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TFAM downregulation promotes autophagy and ESCC survival through mtDNA stress-mediated STING pathway

Oncogene volume 41, pages 3735–3746 (2022)Cite this article

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Abstract

The dynamics of mitochondrial biogenesis regulation is critical in maintaining cellular homeostasis for immune regulation and tumor prevention. Here, we report that mitochondrial biogenesis disruption through TFAM reduction significantly impairs mitochondrial function, induces autophagy, and promotes esophageal squamous cell carcinoma (ESCC) growth. We found that TFAM protein reduction promotes mitochondrial DNA (mtDNA) release into the cytosol, induces cytosolic mtDNA stress, subsequently activates the cGAS-STING signaling pathway, thereby stimulating autophagy and ESCC growth. STING depletion or mtDNA degradation by DNase I abrogates mtDNA stress response, attenuates autophagy, and decreases the growth of TFAM depleted cells. In addition, autophagy inhibitor also ameliorates mitochondrial dysfunction-induced activation of the cGAS-STING signaling pathway and ESCC growth. In conclusion, our results indicate that mtDNA stress induced by mitochondria biogenesis perturbation activates the cGAS-STING pathway and autophagy to promote ESCC growth, revealing an underappreciated therapeutic strategy for ESCC.

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Fig. 1: TFAM downregulation accelerates ESCC cancer growth in cell culture and xenograft tumors.
Fig. 2: TFAM deficiency induces mitochondrial dysfunction of ESCC cells.
Fig. 3: TFAM deficiency-induced mitochondrial dysfunction facilitate autophagy in ESCC cells.
Fig. 4: TFAM deficiency-induced mitochondrial dysfunction mediated cytosolic mtDNA stress by mPTP.
Fig. 5: Cytosolic mtDNA stress is involved in TFAM deficiency-mediated autophagy in ESCC cells.
Fig. 6: Cytosolic mtDNA stress promotes autophagy by cGAS-STING signaling pathway.
Fig. 7: Blocking cGAS-STING pathway-mediated autophagy inhibits mtDNA stress induced ESCC progression.

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Data availability

All data are available in the main text or the Supplementary Materials. Sequencing data have been deposited in GEO under accession No. GSE182710.

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Acknowledgements

We thank Dr. Jinliang Xing of State Key Laboratory of Cancer Biology and Department of Physiology and Pathophysiology, Fourth Military Medical University for providing the plasmid vectors with TFAM.

Funding

Project funded by China Postdoctoral Science Foundation (NO. 2020M682286, 2021T140180) to DB, the Young Core Instructor of Henan (NO. 2021GGJS027) to DB. Thanks for startup fund from Henan University to YW and DB.

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Author notes

  1. These authors contributed equally: Yujia Li, Qi Yang, Hui Chen.

Authors and Affiliations

  1. Laboratory of Cancer Biomarkers and Liquid Biopsy, School of Pharmacy, Henan University, Kaifeng, Henan, 475004, China

    Yujia Li, Qi Yang, Hui Chen, Xiaotian Yang, Jingru Han, Xiaojuan Yao, Xiajie Wei, Jiaoyang Si, Hongliang Liu & Dengke Bao

  2. School of Life Sciences, Henan University, Kaifeng, Henan, 475004, China

    Yujia Li, Qi Yang, Huanling Yao & Yanming Wang

  3. Nanyang central Hospital, Henan University, Nanyang, Henan, 473000, China

    Lixin Wan & Dengke Bao

  4. Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA

    Hushan Yang

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Contributions

This study was conceived and led by DB. YL, QY and HC performed the cell culture experiments. QY, HC, JH, XY, and XY performed the animal studies. YW, XW, JS, HY, HL, HY, and LW helped with the data analysis. LW, QY and YL performed the histological analysis and pathological diagnosis. DB, YW and HY wrote the manuscript and organized figures. All authors read and approved the final manuscript.

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Correspondence to Hushan Yang, Yanming Wang or Dengke Bao.

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Li, Y., Yang, Q., Chen, H. et al. TFAM downregulation promotes autophagy and ESCC survival through mtDNA stress-mediated STING pathway. Oncogene 41, 3735–3746 (2022). https://doi.org/10.1038/s41388-022-02365-z

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