School of Pharmacy, Second Military Medical University, Shanghai, China.
Department of Pharmacy, Tianjin Rehabilitation Center of Joint Logistics Support Force, Tianjin, China.
Front Immunol. 2021 Oct 20;12:761326. doi: 10.3389/fimmu.2021.761326. eCollection 2021.
DNA methylation is a vital epigenetic change that regulates gene transcription and helps to keep the genome stable. The deregulation hallmark of human cancer is often defined by aberrant DNA methylation which is critical for tumor formation and controls the expression of several tumor-associated genes. In various cancers, methylation changes such as tumor suppressor gene hypermethylation and oncogene hypomethylation are critical in tumor occurrences, especially in breast cancer. Detecting DNA methylation-driven genes and understanding the molecular features of such genes could thus help to enhance our understanding of pathogenesis and molecular mechanisms of breast cancer, facilitating the development of precision medicine and drug discovery. In the present study, we retrospectively analyzed over one thousand breast cancer patients and established a robust prognostic signature based on DNA methylation-driven genes. Then, we calculated immune cells abundance in each patient and lower immune activity existed in high-risk patients. The expression of leukocyte antigen (HLA) family genes and immune checkpoints genes were consistent with the above results. In addition, more mutated genes were observed in the high-risk group. Furthermore, a screening of druggable targets and compounds from CTRP and PRISM databases was performed, resulting in the identification of five target genes (HMMR, CCNB1, CDC25C, AURKA, and CENPE) and five agents (oligomycin A, panobinostat, (+)-JQ1, voxtalisib, and arcyriaflavin A), which might have therapeutic potential in treating high-risk breast cancer patients. Further evaluation confirmed that (+)-JQ1 had the best cancer cell selectivity and exerted its anti-breast cancer activity through CENPE. In conclusion, our study provided new insights into personalized prognostication and may inspire the integration of risk stratification and precision therapy.
DNA 甲基化是一种重要的表观遗传变化，可调节基因转录并有助于保持基因组稳定。人类癌症的失调标志通常由异常的 DNA 甲基化定义，这对于肿瘤形成至关重要，并控制着几个肿瘤相关基因的表达。在各种癌症中，甲基化变化，如肿瘤抑制基因高甲基化和癌基因低甲基化，在肿瘤发生中起着关键作用，特别是在乳腺癌中。检测 DNA 甲基化驱动的基因并了解这些基因的分子特征，有助于增强我们对乳腺癌发病机制和分子机制的理解，促进精准医学和药物发现的发展。在本研究中，我们回顾性分析了超过一千名乳腺癌患者，基于 DNA 甲基化驱动的基因建立了一个稳健的预后签名。然后，我们计算了每个患者的免疫细胞丰度，发现高危患者的免疫活性较低。白细胞抗原（HLA）家族基因和免疫检查点基因的表达与上述结果一致。此外，在高危组中观察到更多的突变基因。此外，还从 CTRP 和 PRISM 数据库中筛选了可成药的靶点和化合物，鉴定了五个靶基因（HMMR、CCNB1、CDC25C、AURKA 和 CENPE）和五个药物（寡霉素 A、帕比司他、（+）-JQ1、沃克替比司和岩藻黄素 A），它们可能具有治疗高危乳腺癌患者的潜力。进一步评估证实，（+）-JQ1 对癌细胞具有最佳的选择性，通过 CENPE 发挥其抗乳腺癌活性。总之，本研究为个性化预后预测提供了新的见解，并可能激发风险分层与精准治疗的整合。
