Epigenetic reprogramming of epithelial-mesenchymal transition promotes ferroptosis of head and neck cancer

• Published in: Redox biology 2020-10, Vol.37, p.101697-101697, Article 101697
• Main Authors: Lee, Jaewang, You, Ji Hyeon, Kim, Min-Su, Roh, Jong-Lyel
• Format: Article
• Language: English
• Subjects: E-cadherin; Epigenetic reprogramming; Epithelial-mesenchymal transition; Ferroptosis; Research Paper; ZEB1
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2020.101697

Ferroptosis is a newly defined form of cell death induced by iron-dependent accumulation of lethal lipid peroxidation. Ferroptosis represent a therapeutic strategy to suppress therapy-resistant cancer cells with more property of epithelial-mesenchymal transition (EMT). However, epigenetic reprogramming of EMT has been rarely studied in the context of ferroptosis susceptibility. Therefore, we examined the therapeutic potentiality of EMT epigenetic reprogramming in promoting ferroptosis in head and neck cancer (HNC) cells. The effects of ferroptosis inducers and EMT inhibition or induction were tested in HNC cell lines and mouse tumor xenograft models. These effects were analyzed concerning cell viability and death, lipid reactive oxygen species and iron production, labile iron pool, glutathione contents, NAD/NADH levels, and mRNA/protein expression. Cell density and the expression levels of E-cadherin, vimentin, and ZEB1 were associated with the different susceptibility to ferroptosis inducers. CDH1 silencing or ZEB1 overexpression increased the susceptibility to ferroptosis, whereas CDH overexpression or ZEB1 silencing decreased the susceptibility, in vitro and in vivo. Histone deacetylase SIRT1 gene silencing or pharmacological inhibition by EX-527 suppressed EMT and consequently decreased ferroptosis, whereas SIRT inducers, resveratrol and SRT1720, increased ferroptosis. MiR-200 family inhibitors induced EMT and increased ferroptosis susceptibility. In HNC cells with low expression of E-cadherin, the treatment of 5-azacitidine diminished the hypermethylation of CDH1, resulting in increased E-cadherin expression and decreased ferroptosis susceptibility. Our data suggest that epigenetic reprogramming of EMT contributes to promoting ferroptosis in HNC cells. Epigenetic reprogramming of epithelial-mesenchymal transition (EMT) promotes ferroptosis of cancer cells. The EMT markers of E-cadherin (CDH1) and ZEB1 are closely related to ferroptosis sensitivity in cancer cells. Epigenetic reprogramming of EMT to gain a mesenchymal phenotype, such as SIRT1 activation or miR-200 family inhibition, promotes ferroptosis in HNC cells retaining relatively high epithelial traits and low ferroptosis sensitivity. However, 5-azacitidine induces CDH1 demethylation that contributed to reducing EMT and decreasing ferroptosis. [Display omitted] •The EMT markers of E-cadherin and ZEB1 were closely related to ferroptosis susceptibility.•Transition to epithelial traits by CDH overe