Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
CNS Neurosci Ther. 2024 Mar;30(3):e14649. doi: 10.1111/cns.14649.
Glioblastoma multiforme (GBM) is among the most aggressive cancers, with current treatments limited in efficacy. A significant hurdle in the treatment of GBM is the resistance to the chemotherapeutic agent temozolomide (TMZ). The methylation status of the MGMT promoter has been implicated as a critical biomarker of response to TMZ.
To explore the mechanisms underlying resistance, we developed two TMZ-resistant GBM cell lines through a gradual increase in TMZ exposure. Transcriptome sequencing of TMZ-resistant cell lines revealed that alterations in histone post-translational modifications might be instrumental in conferring TMZ resistance. Subsequently, multi-omics analysis suggests a strong association between histone H3 lysine 9 acetylation (H3K9ac) levels and TMZ resistance.
We observed a significant correlation between the expression of H3K9ac and MGMT, particularly in the unmethylated MGMT promoter samples. More importantly, our findings suggest that H3K9ac may enhance MGMT transcription by facilitating the recruitment of the SP1 transcription factor to the MGMT transcription factor binding site. Additionally, by analyzing single-cell transcriptomics data from matched primary and recurrent GBM tumors treated with TMZ, we modeled the molecular shifts occurring upon tumor recurrence. We also noted a reduction in tumor stem cell characteristics, accompanied by an increase in H3K9ac, SP1, and MGMT levels, underscoring the potential role of H3K9ac in tumor relapse following TMZ therapy.
The increase in H3K9ac appears to enhance the recruitment of the transcription factor SP1 to its binding sites within the MGMT locus, consequently upregulating MGMT expression and driving TMZ resistance in GBM.
多形性胶质母细胞瘤（GBM）是最具侵袭性的癌症之一，目前的治疗方法疗效有限。在 GBM 的治疗中，一个显著的障碍是对化疗药物替莫唑胺（TMZ）的耐药性。MGMT 启动子的甲基化状态已被认为是对 TMZ 反应的关键生物标志物。
为了探索耐药的机制，我们通过逐渐增加 TMZ 暴露来开发两种 TMZ 耐药的 GBM 细胞系。TMZ 耐药细胞系的转录组测序表明，组蛋白翻译后修饰的改变可能在赋予 TMZ 耐药性方面发挥重要作用。随后，多组学分析表明，组蛋白 H3 赖氨酸 9 乙酰化（H3K9ac）水平与 TMZ 耐药性之间存在很强的关联。
我们观察到 H3K9ac 的表达与 MGMT 之间存在显著相关性，特别是在未甲基化的 MGMT 启动子样本中。更重要的是，我们的研究结果表明，H3K9ac 可能通过促进 SP1 转录因子募集到 MGMT 转录因子结合位点来增强 MGMT 转录。此外，通过分析来自匹配的原发性和复发性 GBM 肿瘤的 TMZ 治疗的单细胞转录组学数据，我们对肿瘤复发时发生的分子变化进行了建模。我们还注意到肿瘤干细胞特征的减少，同时 H3K9ac、SP1 和 MGMT 水平增加，这突出了 H3K9ac 在 TMZ 治疗后肿瘤复发中的潜在作用。
H3K9ac 的增加似乎增强了转录因子 SP1 向其在 MGMT 基因座内结合位点的募集，从而上调 MGMT 表达并在 GBM 中驱动 TMZ 耐药性。
