Open AccessHypoxia blocks ferroptosis of hepatocellular carcinoma via suppression of METTL14 triggered YTHDF2‐dependent silencing of SLC7A11
Author(s) -
Fan Zhuoyang,
Yang Guowei,
Zhang Wei,
Liu Qian,
Liu Guangqin,
Liu Pingping,
Xu Ligang,
Wang Jianhua,
Yan Zhiping,
Han Hong,
Liu Rong,
Shu Minfeng
Publication year - 2021
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.16957
Subject(s) - apoptosis , flow cytometry , biology , hepatocellular carcinoma , cancer research , in vivo , hypoxia (environmental) , cell growth , microbiology and biotechnology , chemistry , biochemistry , oxygen , organic chemistry
Residue hepatocellular carcinoma (HCC) cells enduring hypoxic environment triggered by interventional embolization obtain more malignant potential with little clarified mechanism. The N 6 ‐methyladenosine (m 6 A) biological activity plays essential roles in diverse physiological processes. However, its role under hypoxic condition remains largely unexplored. RT‐qPCR and Western blot were used to evaluate METTL14 expression in hypoxic HCC cells. MDA assay and electronic microscopy photography were used to evaluate ferroptosis. The correlation between SLC7A11 and METTL14 was conducted by bioinformatical analysis. Flow cytometry was used to verify the effect of SLC7A11 on ROS production. Cell counting kit‐8 assay was performed to detect cells proliferation ability. Hypoxia triggered suppression of METTL14 in a HIF‐1α–dependent manner potently abrogated ferroptosis of HCC cells. Mechanistic investigation identified SLC7A11 was a direct target of METTL14. Both in vitro and in vivo assay demonstrated that METTL14 induced m 6 A modification at 5’UTR of SLC7A11 mRNA, which in turn underwent degradation relied on the YTHDF2‐dependent pathway. Importantly, ectopic expression of SLC7A11 strongly blocked METTL14‐induced tumour‐suppressive effect in hypoxic HCC. Our investigations lay the emphasis on the hypoxia‐regulated ferroptosis in HCC cells and identify the HIF‐1α /METTL14/YTHDF2/SLC7A11 axis as a potential therapeutic target for the HCC interventional embolization treatment.