Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Activating STING/TBK1 suppresses tumor growth via degrading HPV16/18 E7 oncoproteins in cervical cancer

Cell Death & Differentiation volume 31, pages 78–89 (2024)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Activation of STING reduces HPV16/18 E7 oncoproteins in cells.
Fig. 2: Activation of STING promotes the ubiquitination and degradation of HPV16/18 E7 oncoproteins by E3 ligase HUWE1.
Fig. 3: TBK1-mediated phosphorylation of HPV16/18 E7 oncoproteins promotes their ubiquitination and degradation upon STING activation.
Fig. 4: Activated STING inhibits cell proliferation of cervical cancer cells by degrading E7 oncoproteins in a TBK1-dependent manner.
Fig. 5: STING agonist enhances the inhibitory effects of radiation on HPV16 E7 oncoprotein, cell proliferation and clone formation in Caski cells.
Fig. 6: STING activation inhibits tumor growth of HPV-infected cervical cancer via degrading E7 oncoproteins.
Fig. 7: The proposed model for the crosstalk between STING/TBK1 and HPV E7 oncoproteins in HPV-positive cervical cancer.

Similar content being viewed by others

Data availability

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).

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71:209–49.

    Article  PubMed  Google Scholar 

  2. zur Hausen H. Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer. 2002;2:342–50.

    Article  CAS  PubMed  Google Scholar 

  3. Vonsky M, Shabaeva M, Runov A, Lebedeva N, Chowdhury S, Palefsky JM, et al. Carcinogenesis associated with human papillomavirus infection. mechanisms and potential for immunotherapy. Biochemistry (Mosc). 2019;84:782–99.

    Article  CAS  PubMed  Google Scholar 

  4. Moody CA, Laimins LA. Human papillomavirus oncoproteins: pathways to transformation. Nat Rev Cancer. 2010;10:550–60.

    Article  CAS  PubMed  Google Scholar 

  5. Gupta S, Kumar P, Das BC. HPV: molecular pathways and targets. Curr Probl Cancer. 2018;42:161–74.

    Article  PubMed  Google Scholar 

  6. Münger K, Basile JR, Duensing S, Eichten A, Gonzalez SL, Grace M, et al. Biological activities and molecular targets of the human papillomavirus E7 oncoprotein. Oncogene. 2001;20:7888–98.

    Article  PubMed  Google Scholar 

  7. Lo Cigno I, Calati F, Albertini S, Gariglio M. Subversion of host innate immunity by human papillomavirus oncoproteins. Pathogens. 2020;9:292.

  8. Bhattacharjee R, Das SS, Biswal SS, Nath A, Das D, Basu A, et al. Mechanistic role of HPV-associated early proteins in cervical cancer: Molecular pathways and targeted therapeutic strategies. Crit Rev Oncol Hematol. 2022;174:103675.

    Article  PubMed  Google Scholar 

  9. Nagarsheth NB, Norberg SM, Sinkoe AL, Adhikary S, Meyer TJ, Lack JB, et al. TCR-engineered T cells targeting E7 for patients with metastatic HPV-associated epithelial cancers. Nat Med. 2021;27:419–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zhen S, Lu J, Liu YH, Chen W, Li X. Synergistic antitumor effect on cervical cancer by rational combination of PD1 blockade and CRISPR-Cas9-mediated HPV knockout. Cancer Gene Ther. 2020;27:168–78.

    Article  CAS  PubMed  Google Scholar 

  11. Aarthy M, Kumar D, Giri R, Singh SK. E7 oncoprotein of human papillomavirus: Structural dynamics and inhibitor screening study. Gene. 2018;658:159–77.

    Article  CAS  PubMed  Google Scholar 

  12. Borysiewicz LK, Fiander A, Nimako M, Man S, Wilkinson GWG, Westmoreland D, et al. A recombinant vaccinia virus encoding human papillomavirus types 16 and 18, E6 and E7 proteins as immunotherapy for cervical cancer. Lancet. 1996;347:1523–7.

