Hypoxia-induced degradation of PICK1 by RBCK1 promotes the proliferation of nasopharyngeal carcinoma cells

• Published in: Life sciences (1973) 2023-05, Vol.321, p.121594-121594, Article 121594
• Main Authors: Zhang, Yingzi, Lu, Yue, Xu, Yiqing, Le, Ziyu, Liu, Yi, Tu, Wenzhi, Liu, Yong
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Carrier Proteins - genetics; Cell Line, Tumor; Cell Proliferation; HIF-1α; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms - genetics; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; PICK1; RBCK1; Transcription Factors - metabolism; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2023.121594

Hypoxia is an important feature of nasopharyngeal carcinoma (NPC). “Protein interacting with PRKCA 1” (PICK1) is commonly downregulated in human malignancies and is functionally related to poor prognosis. However, there is a limited understanding of the upstream mechanisms regulating PICK1 currently. PICK1 and HIF-1α expression levels were analyzed by Immunohistochemistry (IHC), western blotting, and quantitative real-time PCR assay. Protein stability and ubiquitin assays were used to investigate PICK1 protein degradation. Immunofluorescence and co-immunoprecipitation assays were used to demonstrate the interaction between RBCK1 and PICK1. Gene knockdown by siRNA transfection was used to investigate the role of HIF-1α and RBCK1 in hypoxia-induced PICK1 degradation. Cell Counting Kit-8 (CCK-8), 5-Ethynyl-2′-deoxyuridine (EdU) assays and subcutaneous xenograft nude models were used to explore the roles of RBCK1 and PICK1 in NPC cell proliferation. PICK1 expression in NPC tissue was negatively relative to that of HIF-1α. HIF-1α downregulated PICK1 expression by facilitating its ubiquitination by the E3 ligases RANBP2-type and C3HC4-type zinc finger containing 1 (RBCK1), thereby enhancing proteasome-mediated PICK1 degradation. RBCK1 knockdown inhibited NPC cell proliferation, which was ameliorated by double knockdown of RBCK1/PICK1. These data provide evidence for an NPC cell adaptation mechanism to hypoxia, where HIF-1α regulates RBCK1, which targets PICK1 for degradation to promote cell proliferation. •HIF-1α is negatively correlated with PICK1 expression levels in human NPC.•Hypoxia induces ubiquitination degradation of PICK1 protein.•E3 ubiquitin ligase RBCK1 regulates PICK1 degradation under hypoxia.•RBCK1-mediated PICK1 expression down-regulation contributes to the proliferation of NPC cells.