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:

Cervical cancer is addicted to SIRT1 disarming the AIM2 antiviral defense

Oncogene volume 37, pages 5191–5204 (2018)Cite this article

Subjects

Abstract

Mammalian cells are equipped with antiviral innate immunity. To survive and grow, human papilloma virus (HPV)-infected cervical cancer cells must overcome this host defense system. However, the precise mechanism whereby cervical cancer cells evade the immunity is not fully understood. We noted that Sirtuin 1 (SIRT1) is overexpressed in HPV-infected cervical cancer cells and hypothesized that SIRT1 counteracts antiviral immunity. Here, we found that cervical cancer cells undergo massive death by SIRT1 knockdown, but this effect is reversed by SIRT1 restoration. SIRT1-knocked-down cells showed representative features of pyroptosis, as well as highly expressed absent in melanoma 2 (AIM2) and its downstream genes related to the inflammasome response. Mechanistically, SIRT1 repressed the NF-κB-driven transcription of the AIM2 gene by destabilizing the RELB mRNA. Interestingly, pyroptotic death signaling in SIRT1-knocked-down cells was transmitted to naïve cervical cancer cells, which was mediated by extracellular vesicles carrying AIM2 inflammasome proteins. Furthermore, the growth of cervical cancer xenografts was significantly inhibited by either SIRT1-targeting siRNAs or SIRT1-knockdown-derived extracellular vesicles. Immunohistochemical analyses showed that SIRT1 expression correlated with poor clinical outcomes in cervical cancer. In conclusion, SIRT1 enabled HPV-infected cervical cancer cells to continue growing by nullifying AIM2 inflammasome-mediated immunity. Without SIRT1, cervical cancer cells could no longer survive because of the derepression of the AIM2 inflammasome. SIRT1 could therefore be a target for the effective treatment of 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
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Small W Jr, Bacon MA, Bajaj A, Chuang LT, Fisher BJ, Harkenrider MM, et al. Cervical cancer: a global health crisis. Cancer. 2017;123:2404–12.

    Article  PubMed  Google Scholar 

  2. Crosbie EJ, Einstein MH, Franceschi S, Kitchener HC. Human papillomavirus and cervical cancer. Lancet. 2013;382:889–99.

    Article  PubMed  Google Scholar 

  3. Woodman CB, Collins SI, Young LS. The natural history of cervical HPV infection: unresolved issues. Nat Rev Cancer. 2007;7:11–22.

    Article  CAS  PubMed  Google Scholar 

  4. Rathinam VA, Fitzgerald KA. Innate immune sensing of DNA viruses. Virology. 2011;411:153–62.

    Article  CAS  PubMed  Google Scholar 

  5. Scheffner M, Huibregtse JM, Vierstra RD, Howley PM. The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell. 1993;75:495–505.

    Article  CAS  PubMed  Google Scholar 

  6. Boyer SN, Wazer DE, Band V. E7 protein of human papilloma virus-16 induces degradation of retinoblastoma protein through the ubiquitin-proteasome pathway. Cancer Res. 1996;56:4620–4.

    CAS  PubMed  Google Scholar 

  7. Frye RA. Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity. Biochem Biophys Res Commun. 1999;260:273–9.

    Article  CAS  PubMed  Google Scholar 

  8. Imai S, Armstrong CM, Kaeberlein M, Guarente L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature. 2000;403:795–800.

    Article  CAS  PubMed  Google Scholar 

  9. Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science. 2004;303:2011–5.

    Article  CAS  PubMed  Google Scholar 

  10. Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature. 2005;434:113–8.

    Article  CAS  PubMed  Google Scholar 

  11. Gillum MP, Kotas ME, Erion DM, Kursawe R, Chatterjee P, Nead KT, et al. SirT1 regulates adipose tissue inflammation. Diabetes. 2011;60:3235–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wang C, Chen L, Hou X, Li Z, Kabra N, Ma Y, et al. Interactions between E2F1 and SirT1 regulate apoptotic response to DNA damage. Nat Cell Biol. 2006;8:1025–31.

    Article  CAS  PubMed  Google Scholar 

  13. Yeung F, Hoberg JE, Ramsey CS, Keller MD, Jones DR, Frye RA, et al. Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J. 2004;23:2369–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Velez-Perez A, Wang XI, Li M, Zhang S. SIRT1 overexpression in cervical squamous intraepithelial lesions and invasive squamous cell carcinoma. Hum Pathol. 2017;59:102–7.

