Ferroptosis is governed by differential regulation of transcription in liver cancer
Ferroptosis is governed by differential regulation of transcription in liver cancer
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肝癌中铁死亡由转录的差异调节控制
DOI：
10.1016/j.redox.2019.101211
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发表时间：
2019-06-01
期刊：
影响因子：
11.4
通讯作者：
Wang, Jiayi
中科院分区：
文献类型：
--
作者：
Zhang, Xiao;Du, Lutao;Wang, Jiayi
铁缺乏症是代谢紊乱的结果，与肝癌密切相关。然而，肝癌中铁凋亡的精细调节机制仍不清楚。在这里，我们已经确定了两类基因：铁凋亡上调因子（FUF）和铁凋亡下调因子（FDF），通过影响GSH的合成来刺激和抑制铁凋亡。FUF受一个转录因子调控，而FDF受另一个转录因子HNF 4A调控。铁凋亡的发生可能依赖于组蛋白乙酰转移酶KAT 2B。在铁凋亡的刺激下，KAT 2B的解离阻止HNF 4A与FDF启动子结合。这种作用发生在KAT 2B募集到FUF启动子之前，这促进了KAT 2B 1结合以转录FUF。在临床上，HNF 1和HNF 4A与肝癌的肿瘤分期相反。低HNF 1和高HNF 4A的患者预后较差。破坏HNF-4A和HNF-1之间的平衡可能有助于治疗肝癌。
Ferroptosis is an outcome of metabolic disorders and closely linked to liver cancer. However, the mechanism underlying the fine regulation of ferroptosis in liver cancer remains unclear. Here, we have identified two categories of genes: ferroptosis up-regulated factors (FUF) and ferroptosis down-regulated factors (FDF), which stimulate and suppress ferroptosis by affecting the synthesis of GSH. Furthermore, FUF are controlled by one transcription factor HIC1, while FDF controlled by another transcription factor HNF4A. Occurrence of ferroptosis might depend on the histone acetyltransferase KAT2B. Upon stimulation of ferroptosis, dissociation of KAT2B prevents HNF4A from binding to the FDF promoter. This effect happens prior to the recruitment of KAT2B to the FUF promoter, which facilitates HIC1 binding to transcribe FUF. Clinically, HIC1 and HNF4A conversely correlate with tumor stage in liver cancer. Patients with lower HIC1 and higher HNF4A exhibit poorer prognostic outcomes. Disrupting the balance between HIC1 and HNF4A might be helpful in treating liver cancer.