Schmidt Thomas, Sticht Carsten
Department of Anatomy and Developmental Biology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.
Department of Bioinformatics, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.
Genes (Basel). 2024 Dec 20;15(12):1634. doi: 10.3390/genes15121634.
Epigenetic dysregulation is a common feature of cancer. Promoter demethylation of tumor-promoting genes and global DNA hypomethylation may trigger tumor progression. Epigenetic changes are unstable; thus, research has focused on detecting remedies that target epigenetic regulators. Previous studies have suggested that concordantly targeting hypomethylation and hypermethylation is beneficial for suppressing both the oncogenic and pro-metastatic functions of cancer cells. Therefore, we aimed to investigate the effect of a combination of S-adenosylmethionine (SAM) and the demethylating agent decitabine on prostate cancer cells. Prostate cancer cells (PC-3) were treated with SAM, decitabine, or a combination of both. Proliferation, migration, invasion, and methylation assays were also performed. A transcriptome study was conducted to detect different gene clusters between the treatment groups, followed by analyses using the Kyoto Encyclopedia of Genes and Genomes pathway and ingenuity pathway analysis. Finally, to gain information on differential gene expression, promoter methylation studies were performed. Groups treated with decitabine, SAM, or their combination showed reduced proliferative capacity. The decitabine-treated group showed a marginal increase in cell migration and invasion, whereas the SAM-treated and combination treatment groups showed reduced invasion and migration potential. Methylation assays demonstrated the restoration of decitabine-induced demethylation in prostate cancer samples, whereas the transcriptome study revealed the upregulation of different gene clusters between the treatment groups. Methylation studies confirmed that SAM could restore the decitabine-induced demethylation of proto-oncogenes, but it did not induce the re-methylation of tumor-suppressor genes. Combination treatment with SAM and decitabine had an additive effect and did not nullify each other.
表观遗传失调是癌症的一个常见特征。促癌基因的启动子去甲基化和全基因组DNA低甲基化可能会引发肿瘤进展。表观遗传变化是不稳定的；因此，研究集中在寻找针对表观遗传调节因子的治疗方法。先前的研究表明，同时靶向低甲基化和高甲基化有利于抑制癌细胞的致癌和促转移功能。因此，我们旨在研究S-腺苷甲硫氨酸（SAM）和去甲基化药物地西他滨联合使用对前列腺癌细胞的影响。用SAM、地西他滨或两者的组合处理前列腺癌细胞（PC-3）。还进行了增殖、迁移、侵袭和甲基化检测。进行了转录组研究以检测治疗组之间不同的基因簇，随后使用京都基因与基因组百科全书通路和 Ingenuity 通路分析进行分析。最后，为了获得差异基因表达的信息，进行了启动子甲基化研究。用地西他滨、SAM或其组合处理的组显示增殖能力降低。地西他滨处理组的细胞迁移和侵袭略有增加，而SAM处理组和联合处理组的侵袭和迁移潜力降低。甲基化检测证明了前列腺癌样本中地西他滨诱导的去甲基化得以恢复，而转录组研究揭示了治疗组之间不同基因簇的上调。甲基化研究证实，SAM可以恢复地西他滨诱导的原癌基因去甲基化，但不会诱导抑癌基因的重新甲基化。SAM和地西他滨联合治疗具有相加作用，不会相互抵消。
