Hypoxia promotes stem cell phenotypes and poor prognosis through epigenetic regulation of DICER [HMLER]

MicroRNAs are small regulatory RNAs that post-transcriptionally control gene expression. Reduced expression of DICER, the enzyme involved in microRNA processing, is frequently observed in cancer and is associated with poor clinical outcome in various malignancies. Yet the underlying mechanisms are not well understood. Here, we identify tumor hypoxia as a regulator of DICER expression in large cohorts of breast cancer patients. We show that DICER expression is suppressed by hypoxia through an epigenetic mechanism that involves inhibition of oxygen-dependent H3K27me3 demethylases KDM6A/B and results in silencing of the DICER promoter. Subsequently, reduced miRNA processing leads to derepression of the miR-200 target ZEB1, stimulates the epithelial to mesenchymal transition and ultimately results in the acquisition of stem cell phenotypes in human mammary epithelial cells. Our study uncovers a previously unknown relationship between oxygen-sensitive epigenetic regulators, miRNA biogenesis and tumor stem cell phenotypes that may underlie poor outcome in breast cancer. A total of 12 samples were analyzed. For each condition tested, 3 independent experiments were carried out (biological repicates).

微小RNA（microRNAs）是一类在转录后水平调控基因表达的小型调控RNA。在多种恶性肿瘤中，常可观察到参与微小RNA加工的酶DICER（DICER）的表达下调，且该现象与各类恶性肿瘤的不良临床预后密切相关，但其背后的分子机制尚未得到充分阐释。本研究在大样本乳腺癌患者队列中，证实肿瘤缺氧可调控DICER的表达。我们发现，缺氧通过表观遗传机制抑制DICER表达：该机制通过抑制氧依赖型H3K27me3去甲基化酶KDM6A/B，最终导致DICER启动子发生沉默。后续实验显示，微小RNA加工能力的下调会导致miR-200的靶基因ZEB1去抑制，促进上皮间质转化，最终使人乳腺上皮细胞获得干细胞表型。本研究揭示了氧敏感型表观遗传调控因子、微小RNA生物发生与肿瘤干细胞表型之间此前未被发现的关联，该关联或可解释乳腺癌患者的不良预后。本研究共分析了12份样本，针对每种测试条件均开展了3次独立生物学重复实验。