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
Affiliations
Xiao Zhang
Department of Clinical Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai, 200072, China
Lutao Du
Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, 250033, Shandong province, China
Yongxia Qiao
School of Public Health, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
Xiaobai Zhang
School of Life Science and Technology, Shanghai Key Laboratory of Signaling and Disease Research, Tongji University, Shanghai, 200092, China
Weisheng Zheng
School of Life Science and Technology, Shanghai Key Laboratory of Signaling and Disease Research, Tongji University, Shanghai, 200092, China
Qi Wu
Department of Clinical Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai, 200072, China
Yan Chen
Department of Clinical Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai, 200072, China
Guoqing Zhu
Department of Clinical Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai, 200072, China
Ya Liu
Department of Clinical Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai, 200072, China
Zhixuan Bian
Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, 200127, China
Susu Guo
Department of Clinical Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai, 200072, China
Yueyue Yang
Department of Clinical Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai, 200072, China
Lifang Ma
Shanghai Institute of Thoracic Tumors, Shanghai Chest Hospital, Shanghai, 200030, China
Yongchun Yu
Shanghai Chest Hospital, Shanghai, 200030, China
Qiuhui Pan
Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, 200127, China; Corresponding author.
Fenyong Sun
Department of Clinical Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai, 200072, China; Corresponding author.
Jiayi Wang
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; Corresponding author. Department of Clinical Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai, 200072, China.
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: HIC1, HNF4A, GSH, Acetyltransferase, Promoter, Metabolism
