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Cellular and Molecular

DRP1 inhibition-mediated mitochondrial elongation abolishes cancer stemness, enhances glutaminolysis, and drives ferroptosis in oral squamous cell carcinoma

British Journal of Cancer (2024)Cite this article

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Abstract

Background

Mitochondrial dynamics play a fundamental role in determining stem cell fate. However, the underlying mechanisms of mitochondrial dynamics in the stemness acquisition of cancer cells are incompletely understood.

Methods

Metabolomic profiling of cells were analyzed by MS/MS. The genomic distribution of H3K27me3 was measured by CUT&Tag. Oral squamous cell carcinoma (OSCC) cells depended on glucose or glutamine fueling TCA cycle were monitored by 13C-isotope tracing. Organoids and tumors from patients and mice were treated with DRP1 inhibitors mdivi-1, ferroptosis inducer erastin, or combination with mdivi-1 and erastin to evaluate treatment effects.

Results

Mitochondria of OSCC stem cells own fragment mitochondrial network and DRP1 is required for maintenance of their globular morphology. Imbalanced mitochondrial dynamics induced by DRP1 knockdown suppressed stemness of OSCC cells. Elongated mitochondria increased α-ketoglutarate levels and enhanced glutaminolysis to fuel the TCA cycle by increasing glutamine transporter ASCT2 expression. α-KG promoted the demethylation of histone H3K27me3, resulting in downregulation of SNAI2 associated with stemness and EMT. Significantly, suppressing DRP1 enhanced the anticancer effects of ferroptosis.

Conclusion

Our study reveals a novel mechanism underlying mitochondrial dynamics mediated cancer stemness acquisition and highlights the therapeutic potential of mitochondria elongation to increase the susceptibility of cancer cells to ferroptosis.

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Fig. 1: OSCCSCs and non-OSCCSCs tumor cells display distinct mitochondrial morphologies.
Fig. 2: DRP1 knockdown suppressed cancer cell proliferation, migration and stemness.
Fig. 3: Mitochondrial fusion promote enhanced mitochondrial respiration and abundant TCA cycle metabolites.
Fig. 4: Elongated mitochondria enhance glutaminolysis to fuel the TCA cycle by increasing ASCT2 expression.
Fig. 5: α-KG alters H3K27 trimethylation and its occupancy at stemness associated gene and snai2 gene region to inhibit their expression in DRP1 knockdown cells.
Fig. 6: Combination of inhibition DRP1 and ferroptosis inducer erastin is therapeutic.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by grants from National Natural Science Foundation of China (81902784, 82370974, 81771086), by the Fund of Sichuan Provincial Department of science and technology (2022YFSY0058, 2022YFS0039, 2022YFS0003), the Research and Develop Program, West China Hospital of Stomatology, Sichuan University (LCYJ2023-DL-2, RD-02-202002), the CAMS Innovation Fund for Medical Sciences (CIFMS, 2019-I2M-5-004). The funding agencies had no role in the study design, collection, analysis, or interpretation of data, writing of the report, or the decision to submit the article for publication.

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Authors and Affiliations

  1. State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China

    Zhen Wang, Shouyi Tang, Luyao Cai, Qing Wang, Dan Pan, Yunmei Dong, Jing Li, Ning Ji, Xin Zeng, Yu Zhou, Ying-qiang Shen & Qianming Chen

  2. Department of Stomatology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China

    Hao Zhou

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  1. Zhen Wang
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Contributions

Zhen Wang: Conceptualization, data curation, investigation, writing–original draft. Shouyi Tang: Conceptualization, data curation, formal analysis, investigation, writing–original draft, writing–review and editing. Luyao Cai, Yunmei Dong, Dan Pan, Qing Wang: Conceptualization, data curation, Investigation. Hao Zhou, Jing Li, Ning Ji, Xin Zeng: Conceptualization, resources, supervision, project administration, writing–review and editing. Yu Zhou: Conceptualization, resources, supervision, funding acquisition, writing–original draft, project administration, writing–review and editing. Yingqiang Shen: Conceptualization, resources, supervision, funding acquisition, writing–original draft, project administration, writing–review and editing. Qianming Chen: Conceptualization, resources, supervision, funding acquisition, writing–original draft, project administration, writing–review and editing.

Corresponding authors

Correspondence to Yu Zhou or Ying-qiang Shen.

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Ethics approval and consent to participate

This study was approved by the ethics committees of the West China Hospital of Stomatology [WCHSIRB-D-2019-006]. This study was conducted following the Declaration of Helsinki. All participants eligible for this study had completed a written informed consent form.

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Wang, Z., Tang, S., Cai, L. et al. DRP1 inhibition-mediated mitochondrial elongation abolishes cancer stemness, enhances glutaminolysis, and drives ferroptosis in oral squamous cell carcinoma. Br J Cancer (2024). https://doi.org/10.1038/s41416-024-02670-2

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