MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, 310058, Hangzhou, Zhejiang, China.
Cancer Center, Zhejiang University, 310058, Hangzhou, Zhejiang, China.
Nat Commun. 2023 Apr 20;14(1):2253. doi: 10.1038/s41467-023-37871-5.
Iron metabolism dysregulation is tightly associated with cancer development. But the underlying mechanisms remain poorly understood. Increasing evidence has shown that long noncoding RNAs (lncRNAs) participate in various metabolic processes via integrating signaling pathway. In this study, we revealed one iron-triggered lncRNA, one target of YAP, LncRIM (LncRNA Related to Iron Metabolism, also named ZBED5-AS1 and Loc729013), which effectively links the Hippo pathway to iron metabolism and is largely independent on IRP2. Mechanically, LncRIM directly binds NF2 to inhibit NF2-LATS1 interaction, which causes YAP activation and increases intracellular iron level via DMT1 and TFR1. Additionally, LncRIM-NF2 axis mediates cellular iron metabolism dependent on the Hippo pathway. Clinically, high expression of LncRIM correlates with poor patient survival, suggesting its potential use as a biomarker and therapeutic target. Taken together, our study demonstrated a novel mechanism in which LncRIM-NF2 axis facilitates iron-mediated feedback loop to hyperactivate YAP and promote breast cancer development.
铁代谢失调与癌症的发生发展密切相关。但其潜在机制仍知之甚少。越来越多的证据表明，长链非编码 RNA（lncRNA）通过整合信号通路参与各种代谢过程。在本研究中，我们揭示了一个铁触发的 lncRNA，YAP 的一个靶点，LncRIM（与铁代谢相关的 lncRNA，也称为 ZBED5-AS1 和 Loc729013），它有效地将 Hippo 通路与铁代谢联系起来，并且在很大程度上独立于 IRP2。从机制上讲，LncRIM 直接结合 NF2 抑制 NF2-LATS1 相互作用，导致 YAP 激活，并通过 DMT1 和 TFR1 增加细胞内铁水平。此外，LncRIM-NF2 轴介导依赖 Hippo 通路的细胞铁代谢。临床上，LncRIM 的高表达与患者预后不良相关，提示其可能作为生物标志物和治疗靶点。综上所述，本研究揭示了一个新的机制，即 LncRIM-NF2 轴促进铁介导的反馈回路过度激活 YAP，从而促进乳腺癌的发展。
