Integrated transcriptome analysis of CSE1L regarding poor prognosis and immune infiltration in bladder urothelial carcinoma and experimental verification.

Background: Bladder urothelial carcinoma (BLCA) is one of the most prevalent tumors globally, with its incidence rising notably in developed countries, significantly affecting human health. CSE1L encodes a protein that is involved in various cellular processes and plays a critical role in cancer initiation and progression. However, its role in BLCA remains underexplored. Methods: CSE1L expression in BLCA was analyzed using TCGA data and validated by qRT-PCR and Western blot in clinical samples. Survival analysis and Cox regression models were used to evaluate its prognostic value. Functional enrichment and protein interaction analyses were performed, and immune cell infiltration was assessed using CIBERSORT. Drug sensitivity was analyzed using GDSC data. In vitro assays evaluated the effects of CSE1L knockdown on cell proliferation, migration, and invasion. Results: CSE1L was found to be significantly overexpressed in BLCA tissues compared to normal tissues. High CSE1L expression was associated with poor overall survival and unfavorable clinicopathological features. Functional enrichment analysis revealed that DEGs related to CSE1L were involved in cell cycle regulation and immune-related pathways. Immune infiltration analysis indicated a significant correlation between CSE1L expression and various immune cell types, particularly T cells and macrophages. Drug sensitivity analysis identified several chemotherapeutic agents, including MG-132, Palbociclib, and Nutlin-3a, which were more effective in the low-CSE1L expression group, while the high-CSE1L expression group showed sensitivity to drugs like S-Trityl-L-cysteine, Bleomycin, and Cisplatin. In vitro knockdown of CSE1L in BLCA cell lines inhibited cell proliferation, migration, and invasion. Conclusions: The overexpression of CSE1L is associated with the progression and poor prognosis of bladder cancer, suggesting it could be a promising target for bladder cancer in the future.

CSE1L as a prognostic biomarker associated with pan cancer immune infiltration and drug sensitivity.

BACKGROUND: Rising cancer-related mortality underscores the importance of biomarkers for treatment and prognosis, with Chromosome Segregation 1 Like (CSE1L) linked to various cancers yet its roles remain partially understood. This study investigates CSE1L's expression and oncogenic mechanisms in solid tumors. RESEARCH DESIGN AND METHODS: We analyzed multi-omics data from 31 solid tumors, measured CSE1L in 41 head and neck carcinoma patients post-chemotherapy via qRT-PCR, and evaluated the impact of CSE1L knockdown on cell proliferation in A549 and HepG2 cells. RESULTS: In this study, we observed significantly elevated levels of CSE1L RNA in 13 tumor tissues and protein levels in 8 tumor tissues compared to their corresponding adjacent normal tissues. Additionally, our investigation unveiled a correlation between heightened CSE1L expression in tumor tissues and worsened patient prognosis, poor response to immunotherapy, and diminished effectiveness of neoadjuvant chemotherapy. Through an analysis of CSE1L mechanisms, we discovered its potential involvement in promoting tumor cell proliferation, enhancing drug resistance, and influencing immune infiltration, thereby impacting patient prognosis and treatment outcomes. Finally, we delved into the potential mechanisms underlying upregulation of CSE1L in tumor tissues. CONCLUSION: Our findings demonstrate that CSE1L promotes tumor development in various malignancies, highlighting its potential as both a therapeutic target and prognostic indicator.

DDX27 regulates oral squamous cell carcinoma development through targeting CSE1L.

THE HEADINGS AIMS: DEAD-box helicase 27 (DDX27), a member of the DEAD-Box nucleic acid helicase family, holds an elusive role in oral squamous cell carcinoma (OSCC). This study aims to unravel the regulatory functions of DDX27 in OSCC and explore its downstream targets. MATERIALS AND METHODS: A commercial oral squamous cell carcinoma (OSCC) tissue microarray (TMA) was utilized. We analyzed differentially expressed genes in OSCC through the GEO database. Target gene silencing was achieved using the shRNA-mediated lentivirus method. Coexpedia analysis identified co-expressed genes associated with DDX27. Additionally, a Co-Immunoprecipitation (Co-IP) experiment confirmed the protein interaction between DDX27 and CSE1L. Xenograft tumor models were employed to evaluate DDX27's role in OSCC tumor formation. KEY FINDINGS: Elevated DDX27 expression in OSCC correlated with a higher pathological grade. DDX27 knockdown resulted in decreased cell proliferation, increased apoptosis, inhibited cell migration, and induced G2/M phase cell cycle arrest, as well as impaired tumor outgrowth. Coexpedia analysis identified STAU1, NELFCD, and CSE1L as top co-expressed genes. Lentiviral vectors targeting STAU1, NELFCD, and CSE1L revealed that silencing CSE1L significantly impaired cell growth, indicating it as a downstream target of DDX27. Cell rescue experiments demonstrated that increased DDX27 levels ameliorated cell proliferation, attenuated apoptosis, and CSE1L depletion blocked cell development induced by DDX27 overexpression. SIGNIFICANCES: This study highlighted DDX27 as a potential therapeutic target for OSCC treatment, shedding light on its crucial role in OSCC development. Targeting DDX27 or its downstream effector, CSE1L, holds promise for innovative OSCC therapies.

