Developing safe and effective therapeutic modalities remains a critical challenge for improving the prognosis of patients with colorectal cancer (CRC). In this regard, targeting epigenetic regulation in cancers has recently emerged as a promising therapeutic approach. Since several natural compounds have recently been shown to be important epigenetic modulators, we hypothesized that Ginseng might exert its anticancer activity by regulating DNA methylation alterations in CRC. In this study, a series of cell culture studies were conducted, followed by their interrogation in patient-derived 3D organoid models to evaluate Ginseng's anticancer activity in CRC. Genome-wide methylation alterations were interrogated by undertaking MethylationEpic BeadChip microarrays. First, 50% inhibitory concentrations (IC50) were determined by cell viability assays, and subsequent Ginseng treatment demonstrated a significant anticancer effect on clonogenicity and cellular migration in CRC cells. Treatment with Ginseng potentiated cellular apoptosis through regulation of apoptosis-related genes in CRC cells. Furthermore, Ginseng treatment downregulated the expression of DNA methyltransferases (DNMTs) and decreased the global DNA methylation levels in CRC cells. The genome-wide methylation profiling identified Ginseng-induced hypomethylation of transcriptionally silenced tumor suppressor genes. Finally, cell culture-based findings were successfully validated in patient-derived 3D organoids. In conclusion, we demonstrate that Ginseng exerts its antitumorigenic potential by regulating cellular apoptosis via the downregulation of DNMTs and reversing the methylation status of transcriptionally silenced genes in CRC.

中文翻译：

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人参通过抑制结直肠癌中 DNMT 的表达并重新激活甲基化沉默基因来介导其抗癌活性。

开发安全有效的治疗方式仍然是改善结直肠癌（CRC）患者预后的关键挑战。在这方面，针对癌症的表观遗传调控最近已成为一种有前途的治疗方法。由于几种天然化合物最近被证明是重要的表观遗传调节剂，我们推测人参可能通过调节 CRC 中 DNA 甲基化的改变来发挥其抗癌活性。在这项研究中，进行了一系列细胞培养研究，然后在患者衍生的 3D 类器官模型中进行研究，以评估人参在结直肠癌中的抗癌活性。通过进行 MmethylationEpic BeadChip 微阵列来探究全基因组甲基化改变。首先，通过细胞活力测定确定 50% 抑制浓度 (IC50)，随后的人参治疗证明对 CRC 细胞的克隆形成和细胞迁移具有显着的抗癌作用。人参治疗通过调节 CRC 细胞中的凋亡相关基因来增强细胞凋亡。此外，人参治疗下调了 DNA 甲基转移酶 (DNMT) 的表达，并降低了 CRC 细胞中的整体 DNA 甲基化水平。全基因组甲基化分析鉴定了人参诱导的转录沉默肿瘤抑制基因的低甲基化。最后，基于细胞培养的研究结果在源自患者的 3D 类器官中得到了成功验证。总之，我们证明人参通过下调 DNMT 调节细胞凋亡并逆转 CRC 中转录沉默基因的甲基化状态来发挥其抗肿瘤潜力。