Department of Cell Biology and Genetics, Chongqing Medical University, 1 Yixueyuan Road, Chongqing 400016 P.R. China.
Department of Endocrine and breast surgery, The First Affiliated Hospital of Chongqing Medical University, 1 Yixueyuan Road, Chongqing 400016, P.R. China.
Int J Biol Sci. 2022 Jun 6;18(9):3888-3907. doi: 10.7150/ijbs.72842. eCollection 2022.
Hypoxic microenvironment and circular RNAs (circRNAs) have shown critical implications in breast cancer (BC) progression. However, the specific functions and underlying mechanisms of circRNAs in BC under hypoxia remain largely unknown. We first screened for differentially expressed circRNAs in normoxic and hypoxic MCF-7 cells using circRNA microarray. A novel hypoxia-induced circRNA, circPFKFB4, was identified. Clinical investigation showed that circPFKFB4 was highly expressed in BC tissues and cell lines, and its overexpression was positively correlated with the advanced clinical stage and poor prognosis of BC patients. Functionally, circPFKFB4 promoted the proliferation of BC cells both and . Mechanistically, HIF1α bound to hypoxia response elements in the promoter region of the PFKFB4 gene to facilitate the biogenesis of circPFKFB4 under hypoxia. Hypoxia-induced circPFKFB4 directly bound to both DDB1 and DDB2 and promoted the CRL4 E3 ubiquitin ligase assembly, resulting in p27 ubiquitination and BC progression under hypoxia. Our findings revealed a novel interaction between circPFKFB4 and the CRL4 E3 ubiquitin ligase, suggesting that circPFKFB4 might serve as a promising biomarker and therapeutic target for BC.
缺氧微环境和环状 RNA（circRNA）在乳腺癌（BC）进展中具有重要意义。然而，缺氧条件下 circRNA 在 BC 中的具体功能和潜在机制在很大程度上仍不清楚。我们首先使用 circRNA 微阵列筛选出常氧和缺氧 MCF-7 细胞中差异表达的 circRNA。鉴定出一种新型缺氧诱导的 circRNA，circPFKFB4。临床研究表明，circPFKFB4 在 BC 组织和细胞系中高表达，其过表达与 BC 患者的晚期临床分期和不良预后呈正相关。功能上，circPFKFB4 促进 BC 细胞的增殖。机制上，HIF1α 与 PFKFB4 基因启动子区域的缺氧反应元件结合，促进缺氧条件下 circPFKFB4 的生物发生。缺氧诱导的 circPFKFB4 直接与 DDB1 和 DDB2 结合，并促进 CRL4 E3 泛素连接酶组装，导致 p27 泛素化和 BC 进展。我们的研究结果揭示了 circPFKFB4 与 CRL4 E3 泛素连接酶之间的新相互作用，表明 circPFKFB4 可能作为 BC 的有前途的生物标志物和治疗靶点。
