CYLD Alterations in the Tumorigenesis and Progression of Human Papillomavirus-Associated Head and Neck Cancers.

Genetic alterations of (), a tumor-suppressor gene encoding a deubiquitinase (DUB) enzyme, are associated with the formation of tumors in CYLD cutaneous syndrome. Genome sequencing efforts have revealed somatic alterations in multiple human cancers. Moreover, in cancers commonly associated with human papillomavirus (HPV) infection (e.g., head and neck squamous cell carcinoma), alterations are preferentially observed in the HPV-positive versus HPV-negative form of the disease. The CYLD enzyme cleaves K63-linked polyubiquitin from substrate proteins, resulting in the disassembly of key protein complexes and the inactivation of growth-promoting signaling pathways, including pathways mediated by NF-κB, Wnt/β-catenin, and c-Jun N-terminal kinases. Loss-of-function alterations lead to aberrant activation of these signaling pathways, promoting tumorigenesis and malignant transformation. This review summarizes the association and potential role of somatic mutations in HPV-positive cancers, with particular emphasis on the role of these alterations in tumorigenesis, invasion, and metastasis. Potential therapeutic strategies for patients whose tumors harbor alterations are also discussed. IMPLICATIONS: Alterations in gene are associated with HPV-associated cancers, contribute to NF-κB activation, and are implicated in invasion and metastasis.