Dysfunction of Tumour Suppressor Genes (TSGs) is a common feature in carcinogenesis. Epigenetic abnormalities including DNA hypermethylation or aberrant histone modifications in promoter regions have been described for interpreting TSG inactivation. However, in many instances, how TSGs are silenced in tumours are largely unknown. Given that miRNA with low expression in tumours is another recognized signature, we hypothesize that low expression of miRNA may reduce the activity of TSG related enhancers and further lead to inactivation of TSG during cancer development. Here, we reported that low expression of miRNA in cancer as a recognized signature leads to loss of function of TSGs in breast cancer. In 157 paired breast cancer and adjacent normal samples, tumour suppressor gene GPER1 and miR-339 are both downregulated in Luminal A/B and Triple Negative Breast Cancer subtypes. Mechanistic investigations revealed that miR-339 upregulates GPER1 expression in breast cancer cells by switching on the GPER1 enhancer, which can be blocked by enhancer deletion through the CRISPR/Cas9 system. Collectively, our findings reveal novel mechanistic insights into TSG dysfunction in cancer development, and provide evidence that reactivation of TSG by enhancer switching may be a promising alternative strategy for clinical breast cancer treatment.

中文翻译：

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通过 NamiRNA 网络的增强子转换重新激活乳腺癌中的肿瘤抑制因子

肿瘤抑制基因 (TSGs) 的功能障碍是癌症发生的常见特征。已描述表观遗传异常，包括启动子区域中的 DNA 高甲基化或异常组蛋白修饰，用于解释 TSG 失活。然而，在许多情况下，TSGs 如何在肿瘤中被沉默在很大程度上是未知的。鉴于肿瘤中低表达的 miRNA 是另一个公认的特征，我们假设 miRNA 的低表达可能会降低 TSG 相关增强子的活性，并进一步导致 TSG 在癌症发展过程中失活。在这里，我们报道了作为公认特征的癌症中 miRNA 的低表达导致 TSG 在乳腺癌中的功能丧失。在 157 对乳腺癌和相邻的正常样本中，肿瘤抑制基因 GPER1 和 miR-339 在 Luminal A/B 和三阴性乳腺癌亚型中均下调。机制研究表明，miR-339 通过开启 GPER1 增强子上调乳腺癌细胞中 GPER1 的表达，增强子可以通过 CRISPR/Cas9 系统缺失来阻断。总的来说，我们的研究结果揭示了癌症发展中 TSG 功能障碍的新机制见解，并提供证据表明通过增强子转换重新激活 TSG 可能是临床乳腺癌治疗的一种有希望的替代策略。