ENO1 suppresses cancer cell ferroptosis by degrading the mRNA of iron regulatory protein 1.
Tong ZhangLinchong SunYijie HaoCaixia SuoShengqi ShenHaoran WeiWenhao MaPinggen ZhangTing WangXuemei GuShi-Ting LiZhaolin ChenRonghui YanYi ZhangYongping CaiRongbin ZhouWeidong JiaFang HuangPing GaoHuafeng ZhangPublished in: Nature cancer (2021)
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.
Keyphrases
- binding protein
- cell death
- poor prognosis
- cell cycle arrest
- induced apoptosis
- cancer therapy
- signaling pathway
- iron deficiency
- oxidative stress
- transcription factor
- endoplasmic reticulum stress
- long non coding rna
- drug delivery
- small molecule
- protein protein
- risk assessment
- amino acid
- young adults
- cell proliferation
- high glucose