Mechanism of exportin retention in the cell nucleus.

Exportin receptors are concentrated in the nucleus to transport essential cargoes out of it. A mislocalization of exportins to the cytoplasm is linked to disease. Hence, it is important to understand how their containment within the nucleus is regulated. Here, we have studied the nuclear efflux of exportin2 (cellular apoptosis susceptibility protein or CAS) that delivers karyopherinα (Kapα or importinα), the cargo adaptor for karyopherinß1 (Kapß1 or importinß1), to the cytoplasm in a Ran guanosine triphosphate (RanGTP)-mediated manner. We show that the N-terminus of CAS attenuates the interaction of RanGTPase activating protein 1 (RanGAP1) with RanGTP to slow GTP hydrolysis, which suppresses CAS nuclear exit at nuclear pore complexes (NPCs). Strikingly, a single phosphomimetic mutation (T18D) at the CAS N-terminus is sufficient to abolish its nuclear retention and coincides with metastatic cellular behavior. Furthermore, downregulating Kapß1 disrupts CAS nuclear retention, which highlights the balance between their respective functions that is essential for maintaining the Kapα transport cycle. Therefore, NPCs play a functional role in selectively partitioning exportins in the cell nucleus.

[Expression and Clinical Significance of CAS in Acute Myeloid Leukemia Patients].

OBJECTIVE: To explore the expression of cellular apoptosis susceptibility protein （CAS） in acute myeloid leukemia （AML） and its correlation with clinical characteristics. METHODS: The expression of CAS in bone marrow tissue of 54 patients with AML and 24 patients with non-hematological malignant diseases was detected by Western blot and immune-histochemical method, and compared between AML group and control group. Also the relationship of CAS expression in AML and sex, age, WBC count, Hb, platelet count, bone marrow blast cell ratio, ki-67 index, cytogenetic and molecular biological prognostic risk stratification, extramedullary infiltration and other clinical characteristics was analyzed. RESULTS: Western blot showed that the expression of CAS protein in bone marrow biopsies of AML patients was significantly higher than that in control group (P<0.05). Immune-histochemical method revealed that CAS was mainly located in the cytoplasm in both AML group and control group. Among 54 AML patients, 14 patients (25.9%) showed high expression of CAS, while all the 24 patients in the control group showed low expression of CAS. The high expression rate of CAS in AML patients was significantly higher than that in the control group (P<0.05). There were statistically significant differences in prognostic risk stratification and the remission rate of the first chemotherapy between CAS high expression group and CAS low expression group in AML (P<0.05). The proportion of high risk patients and unremission patients after the first chemotherapy in CAS high expression group were significantly higher than those in CAS low expression group (57.1% vs 27.5%, 30.8% vs 7.9%), while the proportion of low risk patients and complete remission patients after the first chemotherapy were significantly lower than those in CAS low expression group (14.3% vs 37.5%, 53.8% vs 84.2%). In AML patients, the ki-67 index of bone marrow tissue in CAS high expression group was higher than that in CAS low expression group (60% vs 50%) (P<0.05). CONCLUSION: CAS is localized in cytoplasm in both AML and non-hematological malignant diseases, and its expression increases in AML. CAS is related to the risk stratification of cytogenetics and molecular biology, the remission rate after the first chemotherapy and ki-67 index in AML, which suggests that CAS may be involved in the occurrence and development of AML.

PHY34 inhibits autophagy through V-ATPase V0A2 subunit inhibition and CAS/CSE1L nuclear cargo trafficking in high grade serous ovarian cancer.

