Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 72388, Saudi Arabia.
Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Malaysia.
Int J Mol Sci. 2021 Nov 13;22(22):12286. doi: 10.3390/ijms222212286.
Cancer cells are able to proliferate in an unregulated manner. There are several mechanisms involved that propel such neoplastic transformations. One of these processes involves bypassing cell death through changes in gene expression and, consequently, cell growth. This involves a complex epigenetic interaction within the cell, which drives it towards oncogenic transformations. These epigenetic events augment cellular growth by potentially altering chromatin structures and influencing key gene expressions. Therapeutic mechanisms have been developed to combat this by taking advantage of the underlying oncogenic mechanisms through chemical modulation. Camptothecin (CPT) is an example of this type of drug. It is a selective topoisomerase I inhibitor that is effective against many cancers, such as colorectal cancer. Previously, we successfully formulated a magnetic nanocarrier-conjugated CPT with β-cyclodextrin and iron NPs (FeO) cross-linked using EDTA (CPT-CEF). Compared to CPT alone, it boasts higher efficacy due to its selective targeting and increased solubility. In this study, we treated HT29 colon cancer cells with CPT-CEF and attempted to investigate the cytotoxic effects of the formulation through an epigenetic perspective. By using RNA-Seq, several differentially expressed genes were obtained ( < 0.05). Enrichr was then used for the over-representation analysis, and the genes were compared to the epigenetic roadmap and histone modification database. The results showed that the DEGs had a high correlation with epigenetic modifications involving histone H3 acetylation. Furthermore, a subset of these genes was shown to be associated with the signaling pathway, which is highly upregulated in a large number of cancer cells. These genes could be investigated as downstream therapeutic targets against the uncontrolled proliferation of cancer cells. Further interaction analysis of the identified genes with the key genes of the signaling pathway in colorectal cancer identified the direct interactors and a few transcription regulators. Further analysis in cBioPortal confirmed their genetic alterations and their distribution across patient samples. Thus, the findings of this study reveal that colorectal cancer could be reversed by treatment with the CPT-CEF nanoparticle-conjugated nanocarrier through an epigenetic mechanism.
癌细胞能够以不受调节的方式增殖。有几个涉及的机制推动这种肿瘤转化。其中一个过程涉及通过基因表达的改变，从而通过细胞生长来绕过细胞死亡。这涉及细胞内复杂的表观遗传相互作用，促使它向致癌转化。这些表观遗传事件通过潜在改变染色质结构和影响关键基因表达来增加细胞生长。治疗机制已经通过利用化学调节来发挥潜在的致癌机制来开发，以对抗这种情况。喜树碱 (CPT) 就是这种药物的一个例子。它是一种选择性拓扑异构酶 I 抑制剂，对多种癌症有效，如结直肠癌。以前，我们成功地将 β-环糊精和铁纳米粒子 (FeO) 交联的磁性纳米载体偶联的 CPT 与 EDTA (CPT-CEF) 进行了配方。与单独的 CPT 相比，由于其选择性靶向和增加的溶解度，它具有更高的功效。在这项研究中，我们用 CPT-CEF 处理 HT29 结肠癌细胞，并试图从表观遗传角度研究该制剂的细胞毒性作用。通过使用 RNA-Seq，获得了几个差异表达基因（<0.05）。然后使用 Enrichr 进行过表达分析，并将基因与表观遗传图谱和组蛋白修饰数据库进行比较。结果表明，差异表达基因与涉及组蛋白 H3 乙酰化的表观遗传修饰具有高度相关性。此外，这些基因中的一部分与高度上调的大量癌细胞中的信号通路有关。这些基因可以作为针对癌细胞不受控制增殖的下游治疗靶点进行研究。进一步分析鉴定的基因与结直肠癌中信号通路的关键基因之间的相互作用，确定了直接相互作用体和一些转录调节剂。在 cBioPortal 中的进一步分析证实了它们的遗传改变及其在患者样本中的分布。因此，这项研究的结果表明，通过使用 CPT-CEF 纳米载体偶联纳米载体进行治疗，可以通过表观遗传机制逆转结直肠癌。
