ENO1 suppresses cancer cell ferroptosis by degrading the mRNA of iron regulatory protein 1.

Tong Zhang,Pinggen Zhang,Shengqi Shen,Haoran Wei,Huafeng Zhang,Ping Gao,Caixia Suo,Rongbin Zhou,Ronghui Yan,Weidong Jia,Fang Huang,Ting Wang,Zhaolin Chen,Linchong Sun,Yijie Hao,Yi Zhang,Xuemei Gu,Yongping Cai,Wenhao Ma,Shiting Li

doi:10.1038/s43018-021-00299-1

Abstract

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.

Highlights

Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei Shengqi Shen
Quantitative reverse transcriptase PCR confirmed that ANXA1, iron regulatory protein 1 (IRP1), KANK1, CAT, BIN1, and MYO6 among 17 genes were strongly suppressed by Enolase 1 (ENO1) at the mRNA levels (Fig. 1c)
We further investigated the expression of the 17 genes in paired clinical hepatocellular carcinoma (HCC) lesions and adjacent noncancerous tissues (Fig. 1d and Extended Data Fig. 1a)

Summary

Introduction

Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei Shengqi Shen. Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China Caixia Suo. Laboratory of Cancer and Stem Cell Metabolism, School of Medicine, Institutes for Life Sciences, South China University of Technology, Guangzhou 510006, China Pinggen Zhang. Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China Zhaolin Chen. The First A liated Hospital of USTC, University of Science and Technology of China Haoran Wei

Methods

Results

Conclusion