title: Cancer-associated missense mutations of caspase-8 activate nuclear factor-κB signaling.
abstract: Head and neck squamous cell carcinoma (HNSCC) is an aggressive cancer with a 5-year survival rate of ~50%. With the use of a custom cDNA-capture system coupled with massively parallel sequencing, we have now investigated transforming mechanisms for this malignancy. The cDNAs of cancer-related genes (n = 906) were purified from a human HNSCC cell line (T3M-1 Cl-10) and subjected to high-throughput resequencing, and the clinical relevance of non-synonymous mutations thus identified was evaluated with luciferase-based reporter assays. A CASP8 (procaspase-8) cDNA with a novel G-to-C point mutation that results in the substitution of alanine for glycine at codon 325 was identified, and the mutant protein, CASP8 (G325A), was found to activate nuclear factor-κB (NF-κB) signaling to an extent far greater than that achieved with the wild-type protein. Moreover, forced expression of wild-type CASP8 suppressed the growth of T3M-1 Cl-10 cells without notable effects on apoptosis. We further found that most CASP8 mutations previously detected in various epithelial tumors also increase the ability of the protein to activate NF-κB signaling. Such NF-κB activation was shown to be mediated through the COOH-terminal region of the second death effector domain of CASP8. Although CASP8 mutations associated with cancer have been thought to promote tumorigenesis as a result of attenuation of the proapoptotic function of the protein, our results now show that most such mutations, including the novel G325A identified here, separately confer a gain of function with regard to activation of NF-κB signaling, indicating another role of CASP8 in the transformation of human malignancies including HNSCC.
authors: Department of Medical Genomics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors: Mizuo
authors: M
authors: Ando
authors: Masahito
authors: M
authors: Kawazu
authors: Toshihide
authors: T
authors: Ueno
authors: Kazutaka
authors: K
authors: Fukumura
authors: Azusa
authors: A
authors: Yamato
authors: Manabu
authors: M
authors: Soda
authors: Yoshihiro
authors: Y
authors: Yamashita
authors: Young L
authors: YL
authors: Choi
authors: Tatsuya
authors: T
authors: Yamasoba
authors: Hiroyuki
authors: H
authors: Mano
mesh_terms: D017209:Apoptosis / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053181:Caspase 8 / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006258:Head and Neck Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020125:Mutation, Missense; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D016328:NF-kappa B; C505530:CASP8 protein, human; D053181:Caspase 8
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