Chemical biology reprogramming epigenetic aberration in malignant brain tumors

几乎所有的癌细胞都有多种表观遗传异常，这些异常与遗传变化相结合，通过沉默肿瘤抑制基因来影响许多细胞过程，包括细胞增殖和细胞凋亡。在本研究中，我们重点研究了神经胶质瘤中DNA低甲基化和CpG岛高甲基化的表观遗传机制。启动子CpG岛的异常高甲基化已被认为是参与癌症相关基因沉默的关键机制，并发生在与肿瘤发生和肿瘤进展相关的多种功能基因上。这种启动子高甲基化可以调节胶质母细胞瘤对药物和放疗的敏感性。例如，MGMT启动子的甲基化是肿瘤对烷基化剂化疗反应的特异性预测性生物标志物。最后，我们还评估了NY-ESO-1作为免疫治疗靶点的潜力，NY-ESO-1是迄今为止发现的最具免疫原性的癌症/睾丸抗原（CTA）。使用有效的基于表观遗传学的治疗癌细胞可能通过表观遗传重编程将异常调节的表观基因组恢复到更正常的状态。因此，表观遗传治疗可能是一种有希望的和有效的治疗人类肿瘤。

Almost all cancer cells have multiple epigenetic abnormalities, which combine with genetic changes to affect many cellular processes, including cell proliferation and apoptosis, by silencing tumor-suppressor genes. In this study, we focused on the epigenetic mechanisms of DNA hypomethylation and CpG island hypermethylation in gliomas. Aberrant hypermethylation in promoter CpG islands has been recognized as a key mechanism involved in the silencing of cancer-associated genes and occurs at genes with diverse functions related to tumorigenesis and tumor progression. Such promoter hypermethylation can modulate the sensitivity of glioblastomas to drugs and radiotherapy. As an example, the methylation of the MGMT promoter is a specific predictive biomarker of tumor responsiveness to chemotherapy with alkylating agents. Finally, we also evaluated the potential of NY-ESO-1, the most immunogenic cancer/testis antigen(CTA) discovered thus far, as an immunotherapy target. The use of potent epigenetics-based therapy for cancer cells might restore the abnormally regulated epigenomes to a more normal state through epigenetic reprogramming. Thus, epigenetic therapy may be a promising and potent treatment for human neoplasia.