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Nuclear translocation of Gasdermin D sensitizes colorectal cancer to chemotherapy in a pyroptosis-independent manner

Oncogene volume 41, pages 5092–5106 (2022)Cite this article

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Abstract

Gasdermin D (GSDMD) has recently been identified as a cytoplasmic effector protein that plays a central role in pyroptosis of immune cells. However, GSDMD is a universally expressed protein, and its function beyond pyroptosis, especially in cancer cells, has not been well characterized. Here, we report that predominant localization of GSDMD in the nucleoplasm in vivo indicates favorable clinical outcomes in colorectal cancer, while a lack of nuclear localization of GSDMD is associated with poor outcomes. Nuclear GSDMD, rather than cytoplasmic GSDMD, inhibits cell growth and promotes apoptosis in colorectal cancer. Hypoxia in the tumor microenvironment accounts for mild or moderate nuclear translocation of GSDMD in vivo. Under the stimulation of chemotherapy drugs, nuclear GSDMD promotes apoptosis via regulation of its subcellular distribution rather than pyroptosis-related cleavage. After nuclear translocation, GSDMD interacts with PARP-1 to dramatically inhibit its DNA damage repair-related function by functioning like the PARP inhibitor olaparib, thus forming a “hypoxia/chemotherapy—GSDMD nuclear translocation—PARP-1 blockade—DNA damage and apoptosis” axis. This study redefines the pyroptosis-independent function of GSDMD and suggests that the subcellular localization of GSDMD may serve as a molecular indicator of clinical outcomes and a promising therapeutic target in colorectal cancer.

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Fig. 1: GSDMD is mainly expressed in the nucleoplasm of colorectal cancer cells, and a lack of nuclear expression of GSDMD is associated with worse clinical outcomes.
Fig. 2: Nuclear translocation of GSDMD inhibits some malignant phenotypes of colorectal cancer.
Fig. 3: Hypoxia induces GSDMD translocation into the nucleus in vivo and in vitro.
Fig. 4: GSDMD enhances chemotherapy drug-induced apoptosis in RKO and SW1116 cells independently of cleavage-related pyroptosis.
Fig. 5: Nuclear GSDMD interacts with PARP-1 to inhibit its DNA damage repair-related function.
Fig. 6: GSDMD inhibits PARP-1 function by binding to the PARP-1 CA domain.
Fig. 7

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Data availability

The data that support the findings “Protein Mass Spectrometry on GSDMD Interacting Protein” of this study are openly available in Figshare at https://doi.org/10.6084/m9.figshare.19544923.

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Acknowledgements

We thank Professor Feng Shao (National Institute of Biological Science) for the kind gift of the PCS2-Flag-tagged GSDMD plasmid. This project was supported by the National Natural Science Foundation of China (NSFC82002427, NSFC 30801132) and the Shanghai Chest Hospital Outstanding Talent Cultivation Project (2018YNZYB03).

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  1. These authors contributed equally: Xiao Peng, Risi Na.

Authors and Affiliations

  1. Department of Biology, Temple University, BioLife Building, 1900 North 12th Street, Philadelphia, PA, 19122-6078, USA

    Xiao Peng & Shohreh Amini

  2. Department of General Surgery, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, 2000 Xiang’an East Road, Xiamen, 361102, China

    Risi Na, Wenting Zhou & Xiaole Meng

  3. Department of Oncological Surgery, Shanghai Chest Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 241 West Huaihai Road, Xuhui District, Shanghai, 200030, China

    Yunhai Yang & Liwei Song

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Contributions

LS, YY, SA: experimental design and drafting of the manuscript; XP, RN: execution of most experiments, such as Western blot, IF and FCM; WZ, XM: clinical data collection and IHC of colorectal cancer TMAs and mouse tumor masses; XP: FCM of apoptosis and statistics; LS, YY: project supervision and guidance. All authors: Approval of the final version to be published.

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Correspondence to Yunhai Yang, Shohreh Amini or Liwei Song.

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Peng, X., Na, R., Zhou, W. et al. Nuclear translocation of Gasdermin D sensitizes colorectal cancer to chemotherapy in a pyroptosis-independent manner. Oncogene 41, 5092–5106 (2022). https://doi.org/10.1038/s41388-022-02503-7

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