USP22 promotes neuroblastoma growth, metastasis, and glycolysis via mediating the deubiquitination of PDK1.

Abstract

Deubiquitinating enzymes are important regulators of cancer progression. We explored the role and regulatory mechanisms of the deubiquitinating enzyme ubiquitin-specific protease 22 (USP22) in neuroblastoma (NB). USP22 expression was upregulated in NB patient tissue samples and its expression correlated with their overall survival. Knockdown of USP22 in NB cell lines suppressed cell proliferation, invasion and glycolysis, and enhanced apoptosis. A coimmunoprecipitation assay identified a relationship between USP22 and 3-phosphoinositide-dependent protein kinase 1 (PDK1). USP22 stabilized PDK1 expression via deubiquitination; PDK1 overexpression reversed the effects of USP22 knockdown on the malignant behaviors of NB cells. Dual-luciferase reporter assay and RNA immunoprecipitation were utilized to clarify the relationship between Yin Yang-1 (YY1) and USP22. Yin Yang-1 regulated PDK1 expression via promoting USP22 transcription. USP22 knockdown in a xenograft assay also inhibited tumor growth via regulating PDK1. Taken together, these results indicate that USP22 regulated by YY1 plays a promotional role in NB progression by mediating the deubiquitination of PDK1.