表观遗传激活 TUSC3 使胶质母细胞瘤对替莫唑胺敏感，与 MGMT 启动子甲基化状态无关。

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

机构信息

Department of Neuro-Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.

Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.

出版信息

Int J Mol Sci. 2023 Oct 14;24(20):15179. doi: 10.3390/ijms242015179.

DOI:10.3390/ijms242015179

PMID:37894860

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10606804/

Abstract

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 O-methylguanine DNA methyltransferase (). 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.

摘要

替莫唑胺（TMZ）是胶质母细胞瘤（GBM）的重要一线治疗药物，但 TMZ 反应在持久性和对 DNA 修复基因 O-甲基鸟嘌呤 DNA 甲基转移酶（MGMT）启动子甲基化状态的依赖性方面存在局限性。MGMT 启动子高甲基化（MGMT-M）GBM 比 MGMT 启动子低甲基化（MGMT-UM）GBM 对 TMZ 更敏感。此外，即使在 TMZ 敏感的 MGMT-M GBM 中，TMZ 耐药性也是不可避免的。因此，迫切需要进行表观遗传重编程策略，以提高 MGMT-M 和 MGMT-UM GBM 对 TMZ 的反应。在这项研究中，我们提供了新的证据表明，肿瘤抑制候选基因 3（TUSC3）的表观遗传再激活可以重新编程 GBM 干细胞（GSCs）对 TMZ 的敏感性，而与 MGMT 启动子甲基化状态无关。TCGA 患者 GBM 数据集的查询证实了 TUSC3 启动子对 TUSC3 表达的调控，并显示 TUSC3 表达与 GBM 患者生存之间存在强烈的正相关。通过使用功能丧失、功能获得和挽救研究的组合，我们证明 TUSC3 的再激活与 MGMT-M 和 MGMT-UM GSCs 中 TMZ 反应的增强有关。此外，我们提供了新的证据表明，去甲基化剂 5-氮杂胞苷（5-Aza）可使 MGMT-M GSCs 中的 TUSC3 表达再激活，而 5-Aza 和 MGMT 抑制剂洛美曲布的组合对于 MGMT-UM GSCs 中的 TUSC3 再激活是必要的。最后，我们提出了一种涉及 TUSC3 的药理学表观遗传再激活策略，该策略可导致 MGMT-M 和 MGMT-UM 原位 GSCs 模型的生存时间显著延长。总的来说，我们的研究结果为进一步探索 TUSC3 介导的表观遗传重编程策略提供了框架和理论依据，这些策略可以提高 GBM 中 TMZ 的敏感性和结果。从这些研究中获得的机制和转化证据可能有助于为目前治疗效果不佳的 MGMT-UM GBM 设计有影响力的临床试验。