Ferroptosis is governed by differential regulation of transcription in liver cancer

Xiao Zhang; Lutao Du; Yongxia Qiao; Xiaobai Zhang; Weisheng Zheng; Qi Wu; Yan Chen; Guoqing Zhu; Ya Liu; Zhixuan Bian; Susu Guo; Yueyue Yang; Lifang Ma; Yongchun Yu; Qiuhui Pan; Fenyong Sun; Jiayi Wang

doi:10.1016/j.redox.2019.101211

Ferroptosis is governed by differential regulation of transcription in liver cancer

Redox Biol. 2019 Jun:24:101211. doi: 10.1016/j.redox.2019.101211. Epub 2019 May 10.

Authors

Xiao Zhang¹, Lutao Du², Yongxia Qiao³, Xiaobai Zhang⁴, Weisheng Zheng⁴, Qi Wu¹, Yan Chen¹, Guoqing Zhu¹, Ya Liu¹, Zhixuan Bian⁵, Susu Guo¹, Yueyue Yang¹, Lifang Ma⁶, Yongchun Yu⁷, Qiuhui Pan⁸, Fenyong Sun⁹, Jiayi Wang¹⁰

Affiliations

¹ Department of Clinical Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai, 200072, China.
² Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, 250033, Shandong province, China.
³ School of Public Health, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China.
⁴ School of Life Science and Technology, Shanghai Key Laboratory of Signaling and Disease Research, Tongji University, Shanghai, 200092, China.
⁵ Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, 200127, China.
⁶ Shanghai Institute of Thoracic Tumors, Shanghai Chest Hospital, Shanghai, 200030, China.
⁷ Shanghai Chest Hospital, Shanghai, 200030, China.
⁸ Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, 200127, China. Electronic address: panqiuhui@263.net.
⁹ Department of Clinical Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai, 200072, China. Electronic address: sunfenyong@126.com.
¹⁰ Department of Clinical Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai, 200072, China; Advanced Institute of Translational Medicine, Tongji University, Shanghai, 200092, China. Electronic address: karajan2@163.com.

Abstract

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.

Keywords: Acetyltransferase; GSH; HIC1; HNF4A; Metabolism; Promoter.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Transformation, Neoplastic / genetics
Cell Transformation, Neoplastic / metabolism
Disease Models, Animal
Female
Ferroptosis / genetics*
Gene Expression Regulation, Neoplastic*
Glutathione / metabolism
Humans
Liver Neoplasms / genetics*
Liver Neoplasms / metabolism
Mice
Mice, Knockout
Models, Biological
Promoter Regions, Genetic
Transcription, Genetic*

Substances

Glutathione