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A moonlighting function of tumoral interleukin-1β precursor promotes metastasis via RACK1-mediated actin remodeling

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  • Quanzhu Chen

    (Central South University, NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine
    FuRong Laboratory
    Central South University, Cancer Research Institute and School of Basic Medical Sciences
    Central South University, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education)

  • Pan Wu

    (Central South University, NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine
    FuRong Laboratory
    Central South University, Cancer Research Institute and School of Basic Medical Sciences
    Central South University, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education)

  • Jing Cai

    (Central South University, Department of Pathology, The Second Xiangya Hospital)

  • Xingxing Lu

    (Central South University, NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine
    FuRong Laboratory
    Central South University, Cancer Research Institute and School of Basic Medical Sciences
    Central South University, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education)

  • Zhaojian Gong

    (Central South University, Department of Oral and Maxillofacial Surgery, The Second Xiangya Hospital)

  • Pan Chen

    (Central South University, NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine)

  • Zhaoyang Zeng

    (Central South University, NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine
    FuRong Laboratory
    Central South University, Cancer Research Institute and School of Basic Medical Sciences
    Central South University, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education)

  • Guiyuan Li

    (Central South University, NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine
    FuRong Laboratory
    Central South University, Cancer Research Institute and School of Basic Medical Sciences
    Central South University, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education)

  • Wei Xiong

    (Central South University, NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine
    FuRong Laboratory
    Central South University, Cancer Research Institute and School of Basic Medical Sciences
    Central South University, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education)

  • Mei Yi

    (FuRong Laboratory
    Central South University, Department of Dermotology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital)

  • Bo Xiang

    (Central South University, NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine
    FuRong Laboratory
    Central South University, Cancer Research Institute and School of Basic Medical Sciences
    Central South University, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education)

Abstract

Interleukin-1β (IL-1β) is a key inflammatory mediator in cancer. Its precursor, Pro-IL-1β, is conventionally considered inactive. Here we demonstrate that head and neck squamous cell carcinoma (HNSCC) cells exhibit significantly elevated Pro-IL-1β expression, driven by super-enhancer-mediated transcription of the IL1B gene. We show that intracellular Pro-IL-1β promotes tumor invasion and metastasis independent of IL-1β processing. Mechanistically, Pro-IL-1β binds RACK1 and inhibits its UBE2T-mediated ubiquitination, thereby stabilizing RACK1 and activating RhoA signaling to induce actin cytoskeleton remodeling and pseudopodia formation. Genetic inhibition of RACK1 abolishes Pro-IL-1β-induced metastasis. Clinically, RACK1 protein levels correlate with Pro-IL-1β expression in HNSCC specimens. Furthermore, we identify the natural compound Q3MG as a direct binder of Pro-IL-1β; it promotes lysosomal degradation of Pro-IL-1β and suppresses metastatic progression both in vitro and in vivo. Our study reveals a non-canonical, moonlighting function of Pro-IL-1β in tumor progression and highlights Q3MG as a promising therapeutic agent against metastatic cancer.

Suggested Citation

  • Quanzhu Chen & Pan Wu & Jing Cai & Xingxing Lu & Zhaojian Gong & Pan Chen & Zhaoyang Zeng & Guiyuan Li & Wei Xiong & Mei Yi & Bo Xiang, 2025. "A moonlighting function of tumoral interleukin-1β precursor promotes metastasis via RACK1-mediated actin remodeling," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65220-1
    DOI: 10.1038/s41467-025-65220-1
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    References listed on IDEAS

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    1. Na Zhang & Yang Meng & Song Mao & Huiling Ni & Canhua Huang & Licong Shen & Kun Fu & Lu Lv & Chunhong Yu & Piyanat Meekrathok & Chunmei Kuang & Fang Chen & Yu Zhang & Kai Yuan, 2025. "FBXO31-mediated ubiquitination of OGT maintains O-GlcNAcylation homeostasis to restrain endometrial malignancy," Nature Communications, Nature, vol. 16(1), pages 1-22, December.
    2. Emre Balta & Robert Hardt & Jie Liang & Henning Kirchgessner & Christian Orlik & Beate Jahraus & Stefan Hillmer & Stefan Meuer & Katrin Hübner & Guido H. Wabnitz & Yvonne Samstag, 2019. "Spatial oxidation of L-plastin downmodulates actin-based functions of tumor cells," Nature Communications, Nature, vol. 10(1), pages 1-18, December.
    3. Swarna L. Vijayaraj & Rebecca Feltham & Maryam Rashidi & Daniel Frank & Zhengyang Liu & Daniel S. Simpson & Gregor Ebert & Angelina Vince & Marco J. Herold & Andrew Kueh & Jaclyn S. Pearson & Laura F., 2021. "The ubiquitylation of IL-1β limits its cleavage by caspase-1 and targets it for proteasomal degradation," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    4. Jiaqiang Dong & Jiong Li & Yang Li & Zhikun Ma & Yongxin Yu & Cun-Yu Wang, 2021. "Transcriptional super-enhancers control cancer stemness and metastasis genes in squamous cell carcinoma," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
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