PHY34 is a synthetic small molecule, inspired by a compound naturally occurring in tropical plants of the Phyllanthus genus. PHY34 was developed to have potent in vitro and in vivo anticancer activity against high grade serous ovarian cancer (HGSOC) cells. Mechanistically, PHY34 induced apoptosis in ovarian cancer cells by late-stage autophagy inhibition. Furthermore, PHY34 significantly reduced tumor burden in a xenograft model of ovarian cancer. In order to identify its molecular target/s, we undertook an unbiased approach utilizing mass spectrometry-based chemoproteomics. Protein targets from the nucleocytoplasmic transport pathway were identified from the pulldown assay with the cellular apoptosis susceptibility (CAS) protein, also known as CSE1L, representing a likely candidate protein. A tumor microarray confirmed data from mRNA expression data in public databases that CAS expression was elevated in HGSOC and correlated with worse clinical outcomes. Overexpression of CAS reduced PHY34 induced apoptosis in ovarian cancer cells based on PARP cleavage and Annexin V staining. Compounds with a diphyllin structure similar to PHY34 have been shown to inhibit the ATP6V0A2 subunit of V(vacuolar)-ATPase. Therefore, ATP6V0A2 wild-type and ATP6V0A2 V823 mutant cell lines were tested with PHY34, and it was able to induce cell death in the wild-type at 246 pM while the mutant cells were resistant up to 55.46 nM. Overall, our data demonstrate that PHY34 is a promising small molecule for cancer therapy that targets the ATP6V0A2 subunit to induce autophagy inhibition while interacting with CAS and altering nuclear localization of proteins.

The microRNA-451a/chromosome segregation 1-like axis suppresses cell proliferation, migration, and invasion and induces apoptosis in nasopharyngeal carcinoma.

MicroRNA-451a (miR-451a) has been implicated in the initiation and progression of multiple cancers. However, the regulatory mechanisms underlying its function in nasopharyngeal carcinoma (NPC) are poorly understood. Thus, we investigated in detail the role of the microRNA-451a/chromosome segregation 1-like (miR-45a/CSE1L) axis and its regulatory mechanism in NPC. We examined the levels of miR-451a and CSE1L in NPC, and assessed the effects of miR-451a and CSE1L on NPC by cell functional experiments. Furthermore, we elucidated the direct regulatory effect of miR-451a on CSE1L by the luciferase reporter assay, RNA pull-down assay, and RNA immunoprecipitation and validated our observations by calculating the Pearson's correlation coefficient. We found that miR-451a was down-regulated in NPC cells, and its over-expression attenuated cell proliferation, migration, and invasion, and tumor growth in 5-8 F and SUNE-1 cells and promoted apoptosis. Moreover, CSE1L was the direct gene target of miR-451a, and its over-expression abrogated miR-451a-dependent inhibition of malignancy in 5-8 F and SUNE-1 cells. The Pearson's correlation coefficient indicated a negative correlation between CSE1L and miR-451a. miR-451a serves as a tumor suppressor and targets CSE1L. miR-451a suppresses CSE1L expression, thereby reducing proliferation, invasion, and migration and increasing apoptosis of NPC cells.

Age-Associated Proteomic Signatures and Potential Clinically Actionable Targets of Colorectal Cancer.

The occurrence and prevalence of colorectal cancer (CRC) is closely associated with age. More than 90% of patients with CRC are diagnosed after 50 years of age. However, CRC incidence of young individuals has been increasing since 1990s, whereas the overall CRC frequency is declining. Distinct overall survival rates between young and aged patients with CRC have been established. Tremendous efforts have been made to clarify the underlying mechanisms of age-dependent clinical differences, but it still remains elusive. Here, we performed proteomic profiling of 50 patients with CRC and revealed proteomic signatures of CRC across age groups. Gene set enrichment analysis showed that distinct age-dependent clinical outcomes might mainly attribute to varied MYC targets V1/V2, E2F targets and G2M checkpoint gene sets, which were associated with cancer cell proliferation, cell apoptosis, tumor growth, and tumor metastasis. Multiple linear regression analysis revealed a large number of functional proteins, such as NOP2, CSE1L, NHP2, NOC2L and CDK1, with adjusted expression significantly correlated with age (p < 0.05). Among them, NHP2 is a core component of the telomerase complex associated with age. High NHP2 expression predicted poor overall survival, with a more significant correlation in aged patients with CRC. Knockdown of NHP2 significantly suppressed cancer cell proliferation. In addition, we revealed some age-related potential clinically actionable targets, such as PSEN1, TSPO, and CDK1, which might be more suitable for patients with late-onset CRC. Collectively, this study identifies age-associated proteomic signatures and potential therapeutic targets of CRC and may help make a precise decision on CRC treatment.

