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

Cell Death & Differentiation volume 32, pages 1397–1412 (2025)Cite this article

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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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Fig. 1: ATOH8 is upregulated during ferroptosis.
Fig. 2: ATOH8 enhances the sensitivity to ferroptosis in tumors.
Fig. 3: ATOH8 binds TCF3 to form a transcriptional complex.
Fig. 4: ATOH8 enhances susceptibility of tumor cells to ferroptosis by suppressing SCD expression.
Fig. 5: ATOH8 suppresses SCD expression requiring TCF3.
Fig. 6: EZH2 epigenetically suppresses ATOH8 expression.
Fig. 7: Inhibition of EZH2 synergizes with the treatment of a ferroptosis inducer (IKE) suppresses tumor growth in vivo.

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Data availability

The ChIP-seq and mRNA-seq data generated in this study have been deposited in the NCBI Gene Expression Omnibus (GEO) database under accession numbers GSE282996 (ChIP-seq) and GSE282997 (mRNA-seq). The lipidomic data are available within the Original Data File. All other data are available from the corresponding authors upon request.

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Acknowledgements

This work was supported by the National Key Research and Development Program of China (2023YFC1404101 and 2022YFA1302704 to W.Q.G.), the National Natural Science Foundation of China (82072843 to Y.X.F., W2431055 and U23A20441 to W.Q.G. and 82372698 to B.D.), the Science and Technology Commission of Shanghai Municipality (21JC1404100 to W.Q.G. and 19411967400 to B.D.), the Peak Disciplines (Type IV) of Institutions of Higher Learning in Shanghai to W.Q.G., 111 Project (B21024) and KC Wong foundation to W.Q.G., Summit Plateau Program, Research Physician Program, Shanghai Jiao Tong University School of Medicine to B.D., Shanghai Municipal Health Commission (2019LJ11, 2020CXJQ03) to B.D.

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Author notes

  1. These authors contributed equally: Huixiang Xiao, Xinxing Du, Huan Hou, Wenyun Guo.

Authors and 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

    Huixiang Xiao, Wenyun Guo, Zhenkeke Tao, Shijia Bao, Zhenzhen Wen, Wei-Qiang Gao & Yu-Xiang Fang

  2. Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China

    Xinxing Du & Baijun Dong

  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

    Huan Hou

  4. School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, 200030, China

    Nan Jing & Wei-Qiang Gao

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  1. Huixiang Xiao
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Contributions

Experiments were conceived and designed by Y.F., W.Q.G. and B.D. Experiments were performed by H.X., X.D., H.H. and W.G. Data were analyzed by H.X., H.H., Z.T., S.B. and Z.W. The paper was written by H.X., Y.F. and W.Q.G. All authors read and approved the final manuscript.

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Correspondence to Wei-Qiang Gao, Baijun Dong or Yu-Xiang Fang.

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Xiao, H., Du, X., Hou, H. et al. ATOH8 confers the vulnerability of tumor cells to ferroptosis by repressing SCD expression. Cell Death Differ 32, 1397–1412 (2025). https://doi.org/10.1038/s41418-025-01482-y

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