    Article  CAS  PubMed  Google Scholar 

  15. Wang J, YujingWang, Liu C, Yu H. The effects of siRNA SIRT1 on the proliferation of human cervical cancer cells. Int J Sci. 2016;5:133–6.

    Google Scholar 

  16. Singh S, Kumar PU, Thakur S, Kiran S, Sen B, Sharma S, et al. Expression/localization patterns of sirtuins (SIRT1, SIRT2, and SIRT7) during progression of cervical cancer and effects of sirtuin inhibitors on growth of cervical cancer cells. Tumour Biol. 2015;36:6159–71.

    Article  CAS  PubMed  Google Scholar 

  17. Zimmerman EM, Vaituzis Z, Hetrick FM. Mitochondrial damage and inhibition of respiration in animal cell cultures treated with Triton WR-1339. J Cell Physiol. 1969;74:67–76.

    Article  CAS  PubMed  Google Scholar 

  18. Balaban RS, Nemoto S, Finkel T. Mitochondria, oxidants, and aging. Cell. 2005;120:483–95.

    Article  CAS  PubMed  Google Scholar 

  19. In HY, Cao L, Mostoslavsky R, Lombard DB, Liu J, Bruns NE, et al. A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc Natl Acad Sci USA. 2007;105:3374–9.

    Google Scholar 

  20. Bergsbaken T, Fink SL, Cookson BT. Pyroptosis: host cell death and inflammation. Nat Rev Microbiol. 2009;7:99–109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Fink SL, Bergsbaken T, Cookson BT. Anthrax lethal toxin and Salmonella elicit the common cell death pathway of caspase-1-dependent pyroptosis via distinct mechanisms. Proc Natl Acad Sci USA. 2008;105:4312–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yu J, Nagasu H, Murakami T, Hoang H, Broderick L, Hoffman HM, et al. Inflammasome activation leads to Caspase-1-dependent mitochondrial damage and block of mitophagy. Proc Natl Acad Sci USA. 2014;111:15514–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Fink SL, Cookson BT. Caspase-1-dependent pore formation during pyroptosis leads to osmotic lysis of infected host macrophages. Cell Microbiol. 2006;8:1812–25.

    Article  CAS  PubMed  Google Scholar 

  24. Bergsbaken T, Fink SL, den Hartigh AB, Loomis WP, Cookson BT. Coordinated host responses during pyroptosis: caspase-1-dependent lysosome exocytosis and inflammatory cytokine maturation. J Immunol. 2011;187:2748–54.

    Article  CAS  PubMed  Google Scholar 

  25. Miao EA, Rajan JV, Aderem A. Caspase-1-induced pyroptotic cell death. Immunol Rev. 2011;243:206–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Allison SJ, Jiang M, Milner J. Oncogenic viral protein HPV E7 up-regulates the SIRT1 longevity protein in human cervical cancer cells. Aging. 2009;1:316–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhang D, Li S, Cruz P, Kone BC. Sirtuin 1 functionally and physically interacts with disruptor of telomeric silencing-1 to regulate alpha-ENaC transcription in collecting duct. J Biol Chem. 2009;284:20917–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Pfister JA, Ma C, Morrison BE, Dmello SR. Opposing effects of sirtuins on neuronal survival: SIRT1-mediated neuroprotection is independent of its deacetylase activity. PLoS ONE. 2008;3:e4090.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Campagna M, Herranz D, Garcia MA, Marcos-Villar L, Gonzalez-Santamaria J, Gallego P, et al. SIRT1 stabilizes PML promoting its sumoylation. Cell Death Differ. 2011;18:72–79.

    Article  CAS  PubMed  Google Scholar 

  30. Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Horvath G, Caffrey DR, et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature. 2009;458:514–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Rathinam VA, Vanaja SK, Fitzgerald KA. Regulation of inflammasome signaling. Nat Immunol. 2012;13:333–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Man SM, Karki R, Kanneganti TD. AIM2 inflammasome in infection, cancer, and autoimmunity: role in DNA sensing, inflammation, and innate immunity. Eur J Immunol. 2016;46:269–80.

    Article  CAS  PubMed  Google Scholar 

  33. Wilson JE, Petrucelli AS, Chen L, Koblansky AA, Truax AD, Oyama Y, et al. Inflammasome-independent role of AIM2 in suppressing colon tumorigenesis via DNA-PK and Akt. Nat Med. 2015;21:906–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ma X, Guo P, Qiu Y, Mu K, Zhu L, Zhao W, et al. Loss of AIM2 expression promotes hepatocarcinoma progression through activation of mTOR-S6K1 pathway. Oncotarget. 2016;7:36185–97.

