Epigenetic Activation of TUSC3 Sensitizes Glioblastoma to Temozolomide Independent of MGMT Promoter Methylation Status

by Selleckchem | Jan 10 2024

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.

Comments:

This study seems like a significant step forward in addressing the limitations of Temozolomide (TMZ) treatment for glioblastoma (GBM). The identification of Tumor Suppressor Candidate 3 (TUSC3) as a potential target for epigenetic reprogramming to enhance TMZ sensitivity, regardless of the MGMT promoter methylation status, holds promise for improving treatment outcomes in both MGMT-promoter-hypermethylated (MGMT-M) and MGMT-promoter-hypomethylated (MGMT-UM) GBMs.

The correlation between TUSC3 expression and patient survival, as well as the demonstration of enhanced TMZ response through TUSC3 reactivation in GBM stem cells (GSCs), provides strong support for investigating TUSC3 as a therapeutic target.

The differential response of MGMT-M and MGMT-UM GSCs to demethylating agents like 5-Azacitidine (5-Aza) and the need for a combination strategy involving 5-Aza and the MGMT inhibitor Lomeguatrib for TUSC3 reactivation in MGMT-UM GSCs suggests the complexity of epigenetic regulation in these different GBM subtypes.

The proposal of a pharmacological epigenetic reactivation strategy involving TUSC3, leading to prolonged survival in orthotopic GSC models, is an exciting prospect for potential clinical translation.

Overall, this research offers a compelling framework for further investigations into TUSC3-mediated epigenetic reprogramming strategies that could potentially revolutionize treatment approaches for both MGMT-M and MGMT-UM GBMs, especially for the latter, which currently lack effective treatment options. This could pave the way for more impactful clinical trials and therapeutic interventions in the future.