Department of Oncology, Gansu Provincial Hospital, The First Clinical Medical College of Gansu University of Chinese Medicine, Lanzhou 730000, PR China.
Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200000, PR China.
Hum Mol Genet. 2023 Jan 1;32(1):79-92. doi: 10.1093/hmg/ddac185.
Non-small cell lung cancer (NSCLC) is one of the most malignant epithelial tumors. Studies have suggested that DNA hypermethylation of promoters and abnormal histone modifications could induce tumor suppressor genes (TSGs) downregulation in NSCLC. However, the exact mechanism of TSGs downregulation remains unclear. In this study, we found that there is no difference in the regions of most TSGs promoters in NSCLC. Moreover, we found that there is no DNA methylation difference in the region of VILL promoter in NSCLC compared with adjacent tissue samples by pyrosequencing. We further demonstrated that VILL was markedly reactivated in A549 and H1703 cells infected with miR-26A1 lentivirus while this activation was inhibited by JQ1, an enhancer inhibitor. In addition, we identified that miR-26A1 could function as a tumor suppressor to inhibit proliferation and metastasis of NSCLC cells. Chromatin immunoprecipitation assays revealed that overexpression of miR-26A1 could significantly induce the enrichment of H3K27ac at the enhancer regions in A549 cells. To sum up, our findings revealed that enhancer-mediated TSGs regulation occured in NSCLC, suggesting that miR-26A1 could serve as a key regulator and may be a potential therapeutic target for NSCLC.
非小细胞肺癌（NSCLC）是最恶性的上皮肿瘤之一。研究表明，启动子的 DNA 高甲基化和异常组蛋白修饰可导致 NSCLC 中的肿瘤抑制基因（TSGs）下调。然而，TSGs 下调的确切机制仍不清楚。在本研究中，我们发现 NSCLC 中大多数 TSGs 启动子区域没有差异。此外，我们通过焦磷酸测序发现，与相邻组织样本相比，NSCLC 中 VILL 启动子区域没有 DNA 甲基化差异。我们进一步证明，在感染 miR-26A1 慢病毒的 A549 和 H1703 细胞中，VILL 明显被重新激活，而增强子抑制剂 JQ1 抑制了这种激活。此外，我们发现 miR-26A1 可以作为肿瘤抑制因子抑制 NSCLC 细胞的增殖和转移。染色质免疫沉淀试验显示，miR-26A1 的过表达可显著诱导 A549 细胞增强子区域的 H3K27ac 富集。总之，我们的研究结果揭示了增强子介导的 TSGs 调节在 NSCLC 中发生，表明 miR-26A1 可以作为关键调节剂，并可能成为 NSCLC 的潜在治疗靶点。
