title: Silencing of ASC in Cutaneous Squamous Cell Carcinoma.
abstract: Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is an important adaptor protein for inflammasome activation, mediating the secretion of protumorigenic innate cytokines. However, ASC is also known to trigger apoptosis in tumor cells, acting as a tumor-suppressor gene, which is lost in several human cancers. The aim of this study was to evaluate the clinical significance of ASC in human cutaneous squamous cell carcinoma (SCC). Initially, ASC expression was immunohistochemically evaluated in non-metastic and metastatic SCC. While ASC expression does not correlate with metastatic potential, it correlates with the degree of dedifferentiation. Using methylation specific PCR we were able to demonstrate ASC silencing by promotor specific methylation and impaired inflammasome function in methylated cell lines, linking epigenetic modifications to innate immune activation in keratinocytes. Interestingly, upon ASC restoration by treatment with demethylating agents, we were able to restore AIM2 and NLRP3 activation. In summary, loss of ASC driven tumor development is counterbalanced in the identical cell by the inhibition of pro-tumorigenic inflammation in the tumor cell itself.
authors: Department of Dermatology, University of Tuebingen, Tuebingen, Germany.
authors: Katharina
authors: K
authors: Meier
authors: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.|Biozentrum, University of Basel, Basel, Switzerland.
authors: Stefan K
authors: SK
authors: Drexler
authors: Department of Dermatology, University of Tuebingen, Tuebingen, Germany.
authors: Franziska C
authors: FC
authors: Eberle
authors: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
authors: Karine
authors: K
authors: Lefort
authors: Department of Dermatology, University of Tuebingen, Tuebingen, Germany.
authors: Amir S
authors: AS
authors: Yazdi
mesh_terms: D000368:Aged; D053468:CARD Signaling Adaptor Proteins; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D020868:Gene Silencing; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D008297:Male; D009362:Neoplasm Metastasis; D011401:Promoter Regions, Genetic; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D053468:CARD Signaling Adaptor Proteins; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; C402202:PYCARD protein, human