No abstract

Ubiquitin-specific protease 22 (USP22), a newly discovered member of ubiquitin hydrolase family, exhibits a critical function in cell cycle progression and tumorigenesis. The forkhead box M1 (FoxM1) transcription factor plays a crucial role in cell proliferation, differentiation and transformation. However, the expression and functions of USP22 in pancreatic ductal adenocarcinoma (PDA) and whether FoxM1 is involved in USP22-mediated cell cycle regulation have not been studied. We examined the expression of USP22 and FoxM1 in 136 stage II PDA tissues by immunohistochemistry. Clinical significance was analyzed by multivariate Cox regression analysis, Kaplan-Meier curves and log-rank test. RT-PCR, western blot analysis, luciferase and immunofluorescence assays were used to investigate the molecular function of USP22 and FoxM1 in PDA fresh tissues and cell lines. USP22 and FoxM1 were significantly upregulated in PDA tissues compared with the paired normal carcinoma-adjacent tissues. A statistical correlation was observed between USP22 and FoxM1 expression. The expression of USP/FoxM1 and co-expression of both factors correlated with tumor size, lymph node metastasis and overall survival. Multivariate Cox regression analysis revealed that the expression of USP22/FoxM1, especially the co-expression of both factors, is an independent, unfavorable prognostic factor. USP22 overexpression is accompanied by an increase in FoxM1 expression and USP22 increases FoxM1 expression to promote G1/S transition and cell proliferation through promoting β-catenin nuclear translocation in PDA cell lines. USP22 promotes the G1/S phase transition by upregulating FoxM1 expression via promoting β-catenin nuclear localization. USP22 and FoxM1 may act as prognostic markers and potential targets for PDA.

Epithelial-mesenchymal transition (EMT) contributes to the occurrence and development of tumors, particularly to the promotion of tumor invasion and metastasis. As a newly discovered ubiquitin hydrolase family member, USP22 plays a key role in the malignant transformation of tumors and the regulation of the cell cycle. However, recent studies on USP22 have primarily focused on its role in cell cycle regulation, and the potential mechanism underlying the promotion of tumor invasion and metastasis by abnormal USP22 expression has not been reported. Our studies revealed that the overexpression of USP22 in PANC-1 cells promoted Ezrin redistribution and phosphorylation and cytoskeletal remodeling, upregulated expression of the transcription factors Snail and ZEB1 to promote EMT, and increased cellular invasion and migration. In contrast, blockade of USP22 expression resulted in the opposite effects. In addition, the focal adhesion kinase (FAK) signaling pathway was shown to play a key role in the process of EMT induction in PANC-1 cells by USP22. Thus, the present study suggests that USP22 acts as a regulatory protein for EMT in pancreatic cancer, which may provide a new approach for the targeted therapy of pancreatic cancer.

Resistance to platinum-based chemotherapy is one of the most important reasons for treatment failure in advanced non-small cell lung cancer, but the underlying mechanism is extremely complex and unclear. The present study aimed to investigate the correlation of ubiquitin-specific peptidase 22 (USP22) with acquired resistance to cisplatin in lung adenocarcinoma. In this study, we found that overexpression of USP22 could lead to cisplatin resistance in A549 cells. USP22 and its downstream proteins γH2AX and Sirt1 levels are upregulated in the cisplatin- resistant A549/CDDP cell line. USP22 enhances DNA damage repair and induce cisplatin resistance by promoting the phosphorylation of histone H2AX via deubiquitinating histone H2A. In addition, USP22 decreases the acetylation of Ku70 by stabilizing Sirt1, thus inhibiting Bax-mediated apoptosis and inducing cisplatin resistance. The cisplatin sensitivity in cisplatin-resistant A549/CDDP cells was restored by USP22 inhibition in vivo and vitro. In summary, our findings reveal the dual mechanism of USP22 involvement in cisplatin resistance that USP22 can regulate γH2AX-mediated DNA damage repair and Ku70/Bax-mediated apoptosis. USP22 is a potential target in cisplatin-resistant lung adenocarcinoma and should be considered in future therapeutic practice.

Abstract. Ubiquitin-specific protease 22 (USP22) is a component of the transcription regulatory histone acetylation complex SAGA, which broadly regulates gene transcription and correlates with cancer progression, metastasis and prognosis. Autophagy is a cell pathway with dual functions that promotes cell survival or death. However, it is not known whether USP22 can regulate autophagy in pancreatic cancer. In the present study, we first identified that USP22 was overexpressed in a large number of pancreatic cancer patient samples, concomitant with the increased expression of LC3, a marker of autophagy. Statistical analysis revealed that the increase in USP22 and autophagy was positively correlated with poor prognosis of pancreatic cancer patients. Further investigation using a human pancreatic cancer cell (Panc-1) identified that the overexpression of USP22 increased the processing of LC3 into the active form LC3-II and the number of autophagosomes, thus leading to enhanced autophagy. Activation of ERK1/2 kinase rather than AKT1 by USP22 was found to be one of the mechanisms promoting LC3 processing. USP22-induced autophagy was also found to enhance cell proliferation and resistance to starvation and chemotherapeutic drugs in Panc-1 cells, therefore expressing an overall effect that promotes cell survival. Collectively, the present study demonstrated a new function of USP22 that induces autophagy, thus leading to the poor prognosis of pancreatic cancer.

