MEX3A Impairs DNA Mismatch Repair Signaling and Mediates Acquired Temozolomide Resistance in Glioblastoma

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, providing new insights into the function of MEX3A and suggesting MEX3A as a potential therapeutic target in therapy-resistant glioblastoma.

Resveratrol Enhances Temozolomide Efficacy in Glioblastoma Cells through Downregulated MGMT and Negative Regulators-Related STAT3 Inactivation

“…This further confirmed the correlation between STAT3 level and TMZ resistance. Temozolomide induces DNA methylation of guanine at the O 6 position and triggers the mismatch repair (MMR) system leading to a DNA double strand break that results in cell cycle arrest and apoptosis [27,28]. Nonetheless, in this study another anti-tumor molecular mechanism of TMZ was revealed: preventing cell growth by inhibiting STAT3 signaling.…”

MEX3A is a new diagnostic, independent prognostic biomarker and a promising therapeutic target in gliomas

“…Including the assessment of MEX3A into prognostic and diagnostic glioma models could enhance their predictive accuracy and provide clinicians with valuable insights into patient outcomes. This aspect is particularly of interest because the recently described involvement of MEX3A in resistance to TMZ [40].…”

ROS regulation in gliomas: implications for treatment strategies

“…However, under OS, KEAP1 is oxidized, and NRF2 enters the nucleus and binds to the antioxidant response element (ARE) sequence, thereby activating the expression of the abovementioned series of antioxidant enzymes ( 54 – 58 ). In addition, after DNA damage caused by OS, DNA repair mechanisms in glioma cells are activated to repair damaged DNA and exert indirect antioxidant effects, such as direct repair ( 59 – 61 ), base excision repair (BER) ( 62 ), mismatch repair (MMR) ( 63 , 64 ), and nucleotide excision repair (NER) ( 65 , 66 ). A summary of the antioxidant defence systems in glioma cells is presented in Table 1 .…”