The Hormel Institute, University of Minnesota, Austin, MN, 55912, USA.
The Hormel Institute, University of Minnesota, Austin, MN, 55912, USA.
Chem Biol Interact. 2023 Nov 1;385:110720. doi: 10.1016/j.cbi.2023.110720. Epub 2023 Sep 24.
Breast cancer (BC) is one of the most frequent type of cancer in women worldwide. Current therapeutic strategies for BC are not always effective. In this study, we investigated the anticancer activity of an epigenetic compound UNC0642 and its mechanism of action in suppressing BC cell growth and survival. UNC0642 was developed as a selective inhibitor of G9a that is responsible for histone H3K9 methylation. After screening different BC cell lines, we found UNC0642 had the lowest IC-50 against MDA-MB-231 cells, a triple-negative BC cell line. To identify additional UNC0642 targets, we performed RNA-seq analyses in BC cells following UNC0642 treatment. UNC0642 significantly upregulated mRNA expression of thioredoxin-interacting protein (TXNIP), which was also validated by western blotting. We further showed that TXNIP upregulation was associated with dose-dependent elevation of reactive oxygen species, concurrent with loss of mitochondrial membrane potential and activation of caspase-3-dependent apoptosis. Finally, we demonstrated that UNC0642 treatment induced BC cell apoptosis in vitro and suppression of tumor growth in xenograft mouse models that was coupled with TXNIP activation. Taken together, our results show that UNC0642 exerts its antitumor function via upregulating TXNIP expression and oxidative stress to impair mitochondrial function and induce caspase-dependent cell death. This observation could inform future breast cancer therapies by targeting TXNIP-dependent ROS signaling.
乳腺癌（BC）是全球女性中最常见的癌症类型之一。目前针对 BC 的治疗策略并不总是有效。在这项研究中，我们研究了表观遗传化合物 UNC0642 的抗癌活性及其抑制 BC 细胞生长和存活的作用机制。UNC0642 被开发为 G9a 的选择性抑制剂，G9a 负责组蛋白 H3K9 甲基化。在筛选不同的 BC 细胞系后，我们发现 UNC0642 对 MDA-MB-231 细胞的 IC50 最低，MDA-MB-231 细胞是一种三阴性 BC 细胞系。为了确定 UNC0642 的其他靶标，我们在 UNC0642 处理后对 BC 细胞进行了 RNA-seq 分析。UNC0642 显著上调了硫氧还蛋白相互作用蛋白（TXNIP）的 mRNA 表达，Western blot 也验证了这一点。我们进一步表明，TXNIP 的上调与活性氧（ROS）的剂量依赖性升高有关，同时伴随着线粒体膜电位的丧失和 caspase-3 依赖性细胞凋亡的激活。最后，我们证明 UNC0642 处理在体外诱导 BC 细胞凋亡，并抑制异种移植小鼠模型中的肿瘤生长，同时激活 TXNIP。总之，我们的结果表明，UNC0642 通过上调 TXNIP 表达和氧化应激来损害线粒体功能并诱导 caspase 依赖性细胞死亡来发挥其抗肿瘤功能。这一观察结果可以通过靶向 TXNIP 依赖性 ROS 信号来为未来的乳腺癌治疗提供信息。
