Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China.
Nat Cancer. 2022 Jan;3(1):75-89. doi: 10.1038/s43018-021-00299-1. Epub 2021 Dec 9.
α-Enolase 1 (ENO1) is a critical glycolytic enzyme whose aberrant expression drives the pathogenesis of various cancers. ENO1 has been indicated as having additional roles beyond its conventional metabolic activity, but the underlying mechanisms and biological consequences remain elusive. Here, we show that ENO1 suppresses iron regulatory protein 1 (IRP1) expression to regulate iron homeostasis and survival of hepatocellular carcinoma (HCC) cells. Mechanistically, we demonstrate that ENO1, as an RNA-binding protein, recruits CNOT6 to accelerate the messenger RNA decay of IRP1 in cancer cells, leading to inhibition of mitoferrin-1 (Mfrn1) expression and subsequent repression of mitochondrial iron-induced ferroptosis. Moreover, through in vitro and in vivo experiments and clinical sample analysis, we identified IRP1 and Mfrn1 as tumor suppressors by inducing ferroptosis in HCC cells. Taken together, this study establishes an important role for the ENO1-IRP1-Mfrn1 pathway in the pathogenesis of HCC and reveals a previously unknown connection between this pathway and ferroptosis, suggesting a potential innovative cancer therapy.
α-烯醇酶 1（ENO1）是一种关键的糖酵解酶，其异常表达驱动着各种癌症的发病机制。ENO1 的作用超出了其传统的代谢活性，但潜在的机制和生物学后果仍然难以捉摸。在这里，我们表明 ENO1 通过抑制铁调节蛋白 1（IRP1）的表达来调节肝癌（HCC）细胞的铁稳态和存活。从机制上讲，我们证明 ENO1 作为一种 RNA 结合蛋白，募集 CNOT6 来加速癌细胞中 IRP1 的信使 RNA 降解，导致 mitoferrin-1（Mfrn1）表达的抑制和随后线粒体铁诱导的铁死亡的抑制。此外，通过体外和体内实验以及临床样本分析，我们确定了 IRP1 和 Mfrn1 通过诱导 HCC 细胞中的铁死亡作为肿瘤抑制因子。总之，这项研究确立了 ENO1-IRP1-Mfrn1 通路在 HCC 发病机制中的重要作用，并揭示了该通路与铁死亡之间以前未知的联系，为癌症治疗提供了新的思路。
