The efficacy of temozolomide (TMZ) treatment in glioblastoma (GBM) is influenced by various mechanisms, mainly including the level of O-methylguanine-DNA methyltransferase (MGMT) and the activity of DNA damage repair (DDR) pathways. In our previous study, we had proved that long non-coding RNA HOTAIR regulated the GBM progression and mediated DDR by interacting with EZH2, the catalytic subunit of PRC2. In this study, we developed a small-molecule inhibitor called EPIC-0628 that selectively disrupted the HOTAIR-EZH2 interaction and promoted ATF3 expression. The upregulation of ATF3 inhibited the recruitment of p300, p-p65, p-Stat3 and SP1 to the MGMT promoter. Hence, EPIC-0628 silenced MGMT expression. Besides, EPIC-0628 induced cell cycle arrest by increasing the expression of CDKN1A and impaired DNA double-strand break repair via suppressing the ATF3-p38-E2F1 pathway. Lastly, EPIC-0628 enhanced TMZ efficacy in GBM . Hence, this study provided evidence for the combination of epigenetic drugs EPIC-0628 with TMZ for GBM treatment through the above mechanisms.

中文翻译：

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EPIC-0628 通过促进 ATF3 表达和抑制胶质母细胞瘤中的 DNA 损伤修复来消除 HOTAIR/EZH2 相互作用并增强替莫唑胺疗效

替莫唑胺（TMZ）治疗胶质母细胞瘤（GBM）的疗效受到多种机制的影响，主要包括O-甲基鸟嘌呤-DNA甲基转移酶（MGMT）的水平和DNA损伤修复（DDR）途径的活性。在我们之前的研究中，我们已经证明长链非编码RNA HOTAIR通过与PRC2的催化亚基EZH2相互作用来调节GBM进展并介导DDR。在这项研究中，我们开发了一种名为 EPIC-0628 的小分子抑制剂，它选择性地破坏 HOTAIR-EZH2 相互作用并促进 ATF3 表达。 ATF3 的上调抑制了 p300、p-p65、p-Stat3 和 SP1 向 MGMT 启动子的募集。因此，EPIC-0628 沉默了 MGMT 表达。此外，EPIC-0628 通过增加 CDKN1A 的表达来诱导细胞周期停滞，并通过抑制 ATF3-p38-E2F1 途径来损害 DNA 双链断裂修复。最后，EPIC-0628 增强了 TMZ 对 GBM 的疗效。因此，本研究为表观遗传药物EPIC-0628与TMZ联合通过上述机制治疗GBM提供了证据。