    Article  CAS  PubMed  Google Scholar 

  13. Hu Z, Ding W, Zhu D, Yu L, Jiang X, Wang X, et al. TALEN-mediated targeting of HPV oncogenes ameliorates HPV-related cervical malignancy. J Clin Invest. 2015;125:425–36.

    Article  PubMed  Google Scholar 

  14. Ritchie C, Carozza JA, Li L. Biochemistry, cell biology, and pathophysiology of the innate immune cGAS-cGAMP-STING pathway. Annu Rev Biochem. 2022;91:599–628.

    Article  CAS  PubMed  Google Scholar 

  15. Ishikawa H, Barber GN. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature. 2008;455:674–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ma Z, Damania B. The cGAS-STING defense pathway and its counteraction by viruses. Cell Host Microbe. 2016;19:150–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Cheng Z, Dai T, He X, Zhang Z, Xie F, Wang S, et al. The interactions between cGAS-STING pathway and pathogens. Signal Transduct Target Ther. 2020;5:91.

  18. Ishikawa H, Ma Z, Barber GN. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature. 2009;461:788–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Garland KM, Sheehy TL, Wilson JT. Chemical and biomolecular strategies for STING pathway activation in cancer immunotherapy. Chemical Reviews. 2022;122:5977–6039.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yum S, Li M, Chen ZJ. Old dogs, new trick: classic cancer therapies activate cGAS. Cell Res. 2020;30:639–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Poltorak A, Kurmyshkina O, Volkova T. Stimulator of interferon genes (STING): A “new chapter” in virus-associated cancer research. Lessons from wild-derived mouse models of innate immunity. Cytokine Growth Factor Rev. 2016;29:83–91.

    Article  CAS  PubMed  Google Scholar 

  22. Ramanjulu JM, Pesiridis GS, Yang J, Concha N, Singhaus R, Zhang S, et al. Design of amidobenzimidazole STING receptor agonists with systemic activity. Nature. 2018;564:439–43.

    Article  CAS  PubMed  Google Scholar 

  23. Pan B-S, Perera SA, Piesvaux JA, Presland JP, Schroeder GK, Cumming JN, et al. An orally available non-nucleotide STING agonist with antitumor activity. Science. 2020;369:eaba6098.

  24. Chin EN, Yu C, Vartabedian VF, Jia Y, Kumar M, Gamo AM, et al. Antitumor activity of a systemic STING-activating non-nucleotide cGAMP mimetic. Science. 2020;369:993–9.

    Article  CAS  PubMed  Google Scholar 

  25. McIntosh JA, Liu Z, Andresen BM, Marzijarani NS, Moore JC, Marshall NM, et al. A kinase-cGAS cascade to synthesize a therapeutic STING activator. Nature. 2022;603:439–44.

    Article  CAS  PubMed  Google Scholar 

  26. Lau L, Gray EE, Brunette RL, Stetson DB. DNA tumor virus oncogenes antagonize the cGAS-STING DNA-sensing pathway. Science. 2015;350:568–71.

    Article  CAS  PubMed  Google Scholar 

  27. Lou M, Huang D, Zhou Z, Shi X, Wu M, Rui Y, et al. DNA virus oncoprotein HPV18 E7 selectively antagonizes cGAS‐STING‐triggered innate immune activation. J Med Virol. 2022;95:e28310.

  28. Luo X, Donnelly CR, Gong W, Heath BR, Hao Y, Donnelly LA, et al. HPV16 drives cancer immune escape via NLRX1-mediated degradation of STING. J Clin Invest. 2020;130:1635–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ranoa DRE, Widau RC, Mallon S, Parekh AD, Nicolae CM, Huang X, et al. STING promotes homeostasis via regulation of cell proliferation and chromosomal stability. Cancer Res. 2019;79:1465–79.

    Article  CAS  PubMed  Google Scholar 

  30. Liu S, Guan W. STING signaling promotes apoptosis, necrosis, and cell death: an overview and update. Mediat Inflamm. 2018;2018:1202797.

