Cervical cancer is addicted to SIRT1 disarming the AIM2 antiviral defense

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.

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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

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Correspondence to Jong-Wan Park.

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So, D., Shin, H., 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

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