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Silencing of ASC in Cutaneous Squamous Cell Carcinoma

Katharina Meier1, Stefan K Drexler2,3, Franziska C Eberle1

  • 1Department of Dermatology, University of Tuebingen, Tuebingen, Germany.

Plos One
|October 22, 2016
PubMed

Insights

Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) acts as a tumor suppressor in skin cancer. Epigenetic silencing of ASC impairs immune activation, but its restoration reactivates inflammasomes.

Area of Science:

  • Immunology
  • Oncology
  • Epigenetics

Background:

  • Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is crucial for inflammasome activation and cytokine secretion.
  • ASC also functions as a tumor suppressor by inducing apoptosis, a function lost in many cancers.
  • The role of ASC in cutaneous squamous cell carcinoma (SCC) requires further investigation.

Purpose of the Study:

  • To investigate the clinical significance of ASC in human cutaneous squamous cell carcinoma (SCC).
  • To explore the relationship between ASC expression, tumor dedifferentiation, and metastatic potential in SCC.
  • To elucidate the epigenetic mechanisms, specifically promoter methylation, that regulate ASC expression and inflammasome function in SCC.

Main Methods:

  • Immunohistochemistry was used to evaluate ASC expression in non-metastatic and metastatic SCC.
  • Methylation-specific PCR was employed to detect ASC promoter methylation.
  • Demethylating agents were used to restore ASC expression and assess inflammasome activation (AIM2, NLRP3) in methylated cell lines.

Main Results:

  • ASC expression in SCC correlated with the degree of dedifferentiation but not with metastatic potential.
  • ASC silencing via promoter-specific methylation was observed, leading to impaired inflammasome function.
  • Restoration of ASC expression using demethylating agents reactivated AIM2 and NLRP3 inflammasome activation.

Conclusions:

  • ASC plays a dual role in SCC, acting as a tumor suppressor while its loss is linked to pro-tumorigenic inflammation.
  • Epigenetic silencing of ASC by promoter methylation is a key mechanism contributing to its loss in SCC.
  • Restoring ASC expression can reactivate innate immune pathways, offering potential therapeutic avenues for SCC.

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