Abstract
Cervical cancer is the most common gynecologic cancer, etiologically related to persistent infection of human papillomavirus (HPV). Both the host innate immunity system and the invading HPV have developed sophisticated and effective mechanisms to counteract each other. As a central innate immune sensing signaling adaptor, stimulator of interferon genes (STING) plays a pivotal role in antiviral and antitumor immunity, while viral oncoproteins E7, especially from HPV16/18, are responsible for cell proliferation in cervical cancer, and can inhibit the activity of STING as reported. In this report, we find that activation of STING-TBK1 (TANK-binding kinase 1) promotes the ubiquitin-proteasome degradation of E7 oncoproteins to suppress cervical cancer growth. Mechanistically, TBK1 is able to phosphorylate HPV16/18 E7 oncoproteins at Ser71/Ser78, promoting the ubiquitination and degradation of E7 oncoproteins by E3 ligase HUWE1. Functionally, activated STING inhibits cervical cancer cell proliferation via down-regulating E7 oncoproteins in a TBK1-dependent manner and potentially synergizes with radiation to achieve better effects for antitumor. Furthermore, either genetically or pharmacologically activation of STING-TBK1 suppresses cervical cancer growth in mice, which is independent on its innate immune defense. In conclusion, our findings represent a new layer of the host innate immune defense against oncovirus and provide that activating STING/TBK1 could be a promising strategy to treat patients with HPV-positive cervical cancer.
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The data generated in this study are available within the article and its supplementary data files. The online version contains supplementary material. Any additional information related to this work is available from the corresponding author on reasonable request. The authenticity of this manuscript was validated by uploading the key raw data to the Research Data Deposit public platform (www.researchdata.org.cn).
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Acknowledgements
We thank Dr. Ying Sun (Sun Yat-sen University Cancer Center) for helpful suggestions. We thank members of Dr. Kang’s laboratory for providing helpful suggestions on this study. This work was supported by the National Key R&D Program of China (2021YFA1300601), and the grants from the National Natural Science Foundation of China (82002428, 81972430, 82103155, 32100544, 82341015, 82030090)
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XH, TK and YG conceived the project, designed the experiments and wrote the manuscript. XH, YG, LH and BX performed most of the experiments and analyzed the data. XH, YO, FC and JL performed the statistical analyses. XH, YG, LH and XZ performed the animal experiments. DW, YW and RZ assisted with experiments and provided technical help. XC provided comments and revised the manuscript. All authors have reviewed the manuscript and approved the final version.
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Animal studies were conducted in strict accordance with the Guide for the Care and Use of Laboratory Animals and the Principles for the Utilization and Care of Vertebrate Animals and approved by the Animal Research Committee of Sun Yat-sen University Cancer Center (SYSUCC) (Approval no. L102042020100L).
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Huang, X., Huo, L., Xiao, B. et al. Activating STING/TBK1 suppresses tumor growth via degrading HPV16/18 E7 oncoproteins in cervical cancer. Cell Death Differ 31, 78–89 (2024). https://doi.org/10.1038/s41418-023-01242-w
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DOI: https://doi.org/10.1038/s41418-023-01242-w
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