缺氧是鼻咽癌（NPC）的重要特征。与PKRCA相互作用的蛋白1（PICK1）在人类恶性肿瘤中通常被抑制，并且与恶劣预后有关。然而，当前对调节PICK1的上游机制的理解有限。通过免疫组织化学（IHC）、Western blot和定量实时PCR测定，分别分析了PICK1和HIF-1α表达水平。使用蛋白质稳定性和泛素化试验来研究PICK1蛋白质的降解。使用免疫荧光和共免疫沉淀试验来证明RBCK1与PICK1之间的相互作用。通过siRNA转染进行基因沉默来研究HIF-1α和RBCK1在缺氧诱导PICK1降解中的作用。使用Cell Counting Kit-8（CCK-8）、5-Ethynyl-2'-deoxyuridine（EdU）试验和皮下异种移植裸鼠模型来探讨RBCK1和PICK1在NPC细胞增殖中的作用。结果表明，NPC组织中的PICK1表达与HIF-1α呈负相关。HIF-1α通过促进E3连接酶RANBP2型和C3HC4型锌指1(RBCK1)的泛素化引起PICK1表达下降，从而增强蛋白酶体介导的PICK1降解。RBCK1沉默抑制了NPC细胞的增殖，RBCK1/PICK1双重沉默则逆转了这种抑制作用。这些数据提供了NPC细胞适应缺氧的机制证据，其中HIF1-α调节RBCK1，后者靶向PICK1进行降解以促进细胞增殖。版权所有©2023 Elsevier Inc. 发布。

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 HIF1-α regulates RBCK1, which targets PICK1 for degradation to promote cell proliferation.Copyright © 2023. Published by Elsevier Inc.