Blockade of deubiquitinating enzyme PSMD14 overcomes chemoresistance in head and neck squamous cell carcinoma by antagonizing E2F1/Akt/SOX2-mediated stemness.

Increasing evidence reveals a close relationship between deubiquitinating enzymes (DUBs) and cancer progression. In this study, we attempted to identify the roles and mechanisms of critical DUBs in head and neck squamous cell carcinoma (HNSCC). Methods: Bioinformatics analysis was performed to screen differentially expressed novel DUBs in HNSCC. Immunohistochemistry assay was used to measure the expression of DUB PSMD14 in HNSCC specimens and adjacent normal tissues. The level of PSMD14 in HNSCC tumorigenesis was investigated using a 4-NQO-induced murine HNSCC model. The function of PSMD14 was determined through loss-of-function assays. Chromatin immunoprecipitation, immunoprecipitation and in vivo ubiquitination assay were conducted to explore the potential mechanism of PSMD14. The anti-tumor activity of PSMD14 inhibitor Thiolutin was assessed by in vitro and in vivo experiments. Results: We identified PSMD14 as one of significantly upregulated DUBs in HNSCC tissues. Aberrant expression of PSMD14 was associated with tumorigenesis and malignant progression of HNSCC and further indicated poor prognosis. The results of in vitro and in vivo experiments demonstrated PSMD14 depletion significantly undermined HNSCC growth, chemoresistance and stemness. Mechanically, PSMD14 inhibited the ubiquitination and degradation of E2F1 to improve the activation of Akt pathway and the transcription of SOX2. Furthermore, PSMD14 inhibitor Thiolutin exhibited a potent anti-tumor effect on HNSCC in vivo and in vitro by impairing DUB activity of PSMD14. Conclusion: Our findings demonstrate the role and mechanism of PSMD14 in HNSCC, and provide a novel and promising target for diagnosis and clinical therapy of HNSCC.

越来越多的证据表明去泛素化酶（DUBs）与癌症进展之间存在密切关系。在本研究中，我们试图确定关键的去泛素化酶在头颈部鳞状细胞癌（HNSCC）中的作用和机制。 方法：进行生物信息学分析以筛选HNSCC中差异表达的新型去泛素化酶。采用免疫组织化学法检测去泛素化酶PSMD14在HNSCC标本及相邻正常组织中的表达。利用4 - 硝基喹啉 - 1 - 氧化物（4 - NQO）诱导的小鼠HNSCC模型研究PSMD14在HNSCC肿瘤发生中的水平。通过功能缺失实验确定PSMD14的功能。进行染色质免疫沉淀、免疫沉淀和体内泛素化实验以探索PSMD14的潜在机制。通过体内和体外实验评估PSMD14抑制剂硫藤黄菌素的抗肿瘤活性。 结果：我们确定PSMD14是HNSCC组织中显著上调的去泛素化酶之一。PSMD14的异常表达与HNSCC的肿瘤发生和恶性进展相关，并进一步预示不良预后。体内和体外实验结果表明，PSMD14的缺失显著抑制了HNSCC的生长、化疗耐药性和干性。从机制上讲，PSMD14抑制E2F1的泛素化和降解，从而提高Akt通路的激活以及SOX2的转录。此外，PSMD14抑制剂硫藤黄菌素通过削弱PSMD14的去泛素化酶活性，在体内和体外对HNSCC表现出强大的抗肿瘤作用。 结论：我们的研究结果阐明了PSMD14在HNSCC中的作用和机制，为HNSCC的诊断和临床治疗提供了一个新颖且有前景的靶点。