Epigenetic reprogramming of epithelial-mesenchymal transition promotes ferroptosis of head and neck cancer
Epigenetic reprogramming of epithelial-mesenchymal transition promotes ferroptosis of head and neck cancer
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DOI：
10.1016/j.redox.2020.101697
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发表时间：
2020-10-01
期刊：
影响因子：
11.4
通讯作者：
Roh, Jong-Lyel
中科院分区：
文献类型：
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作者：
Lee, Jaewang;You, Ji Hyeon;Roh, Jong-Lyel
铁凋亡是一种新定义的细胞死亡形式，由铁依赖的致死性脂质过氧化积累引起。铁凋亡代表了一种治疗策略，以抑制具有更多上皮间质转化（EMT）特性的耐药癌细胞。然而，EMT的表观遗传重编程很少在铁凋亡易感性的背景下进行研究。因此，我们研究了EMT表观遗传重编程在促进头颈癌（HNC）细胞中的铁凋亡中的治疗潜力。在HNC细胞系和小鼠肿瘤异种移植模型中测试了铁凋亡诱导剂和EMT抑制或诱导的作用。这些影响进行了分析，涉及细胞活力和死亡，脂质活性氧和铁的生产，不稳定的铁池，谷胱甘肽含量，NAD/NADH水平，和mRNA/蛋白质表达。细胞密度和E-cadherin、vimentin和ZEB 1的表达水平与对铁凋亡诱导剂的不同敏感性相关。在体外和体内，CDH 1沉默或ZEB 1过表达增加了对铁凋亡的易感性，而CDH过表达或ZEB 1沉默降低了易感性。组蛋白去乙酰化酶SIRT 1基因沉默或EX-527的药理学抑制EMT，从而减少铁凋亡，而SIRT诱导剂白藜芦醇和SRT 1720增加铁凋亡。miR-200家族抑制剂诱导EMT并增加铁凋亡易感性。在E-cadherin低表达的HNC细胞中，5-阿扎胞苷的处理减少了CDH 1的超甲基化，导致E-cadherin表达增加和铁凋亡易感性降低。我们的数据表明，EMT的表观遗传重编程有助于促进HNC细胞中的铁凋亡。
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.