CYLD and melanoma: The cylindromatosis (CYLD), a well-known tumor suppressor, can interact directly with AKT and deubiquitinate its K63-linked ubiquitination in response to the stimulation of growth factors, which results in K48 linkage polyubiquitination via BRCA1 or TTC3 (Fig. 2b).181 The loss of CYLD accelerates tumorigenesis and triggers cisplatin resistance in melanoma and oral squamous cell carcinoma.182,183 Thus, CYLD is considered a molecular switch for the ubiquitination of AKT and determines the localization and activation of AKT during cancer progression.