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Cervical cancer is addicted to SIRT1 disarming the AIM2 antiviral defense

Daeho So1,2,3, Hyun-Woo Shin1,2,3, Jiyoung Kim1,2,3

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

Oncogene
|May 31, 2018
PubMed

Insights

Sirtuin 1 (SIRT1) enables human papillomavirus (HPV)-infected cervical cancer cells to evade antiviral immunity by suppressing the AIM2 inflammasome. Inhibiting SIRT1 triggers pyroptosis and halts tumor growth, suggesting SIRT1 as a therapeutic target.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • Mammalian cells possess innate antiviral immunity, a defense system that human papillomavirus (HPV)-infected cervical cancer cells must overcome to proliferate.
  • The mechanisms by which cervical cancer cells evade host antiviral immunity are not fully elucidated.
  • Sirtuin 1 (SIRT1) is observed to be overexpressed in HPV-infected cervical cancer cells, prompting investigation into its role in immune evasion.

Purpose of the Study:

  • To investigate the role of Sirtuin 1 (SIRT1) in the immune evasion strategies of human papillomavirus (HPV)-infected cervical cancer cells.
  • To determine if SIRT1 counteracts antiviral innate immunity in cervical cancer.
  • To explore the therapeutic potential of targeting SIRT1 in cervical cancer treatment.

Main Methods:

  • SIRT1 knockdown and restoration experiments in cervical cancer cells.
  • Analysis of pyroptosis markers, inflammasome components (AIM2), and downstream signaling pathways.
  • Investigation of SIRT1's mechanism involving NF-κB, RELB mRNA destabilization, and extracellular vesicle-mediated signaling.
  • Assessment of SIRT1-targeting siRNAs and extracellular vesicles in cervical cancer xenograft models.
  • Immunohistochemical analysis of SIRT1 expression in clinical cervical cancer samples.

Main Results:

  • SIRT1 knockdown induced massive cell death in cervical cancer cells, characterized by pyroptosis and upregulation of AIM2 inflammasome components.
  • SIRT1 was found to repress NF-κB-driven AIM2 transcription by destabilizing RELB mRNA.
  • Extracellular vesicles carrying AIM2 inflammasome proteins mediated the transmission of pyroptotic death signals to neighboring cancer cells.
  • SIRT1 inhibition, via siRNAs or extracellular vesicles, significantly suppressed cervical cancer xenograft growth.
  • Elevated SIRT1 expression correlated with poorer clinical outcomes in cervical cancer patients.

Conclusions:

  • SIRT1 facilitates the survival and growth of HPV-infected cervical cancer cells by suppressing AIM2 inflammasome-mediated antiviral immunity.
  • The absence of SIRT1 leads to the derepression of the AIM2 inflammasome, resulting in cancer cell death.
  • SIRT1 represents a promising therapeutic target for the effective treatment of cervical cancer.

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