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Cervical cancer is addicted to SIRT1 disarming the AIM2 antiviral defense

Oncogenevolume 37pages51915204 (2018) | Download Citation


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.

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  1. 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.

  2. 2.

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

  3. 3.

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

  4. 4.

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

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 18.

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

  19. 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.

  20. 20.

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

  21. 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.

  22. 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.

  23. 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.

  24. 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.

  25. 25.

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

  26. 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.

  27. 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.

  28. 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.

  29. 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.

  30. 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.

  31. 31.

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

  32. 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.

  33. 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.

  34. 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.

  35. 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.

  36. 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.

  37. 37.

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

  38. 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.

  39. 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.

  40. 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.

  41. 41.

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

  42. 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.

  43. 43.

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

  44. 44.

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

  45. 45.

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

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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


  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


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The authors declare that they have no conflict of interest.

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Correspondence to Jong-Wan Park.

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