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  • Introduction Activation of epidermal growth factor receptor

    2019-07-19

    Introduction Activation of epidermal growth factor receptor (EGFR)-receptor tyrosine kinases (RTKs) is a key factor in the progression of non-small cell lung cancer (NSCLC). EGFR-RTKs cause proliferation, invasion, metastasis, and angiogenesis, as well as suppress apoptosis, in lung adenocarcinoma (ADC). Mutations in EGFR are detected in about 10%–17% of human ADCs in the United States and Europe and in about 30%–65% of lung cancers in Asia [1,2]. Pharmacologic inhibitors of EGFR-TK, including gefitinib and erlotinib, have notable therapeutic effects in patients with NSCLCs [3,4]. Strategies targeting EGFR-TKIs have been the first therapeutic choice for patients with advanced lung ADC with EGFR mutations. Unfortunately, drug resistance is inevitable in almost all of these patients after a median treatment period of 10–16 months [5]. Furthermore, patients with EGFR gene T790M-mutations are resistant to erlotinib and gefitinib. Although another second-generation EGFR-TKI, afatinib, can circumvent drug resistance to some degree, it has a very narrow therapeutic window due to intolerability. More recently, the third generation anti-EGFR agent osimertinib has been approved to treat NSCLC with the EGFR T790M mutation. However, acquired resistance to osimertinib has already been reported [6]. Therefore, developing new therapeutic strategies to overcome resistance to conventional EGFR inhibitors is urgently required. Deubiquitinating enzymes (DUBs) deconjugate ubiquitin from substrates and negatively regulate ubiquitination. As a newly discovered member of DUBs and a key subunit of the human Spt-Ada-Gcn5-acetyltransferase (hSAGA) transcriptional coactivator complex, ubiquitin-specific protease 22 (USP22) interacts with the hSAGA complex to hydrolyze ubiquitins conjugated to histones H2A and H2B, thus activating target gene transcription by altering histone ubiquitination levels [7]. Increasing evidence suggests that USP22 has clinicopathological significance in oncology. Identified in many kinds of tumors, USP22 plays a key role in cell cycle regulation, embryo development, and telomere homeostasis [[7], [8], [9]]. For example, knockdown of USP22 in Caspase-3, human recombinant proteinase cancer cells led to cell cycle arrest in the G0/G1 phase and resulted in decreased tumor growth in vivo [7,10,11]. Moreover, USP22 was shown to be required for the transcriptional activity of c-MYC, a key player driving tumor growth [7]. Recently, three mammalian DUBs, AMSH, UBPY and USP2a, have been implicated in the endocytic down-regulation of EGFR-RTKs [[12], [13], [14], [15]]. These studies suggested that resistance to EGFR-TKIs is closely related to endocytosis-mediated EGFR activation via ubiquitination. Our previous studies revealed that USP22 promotes tumor progression and induces epithelial-mesenchymal transition (EMT) in lung ADC [16]. Considering the critical roles of USP22 in the pathogenesis of lung ADCs, we sought to understand if USP22 had a non-redundant and independent role in endocytosis-mediated regulation of EGFR-RTKs.
    Materials and methods
    Results
    Discussion Aberrant USP22 expression can promote tumor progression and induce EMT in lung ADC [16,19]. Our previous study also suggests that USP22 expression is significantly increased in NSCLC tissues. However, the underlying mechanisms and the potential regulatory roles of USP22 in the pathogenesis of lung ADC and sensitization of EGFR-mutant targeted drugs have not been fully elucidated. Our current study demonstrates that USP22 promotes EGFR-TKIs resistance by preventing EGFR degradation in EGFR-mutant lung ADC. Our functional characterization of USP22 is critical for understanding the biological significance in lung ADC tumorigenesis and may reveal novel therapeutic targets to advance the development of more effective clinical treatment strategies. To uncover the mechanisms underlying USP22-mediated transformation in lung cancer, we performed microarray analysis using publicly available datasets of human lung ADC patients. We identified 2171 differentially expressed genes in our profiling analysis. Subsequent functional pathway analysis based on the gene signature indicated that multiple pathways involved in cancer progression are affected in lung ADCs (Fig. 1), which we further validated. For example, USP22 positively correlated with cell proliferation and cell invasion in H1975 and PC9 cells in vitro (Figs. 2 and 3). Previous studies showed that USP22 modulates the multidrug resistance of hepatocellular carcinoma [26,27]. Here, we substantiated this finding by showing that higher USP22 expression facilitated resistance to EGFR-TKIs in vitro and in vivo in erlotinib-resistant H1975 cells that harbor a T790M mutation in EGFR (Figs. 3C and 7). Our study and other reports underscore the profound impact of USP22 in impacting on numerous downstream pathways. However, we did not observe morphological changes in cancer cell lines following USP22 knockdown in culture.