    PubMed  PubMed Central  Google Scholar 

  35. Chen IF, Ou-Yang F, Hung JY, Liu JC, Wang H, Wang SC, et al. AIM2 suppresses human breast cancer cell proliferation in vitro and mammary tumor growth in a mouse model. Mol Cancer Ther. 2006;5:1–7.

    Article  CAS  PubMed  Google Scholar 

  36. Reinholz M, Kawakami Y, Salzer S, Kreuter A, Dombrowski Y, Koglin S, et al. HPV16 activates the AIM2 inflammasome in keratinocytes. Arch Dermatol Res. 2013;305:723–32.

    Article  CAS  PubMed  Google Scholar 

  37. Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 2013;200:373–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Tetta C, Ghigo E, Silengo L, Deregibus MC, Camussi G. Extracellular vesicles as an emerging mechanism of cell-to-cell communication. Endocrine. 2013;44:11–19.

    Article  CAS  PubMed  Google Scholar 

  39. Akers JC, Gonda D, Kim R, Carter BS, Chen CC. Biogenesis of extracellular vesicles (EV): exosomes, microvesicles, retrovirus-like vesicles, and apoptotic bodies. J Neurooncol. 2013;113:1–11.

    Article  PubMed  PubMed Central  Google Scholar 

  40. de Rivero Vaccari JP, Brand F, Adamczak S, Lee SW, Perez-Barcena J, Wang MY, et al. Exosome-mediated inflammasome signaling after central nervous system injury. J Neurochem. 2016;136(Suppl 1):39–48.

    Article  CAS  PubMed  Google Scholar 

  41. Waggoner SE. Cervical cancer. Lancet. 2003;361:2217–25.

    Article  PubMed  Google Scholar 

  42. Koh WJ, Greer BE, Abu-Rustum NR, Apte SM, Campos SM, Chan J, et al. Cervical cancer. J Natl Compr Canc Netw. 2013;11:320–43.

    Article  CAS  PubMed  Google Scholar 

  43. Gadducci A, Tana R, Cosio S, Cionini L. Treatment options in recurrent cervical cancer. Oncol Lett. 2010;1:3–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Davidson S. Treatment for advanced cervical cancer: impact on quality of life. Crit Rev Oncol Hematol. 2011;79:24–30.

    Article  PubMed  Google Scholar 

  45. Kamura T, Ushijima K. Chemotherapy for advanced or recurrent cervical cancer. Taiwan J Obstet Gynecol. 2013;52:161–4.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr. Ja Eun Kim (Kyung Hee University) for giving the plasmids for SIRT1 and mutants, and Dr. Woo Ho Kim (Seoul National University) for providing cervical cancer tissue arrays. This work was supported by a grant from the National Research Foundation of Korea (2016R1A2A1A05005082; to JWP).

Authors contributions

Conception and design: HWS, JWP. Development of methodology: DSo, HWS, YSC. Acquisition of data: DSo, JK, JM. Analysis and interpretation of data: DSo, HWS, YSC, JWP. Writing, review, and/or revision of the manuscript: DSo, JWP. Administrative, technical, or material support: HWS, YSC, ML, JWP. Study supervision: JWP

Author information

Authors and Affiliations

  1. Department of Biomedical Science, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea

    Daeho So, Hyun-Woo Shin, Jiyoung Kim, Mingyu Lee, Yang-Sook Chun & Jong-Wan Park

  2. Department of Pharmacology, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea

    Daeho So, Hyun-Woo Shin, Jiyoung Kim, Mingyu Lee & Jong-Wan Park

  3. Cancer Research Institute and Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea

    Daeho So, Hyun-Woo Shin, Jiyoung Kim, Mingyu Lee, Jongyun Myeong, Yang-Sook Chun & Jong-Wan Park

  4. Department of Physiology, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea

    Yang-Sook Chun

Authors
  1. Daeho So
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hyun-Woo Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jiyoung Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mingyu Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jongyun Myeong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yang-Sook Chun
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jong-Wan Park
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jong-Wan Park.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

So, D., Shin, HW., Kim, J. et al. Cervical cancer is addicted to SIRT1 disarming the AIM2 antiviral defense. Oncogene 37, 5191–5204 (2018). https://doi.org/10.1038/s41388-018-0339-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-018-0339-4

This article is cited by

Search

Advanced search

Quick links