysis were performed.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Xinyi Liao

LAB HEAD: Jun Li

PROVIDER: PXD055168 | Pride | 2024-10-28

REPOSITORIES: pride

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Project description:Temozolomide (TMZ) is an important first-line treatment for glioblastoma (GBM), but there are limitations to TMZ response in terms of durability and dependence on the promoter methylation status of the DNA repair gene O6-methylguanine DNA methyltransferase (MGMT). MGMT-promoter-hypermethylated (MGMT-M) GBMs are more sensitive to TMZ than MGMT-promoter-hypomethylated (MGMT-UM) GBMs. Moreover, TMZ resistance is inevitable even in TMZ-sensitive MGMT-M GBMs. Hence, epigenetic reprogramming strategies are desperately needed in order to enhance TMZ response in both MGMT-M and MGMT-UM GBMs. In this study, we present novel evidence that the epigenetic reactivation of Tumor Suppressor Candidate 3 (TUSC3) can reprogram sensitivity of GBM stem cells (GSCs) to TMZ irrespective of MGMT promoter methylation status. Interrogation of TCGA patient GBM datasets confirmed TUSC3 promoter regulation of TUSC3 expression and also revealed a strong positive correlation between TUSC3 expression and GBM patient survival. Using a combination of loss-of-function, gain-of-function and rescue studies, we demonstrate that TUSC3 reactivation is associated with enhanced TMZ response in both MGMT-M and MGMT-UM GSCs. Further, we provide novel evidence that the demethylating agent 5-Azacitidine (5-Aza) reactivates TUSC3 expression in MGMT-M GSCs, whereas the combination of 5-Aza and MGMT inhibitor Lomeguatrib is necessary for TUSC3 reactivation in MGMT-UM GSCs. Lastly, we propose a pharmacological epigenetic reactivation strategy involving TUSC3 that leads to significantly prolonged survival in MGMT-M and MGMT-UM orthotopic GSCs models. Collectively, our findings provide a framework and rationale to further explore TUSC3-mediated epigenetic reprogramming strategies that could enhance TMZ sensitivity and outcomes in GBM. Mechanistic and translational evidence gained from such studies could contribute towards optimal design of impactful trials for MGMT-UM GBMs that currently do not have good treatment options.

			Action	DRS
	20240824.mzid.gz	Mzid
	20240824.mzid.sdrf	Mzid
	LXY-DMSO-repeat1.mgf	Mgf
	LXY-DMSO-repeat1.mzML	Mzml
	LXY-DMSO-repeat1.raw	Raw

Dataset Information

LC-MS/MS analysis of LINC01956-binding protein in GBM cells

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