Lung adenocarcinoma (LUAD) is one of the main causes of cancer deaths globally. Redox is emerging as a crucial contributor to the pathophysiology of LUAD, which can be regulated by long non-coding RNAs (lncRNAs). The aim of our research is to identify a novel redox-related lncRNA prognostic signature (redox-LPS) for better prediction of LUAD prognosis. 535 LUAD samples from The Cancer Genome Atlas (TCGA) database and 226 LUAD samples from the Gene Expression Omnibus (GEO) database were included in our study. 67 redox genes and 313 redox-related lncRNAs were identified. After performing LASSO-Cox regression analysis, a redox-LPS consisting of four lncRNAs (i.e., CRNDE, CASC15, LINC01137, and CYP1B1-AS1) was developed and validated. Our redox-LPS was superior to another three established models in predicting survival probability of LUAD patients. Univariate and multivariate Cox regression analysis revealed that risk score and stage were independent prognostic indicators. A nomogram plot including risk score and stage was constructed to predict survival probability of LUAD patients; this was further verified by calibration curves. Functional enrichment analysis and gene set enrichment analysis, were performed to determine the differences in cellular processes and signaling pathways between the high -and low-risk subgroups. A variety of algorithms (such as single-sample gene set enrichment analysis and CIBERSOFT) were conducted to uncover the landscape of tumor immune microenvironment in the high-and low-risk subgroups. In conclusion, a novel independent redox-LPS was constructed and validated for LUAD patients, which might provide new insights for clinical decision-making and precision medicine. Transcriptome profiling and clinical data of LUAD patients from TCGA (535samples;55268genes) Transcriptome profiling and clinical data of LUAD patients from GEO (226samples;20174genes) Train cohort (TCGA: 246) 71 redox-related genes Univariate cox regression Redox-related lncRNAs with prognostic values Lasso regression Redox-LPS Nomogram plot Calibration curve Vocalno plot GO functional annotation GSEA ssGSEA PCA Survival analysis ROC curve 10089 TCGA -derived lncRNAs Samples from TCGA : 535 Samples from GEO: 226 313 redox -related lncRNAs Multivariate cox regression Test1 cohort (TCGA: 244) Excluded samples (TCGA: 45) Test3 cohort (GEO: 226) Test2 cohort (TCGA: 490) Samples from TCGA : 535 Samples from GEO : 226 18870 intersecting genes Comparative analysis Co-expression analysis Clinical significance analysis ARTICLE HISTORY

Elevated de novo lipogenesis is considered to be a crucial factor in hepatocellular carcinoma (HCC) development. Herein, we identify ubiquitin-specific protease 22 (USP22) as a key regulator for de novo fatty acid synthesis, which directly interacts with deubiquitinates and stabilizes peroxisome proliferator-activated receptor gamma (PPARγ) through K48-linked deubiquitination, and in turn, this stabilization increases acetyl-CoA carboxylase (ACC) and ATP citrate lyase (ACLY) expressions. In addition, we find that USP22 promotes de novo fatty acid synthesis and contributes to HCC tumorigenesis, however, this tumorigenicity is suppressed by inhibiting the expression of PPARγ, ACLY, or ACC in in vivo tumorigenesis experiments. In HCC, high expression of USP22 positively correlates with PPARγ, ACLY or ACC expression, and associates with a poor prognosis. Taken together, we identify a USP22-regulated lipogenesis mechanism that involves the PPARγ-ACLY/ACC axis in HCC tumorigenesis and provide a rationale for therapeutic targeting of lipogenesis via USP22 inhibition.

Breast cancer is the most common malignancy in women and the leading cause of cancer deaths in women worldwide. Breast cancers are heterogenous and exist in many different subtypes (luminal A, luminal B, triple negative, and human epidermal growth factor receptor 2 (HER2) overexpressing), and each subtype displays distinct characteristics, responses to treatment, and patient outcomes. In addition to varying immunohistochemical properties, each subtype contains a distinct gene mutation profile which has yet to be fully defined. Patient treatment is currently guided by hormone receptor status and HER2 expression, but accumulating evidence suggests that genetic mutations also influence drug responses and patient survival. Thus, identifying the unique gene mutation pattern in each breast cancer subtype will further improve personalized treatment and outcomes for breast cancer patients. In this study, we used the Ion Personal Genome Machine (PGM) and Ion Torrent AmpliSeq Cancer Panel to sequence 737 mutational hotspot regions from 45 cancer-related genes to identify genetic mutations in 80 breast cancer samples of various subtypes from Chinese patients. Analysis revealed frequent missense and combination mutations in PIK3CA and TP53, infrequent mutations in PTEN, and uncommon combination mutations in luminal-type cancers in other genes including BRAF, GNAS, IDH1, and KRAS. This study demonstrates the feasibility of using Ion Torrent sequencing technology to reliably detect gene mutations in a clinical setting in order to guide personalized drug treatments or combination therapies to ultimately target individual, breast cancer-specific mutations.Electronic supplementary materialThe online version of this article (doi:10.1186/s40246-015-0024-4) contains supplementary material, which is available to authorized users.