    Article  Google Scholar 

  31. Gao Y, Zheng X, Chang B, Lin Y, Huang X, Wang W, et al. Intercellular transfer of activated STING triggered by RAB22A-mediated non-canonical autophagy promotes antitumor immunity. Cell Res. 2022;32:1086–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Yi J, Lu G, Li L, Wang X, Cao L, Lin M, et al. DNA damage-induced activation of CUL4B targets HUWE1 for proteasomal degradation. Nucleic Acids Res. 2015;43:4579–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Harding SM, Benci JL, Irianto J, Discher DE, Minn AJ, Greenberg RA, et al. Greenberg RA. Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature. 2017;548:466–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Deng L, Liang H, Xu M, Yang X, Burnette B, Arina A, et al. STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity. 2014;41:843–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Liu Y, Jesus AA, Marrero B, Yang D, Ramsey SE, Sanchez GAM, et al. Activated STING in a vascular and pulmonary syndrome. N Engl J Med. 2014;371:507–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Melki I, Rose Y, Uggenti C, Van Eyck L, Fremond ML, Kitabayashi N, et al. Disease-associated mutations identify a novel region in human STING necessary for the control of type I interferon signaling. J Allergy Clin Immunol. 2017;140:543–52. e5

    Article  CAS  PubMed  Google Scholar 

  37. Zhang C, Shang G, Gui X, Zhang X, Bai XC, Chen ZJ. Structural basis of STING binding with and phosphorylation by TBK1. Nature. 2019;567:394–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Massimi P, Banks L. Differential phosphorylation of the HPV-16 E7 oncoprotein during the cell cycle. Virology. 2000;276:388–94.

    Article  CAS  PubMed  Google Scholar 

  39. Tu D, Zhu Z, Zhou AY, Yun CH, Lee KE, Toms AV, et al. Structure and ubiquitination-dependent activation of TANK-binding kinase 1. Cell Rep. 2013;3:747–58.

    Article  CAS  PubMed  Google Scholar 

  40. Shi F, Su J, Wang J, Liu Z, Wang T. Activation of STING inhibits cervical cancer tumor growth through enhancing the anti-tumor immune response. Mol Cell Biochem. 2021;476:1015–24.

    Article  CAS  PubMed  Google Scholar 

  41. Yang A, Jeang J, Cheng K, Cheng T, Yang B, Wu TC, et al. Current state in the development of candidate therapeutic HPV vaccines. Expert Rev Vaccines. 2016;15:989–1007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Gogoi H, Mansouri S, Jin L. The age of cyclic dinucleotide vaccine adjuvants. Vaccines (Basel). 2020;8:453.

  43. Liu Z, Zhou J, Xu W, Deng W, Wang Y, Wang M, et al. A novel STING agonist-adjuvanted pan-sarbecovirus vaccine elicits potent and durable neutralizing antibody and T cell responses in mice, rabbits and NHPs. Cell Res. 2022;32:269–87.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

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)

Author information

Author notes

  1. These authors contributed equally: Xiaodan Huang, Lanqing Huo, Beibei Xiao, Yi Ouyang.

Authors and Affiliations

  1. State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China

    Xiaodan Huang, Lanqing Huo, Beibei Xiao, Yi Ouyang, Foping Chen, Junyun Li, Xueping Zheng, Denghui Wei, Yuanzhong Wu, Ruhua Zhang, Xinping Cao, Tiebang Kang & Ying Gao

  2. Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China

    Xiaodan Huang, Lanqing Huo, Yi Ouyang, Foping Chen, Junyun Li & Xinping Cao

Authors
  1. Xiaodan Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lanqing Huo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Beibei Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yi Ouyang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Foping Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Junyun Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xueping Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Denghui Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yuanzhong Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ruhua Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Xinping Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Tiebang Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ying Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding authors

Correspondence to Xinping Cao, Tiebang Kang or Ying Gao.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval

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).

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41418-023-01242-w

This article is cited by

Search

Advanced search

Quick links