Cancer Research | VOL. 82
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MEX3A Impairs DNA Mismatch Repair Signaling and Mediates Acquired Temozolomide Resistance in Glioblastoma

Publication Date Sep 15, 2022

Abstract

Abstract MutS protein homolog 2 (MSH2) is a key element involved in the DNA mismatch repair (MMR) system, which is responsible for recognizing and repairing mispaired bases. Simultaneously, MSH2 identifies DNA adducts induced by temozolomide (TMZ) and triggers apoptosis and autophagy in tumor cells. Previous work has revealed that reduced MSH2 expression is often observed in patients with glioblastoma (GBM) who relapse after chemotherapy. Elucidation of the mechanism behind TMZ-mediated reduction of MSH2 could help improve GBM treatment. Here, we report significant upregulation of Mex-3 RNA binding family member A (MEX3A) in GBM tissues and cell lines following TMZ treatment. MEX3A bound to the MEX3 recognition element (MRE) of MSH2 mRNA, which in turn recruited CCR4–NOT complexes to target MSH2 mRNA for deadenylation and degradation. In addition, ectopic expression of MEX3A significantly decreased cellular DNA MMR activities and reduced the chemosensitivity of GBM cells via downregulation of MSH2, while depletion of MEX3A sensitized GBM cells to TMZ. In MGMT-deficient patients with GBM, MEX3A expression correlated with MSH2 levels, and high MEX3A expression was associated with poor prognosis. Overall, these findings reveal a potential mechanism by which MSH2 expression is reduced in post-TMZ recurrent GBM. Significance: A MEX3A/CCR4–NOT/MSH2 axis plays a crucial role in promoting temozolomide resistance, ...

Concepts

Glioblastoma Cells Glioblastoma Temozolomide Resistance In Glioblastoma Autophagy In Tumor Cells Downregulation Of MSH2 CCR4 NOT Complexes MSH2 mRNA Resistance In Glioblastoma CCR4 NOT MSH2 Levels

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No potential conflict of interest was reported by the authors. The conception and design of the study, acquisition of data, analysis and interpretatio...

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