2. Academic Validation
  3. ATOH8 confers the vulnerability of tumor cells to ferroptosis by repressing SCD expression

ATOH8 confers the vulnerability of tumor cells to ferroptosis by repressing SCD expression

  • Cell Death Differ. 2025 Mar 25. doi: 10.1038/s41418-025-01482-y.
Huixiang Xiao # 1,  Xinxing Du # 2,  Huan Hou # 3,  Wenyun Guo # 1,  Zhenkeke Tao 1,  Shijia Bao 1,  Zhenzhen Wen 1,  Nan Jing 4,  Wei-Qiang Gao 5 6,  Baijun Dong 7,  Yu-Xiang Fang 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Systems Medicine for Cancer, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
  • 2 Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
  • 3 Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, #1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China.
  • 4 School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, 200030, China.
  • 5 State Key Laboratory of Systems Medicine for Cancer, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. weiqiang@sjtu.edu.cn.
  • 6 School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, 200030, China. weiqiang@sjtu.edu.cn.
  • 7 Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. dongbaijun@renji.com.
  • 8 State Key Laboratory of Systems Medicine for Cancer, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. fyx2003@sjtu.edu.cn.
  • # Contributed equally.
PMID: 40133667 DOI: 10.1038/s41418-025-01482-y
Abstract

Emerging evidence indicates that transcriptional regulation plays pivotal roles in modulating cellular vulnerability to Ferroptosis. However, the intricate mechanisms governing these processes remain poorly understood. In this study, we identify ATOH8, a basic helix-loop-helix (bHLH) transcription factor, as a key player in Ferroptosis regulation. ATOH8 is significantly upregulated in tumor cells following treatment with a Ferroptosis inducer. Overexpression of ATOH8 increases the susceptibility of tumor cells to Ferroptosis, while deletion of ATOH8 promotes Ferroptosis evasion. Mechanistically, ATOH8 confers the sensitivity of tumor cells to Ferroptosis by suppressing the transcription of stearoyl-CoA desaturase (SCD). Additionally, another bHLH family member, TCF3, is found to functions as a co-factor with ATOH8 by forming a TCF3-ATOH8 transcriptional repressive complex that suppresses SCD transcription. Furthermore, searching for upstream element reveals that EZH2 epigenetically suppresses ATOH8 expression by promoting DNA methylation in the ATOH8 promoter region and increasing the level of H3K27 me3. Importantly, pharmacological inhibition of EZH2 in a combined with a Ferroptosis inducer markedly impedes tumor growth both in vitro and in vivo. Collectively, our study elucidates a molecular link between Ferroptosis and epigenetic and transcriptional regulation, highlighting the potential of EZH2 and ATOH8 as therapeutic targets for Cancer treatment.

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