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YTHDC1 as a tumor progression suppressor through modulating FSP1-dependent ferroptosis suppression in lung cancer

Cell Death & Differentiation volume 30, pages 2477–2490 (2023)Cite this article

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Abstract

Ferroptosis is a regulated cell death process initiated by iron-dependent phospholipid peroxidation and is mainly suppressed by GPX4-dependent and FSP1-dependent surveillance mechanisms. However, how the ferroptosis surveillance system is regulated during cancer development remains largely unknown. Here, we report that the YTHDC1-mediated m6A epigenetic regulation of FSP1 alleviates the FSP1-dependent ferroptosis suppression that partially contributes to the tumor suppressive role of YTHDC1 in lung cancer progression. YTHDC1 knockdown promoted the lung tumor progression and upregulated FSP1 protein level that resulted in ferroptosis resistance of lung cancer cells. Silencing FSP1 abrogated YTHDC1 knockdown-induced proliferation increase and ferroptosis resistance. Mechanistically, YTHDC1 binding to the m6A sites in the FSP1 3’-UTR recruited the alternative polyadenylation regulator CSTF3 to generate a less stable shorter 3’-UTR contained FSP1 mRNA, whereas YTHDC1 downregulation generated the longer 3’-UTR contained FSP1 mRNA that is stabilized by RNA binding protein HuR and thus led to the enhanced FSP1 protein level. Therefore, our findings identify YTHDC1 as a tumor progression suppressor in lung cancer and a ferroptosis regulator through modulating the FSP1 mRNA stability and thus suggest a ferroptosis-related therapeutic option for YTHDC1high lung cancer.

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Fig. 1: YTHDC1 is negatively correlated with the progression of lung cancer.
Fig. 2: YTHDC1 suppresses lung cancer progression.
Fig. 3: YTHDC1 promotes ferroptosis activity.
Fig. 4: YTHDC1 regulates FSP1 at the post-transcriptional level in an m6A-dependent manner.
Fig. 5: YTHDC1 knockdown regulates the alternative polyadenylation and increases the long isoform of FSP1 mRNA, which can be bound and stabilized by HuR protein.
Fig. 6: YTHDC1 provides a ferroptotic vulnerability for lung cancer treatment.
Fig. 7: A working model shows how YTHDC1 induces ferroptosis by regulating FSP1 in lung cancer.

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Data availability

All data needed to evaluate the conclusions are present in the paper and the supplementary files.

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Funding

This work was supported by the National Natural Science Foundation of China (No. 82002447 to SY; 82173131 to HH), the Outstanding Young and Middle-aged Talents Training Program of Zhongnan Hospital of Wuhan University (Grant No. ZNYQ2022003 to SY), the Science and Technology Innovation Commission of Shenzhen Municipal Government Grants (JCYJ20210324104007022 to HH), Guangdong provincial fundings: 2021KTSCX108 (to XH), and the Program of Excellent Doctoral (Postdoctoral) of Zhongnan Hospital of Wuhan University (No. ZNYB2020028 to SY).

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Author notes

  1. These authors contributed equally: Shuai Yuan, Shu Xi, Hong Weng.

  2. These authors jointly supervised this work: Yafei Li, Xian-Tao Zeng, Hailiang Hu.

Authors and Affiliations

  1. Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China

    Shuai Yuan, Shu Xi, Hong Weng, Meng-Meng Guo, Jin-Hui Zhang, Zhi-Ping Yu, Meng-Yang Liu, Dao-Jing Ming & Xian-Tao Zeng

  2. Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen, China

    Haozhe Zhang, Zengzhen Xing, Rajiv Kumar Sah, Yi Zhou, Xin Hong & Hailiang Hu

  3. Department of Urology, The Second Affiliated Hospital of Nanchang University, Nanchang, China

    Zhaojun Yu & Tao Zeng

  4. Cancer Center, Faculty of Health Sciences, MoE Frontier Science Center for Precision Oncology, University of Macau, Taipa, Macau, SAR, China

    Gang Li

  5. Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen, China

    Xin Hong & Hailiang Hu

  6. Department of Epidemiology, College of Preventive Medicine, Army Medical University, Chongqing, China

    Yafei Li

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Contributions

HH led the study by designing, interpreting results, obtaining the funding and reviewing the manuscript. SY, SX, and HW participated in performing the experiments, results interpretation, manuscript writing. MMG, JHZ, ZPY, HZ, ZY, ZX, DJM, RKS, YZ, and TZ participated in performing the experiments and collecting the data. MYL performed the bioinformatics analysis and participated in results interpretation. GL and XH participated in the manuscript discussion. YL and XTZ participated in study design, results interpretation and reviewing the manuscript.

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Correspondence to Yafei Li, Xian-Tao Zeng or Hailiang Hu.

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All experimental animal procedures were approved by the Experimental Animal Welfare and Ethics, Zhongnan Hospital of Wuhan University.

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Yuan, S., Xi, S., Weng, H. et al. YTHDC1 as a tumor progression suppressor through modulating FSP1-dependent ferroptosis suppression in lung cancer. Cell Death Differ 30, 2477–2490 (2023). https://doi.org/10.1038/s41418-023-01234-w

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