Epigenetic Activation of TUSC3 Sensitizes Glioblastoma to Temozolomide Independent of MGMT Promoter Methylation Status.
Epigenetic Activation of TUSC3 Sensitizes Glioblastoma to Temozolomide Independent of MGMT Promoter Methylation Status.
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DOI：
10.3390/ijms242015179
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发表时间：
2023-10-14
影响因子：
5.6
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替莫唑胺(TMZ)是治疗胶质母细胞瘤(GBM)的重要一线药物，但在耐受性和对DNA修复基因O6-甲基鸟嘌呤DNA甲基转移酶(MGMT)启动子甲基化状态的依赖方面，TMZ的疗效受到限制。MGMT-启动子高甲基化(MGMT-M)的GBM比MGMT-UM的GBM对TMZ更敏感。此外，即使在对TMZ敏感的MGMT-M GBM中，TMZ抗性也是不可避免的。因此，迫切需要表观遗传重编程策略来增强MGMT-M和MGMT-UM GBM中的TMZ反应。在这项研究中，我们提出了新的证据，表明肿瘤抑制候选基因3(TUSC3)的表观遗传重新激活可以重新编程GBM干细胞(GSCs)对TMZ的敏感性，而与MGMT启动子甲基化状态无关。对TCGA患者GBM数据集的询问证实了TUSC3启动子对TUSC3表达的调节，并显示TUSC3表达与GBM患者生存密切正相关。结合功能丧失、功能获得和救援研究，我们证明在MGMT-M和MGMT-UM GSCs中，TUSC3的重新激活与TMZ反应的增强有关。此外，我们提供了新的证据表明，去甲基化药物5-氮杂胞苷(5-aza)可重新激活MGMT-M GSCs中TUSC3的表达，而5-aza与MGMT抑制剂洛格曲布联合使用则是MGMT-UM GSCs中TUSC3重新激活所必需的。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，该策略可以显著延长MGMT-M和MGMT-UM原位GSCs模型的存活时间。总之，我们的发现为进一步探索TUSC3介导的表观遗传重编程策略提供了一个框架和理论基础，这些策略可以提高TMZ的敏感性和对GBM的结果。从这类研究中获得的机械性和翻译性证据可能有助于对目前没有良好治疗选择的MGMT-UM GBM进行有效试验的最佳设计。
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.
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影响因子：
--
作者：
Borodovsky A;Salmasi V;Turcan S;Fabius AW;Baia GS;Eberhart CG;Weingart JD;Gallia GL;Baylin SB;Chan TA;Riggins GJ
通讯作者：
Riggins GJ
影响因子：
9.8
作者：
Garshasbi, Masoud;Hadavi, Valeh;Kuss, Andreas Walter
通讯作者：
Kuss, Andreas Walter
影响因子：
45.3
作者：
Gilbert, Mark R.;Wang, Meihua;Mehta, Minesh P.
通讯作者：
Mehta, Minesh P.
影响因子：
3.6
作者：
Chen, Guan-di;Qian, De-ying;Wu, Yi-long
通讯作者：
Wu, Yi-long
DOI：
10.1016/j.oooo.2019.01.006
发表时间：
2019-05-01
影响因子：
2.9
作者：
do Amaral, Guilherme C. L. S.;Planello, Aline C.;de Souza, Ana Paula
通讯作者：
de Souza, Ana Paula