Zhen Ning

USP22 promotes epithelial-mesenchymal transition via the FAK pathway in pancreatic cancer cells

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.

Ubiquitin‑specific protease 22‑induced autophagy is correlated with poor prognosis of pancreatic cancer

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.

USP22 Induces Cisplatin Resistance in Lung Adenocarcinoma by Regulating γH2AX-Mediated DNA Damage Repair and Ku70/Bax-Mediated Apoptosis

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.

Tumor-associated macrophages promote Ezrin phosphorylation-mediated epithelial-mesenchymal transition in lung adenocarcinoma through FUT4/LeY up-regulation

Tumor-associated macrophages (TAMs) are key components of tumor microenvironment (TME) during tumorigenesis and progression. However, the role of TAMs in lung adenocarcinoma is still unclear. In this study, we aimed to clarify the mechanism underlying the crosstalk between TAMs and epithelial-mesenchymal transition (EMT) of lung adenocarcinoma. Fucosyltransferase IV (FUT4) and its synthetic cancer sugar antigen Lewis Y (LeY) was aberrantly elevated in various solid tumors, it plays critical role in the invasion and metastasis. Here, we found that in lung adenocarcinoma samples, the density of TAMs correlates with E-cadherin level and LeY level. In vitro assays, M2 macrophages promoted FUT4/LeY expression through the transforming growth factor-β1(TGF-β1)/Smad2/3 signaling pathway. FUT4/LeY was indispensable in M2 macrophages-mediated cytoskeletal remodeling and EMT. Furthermore, fucosylation of Ezrin mediated by FUT4/LeY can promote the phosphorylation of Ezrin, which was the critical mechanism of M2 macrophages-induced EMT. In vivo assays confirmed that M2 macrophages promoted EMT through the up-regulation of LeY and phosphorylated Ezrin. Together, our results revealed that TAMs promote Ezrin phosphorylation-mediated EMT in lung adenocarcinoma through FUT4/LeY- mediated fucosylation. Targeting this newly identified signaling may offer new possibilities for immunotherapy in lung adenocarcinoma.

Integrin-β5, a miR-185-targeted gene, promotes hepatocellular carcinoma tumorigenesis by regulating β-catenin stability

BackgroundThe tumour microenvironment is essential for cancer progress and metastasis. Integrin-β5 (ITGB5), a member of the integrin family, has been implicated to mediate the interactions of cells with the extracellular matrix (ECM) and promote tumorigenesis in several malignancies. However, the role of ITGB5 in hepatocellular carcinoma (HCC) is still unknown.MethodsThe biological function of ITGB5 in HCC was investigated using migration, colony formation assays. The potential molecular mechanism of ITGB5 in regulating HCC tumorigenesis and β-catenin stabilization was investigated by western blotting, co-immunoprecipitation and ubiquitination assays. The expression level of ITGB5 mediated by miR-185 was confirmed by bioinformatic analysis, luciferase assay. The clinical significance of ITGB5 was based on human tissue microarray (TMA) analysis.ResultsHere, we found that the expression of ITGB5 is increased in HCC tissues. Elevated ITGB5 markedly facilitates HCC cell migration and tumorigenesis in vitro and in vivo. Further mechanistic studies revealed that ITGB5, as a partner of β-catenin, directly interacts with β-catenin and inhibits its degradation, thus leading to WNT/β-catenin activity. Subsequently, we also found that ITGB5 is a direct targeted gene of miR-185. The downregulation of miR-185 in HCC cells promotes an increase in ITGB5. An additional increase of ITGB5 is associated with β-catenin upregulation and a miR-185 decrease in HCC tissues.ConclusionsOur data reveal that the miR-185-ITGB5-β-catenin pathway plays an important role in HCC tumorigenesis, and ITGB5 may be a promising specific target for HCC therapy.

USP10 suppresses tumor progression by inhibiting mTOR activation in hepatocellular carcinoma

Dysregulation of deubiquitination pathway is associated with poor prognosis in cancers such as hepatocellular carcinoma (HCC). The mammalian target of rapamycin, mTOR, has become an attractive cancer therapeutic target in HCC. However, whether and how aberrant expression of deubiquitination pathway regulates mTOR pathway has remained elusive. Here we report that ubiquitin-specific protease 10 (USP10) functions as a tumor suppressor which inhibits mTOR pathway by stabilizing PTEN and AMPKα in HCC cells. Mechanistically, USP10 interacts and stabilizes PTEN and AMPKα by inhibiting their polyubiquitylation. This stabilization in turn inhibits AKT phosphorylation and mTOR Complex1 (mTORC1) activation. In human liver cancer, USP10 expression is downregulated in HCC tumor tissues across three independent HCC cohorts, and lower-expression of USP10 will generate poor prognosis outcome. Collectively, our results uncover an undescribed mechanism where USP10, as a tumor suppressor, negatively regulates mTORC1 activation and AKT phosphorylation by stabilizing AMPKα and PTEN in HCC cells. This study sheds light on the theoretical basis of mTOR signaling pathway-oriented targeting treatment in clinic.