CSE1L promotes nuclear accumulation of transcriptional coactivator TAZ and enhances invasiveness of human cancer cells.

The transcriptional coactivator with PDZ-binding motif (TAZ) (WWTR1) induces epithelial-mesenchymal transition and enhances drug resistance in multiple cancers. TAZ has been shown to interact with transcription factors in the nucleus, but when phosphorylated, translocates to the cytoplasm and is degraded through proteasomes. Here, we identified a compound TAZ inhibitor 4 (TI-4) that shifted TAZ localization to the cytoplasm independently of its phosphorylation. We used affinity beads to ascertain a putative target of TI-4, chromosomal segregation 1 like (CSE1L), which is known to be involved in the recycling of importin α and as a biomarker of cancer malignancy. We found that TI-4 suppressed TAZ-mediated transcription in a CSE1L-dependent manner. CSE1L overexpression increased nuclear levels of TAZ, whereas CSE1L silencing delayed its nuclear import. We also found via the in vitro coimmunoprecipitation experiments that TI-4 strengthened the interaction between CSE1L and importin α5 and blocked the binding of importin α5 to TAZ. WWTR1 silencing attenuated CSE1L-promoted colony formation, motility, and invasiveness of human lung cancer and glioblastoma cells. Conversely, CSE1L silencing blocked TAZ-promoted colony formation, motility, and invasiveness in human lung cancer and glioblastoma cells. In human cancer tissues, the expression level of CSE1L was found to correlate with nuclear levels of TAZ. These findings support that CSE1L promotes the nuclear accumulation of TAZ and enhances malignancy in cancer cells.

Mining prognostic markers of Asian hepatocellular carcinoma patients based on the apoptosis-related genes.

BACKGROUND: Apoptosis-related genes(Args)play an essential role in the occurrence and progression of hepatocellular carcinoma(HCC). However, few studies have focused on the prognostic significance of Args in HCC. In the study, we aim to explore an efficient prognostic model of Asian HCC patients based on the Args. METHODS: We downloaded mRNA expression profiles and corresponding clinical data of Asian HCC patients from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases. The Args were collected from Deathbase, a database related to cell death, combined with the research results of GeneCards、National Center for Biotechnology Information (NCBI) databases and a lot of literature. We used Wilcoxon-test and univariate Cox analysis to screen the differential expressed genes (DEGs) and the prognostic related genes (PRGs) of HCC. The intersection genes of DEGs and PGGs were seen as crucial Args of HCC. The prognostic model of Asian HCC patients was constructed by least absolute shrinkage and selection operator (lasso)- proportional hazards model (Cox) regression analysis. Kaplan-Meier curve, Principal Component Analysis (PCA) analysis, t-distributed Stochastic Neighbor Embedding (t-SNE) analysis, risk score curve, receiver operating characteristic (ROC) curve, and the HCC data of ICGC database and the data of Asian HCC patients of Kaplan-Meier plotter database were used to verify the model. RESULTS: A total of 20 of 56 Args were differentially expressed between HCC and adjacent normal tissues (p < 0.05). Univariate Cox regression analysis showed that 10 of 56 Args were associated with survival time and survival status of HCC patients (p < 0.05). There are seven overlapping genes of these 20 and 10 genes, including BAK1, BAX, BNIP3, CRADD, CSE1L, FAS, and SH3GLB1. Through Lasso-Cox analysis, an HCC prognostic model composed of BAK1, BNIP3, CSE1L, and FAS was constructed. Kaplan-Meier curve, PCA, t-SNE analysis, risk score curve, ROC curve, and secondary verification of ICGC database and Kaplan-Meier plotter database all support the reliability of the model. CONCLUSIONS: Lasso-Cox regression analysis identified a 4-gene prognostic model, which integrates clinical and gene expression and has a good effect. The expression of Args is related to the prognosis of HCC patients, but the specific mechanism remains to be further verified.

CSE1L promotes proliferation and migration in oral cancer through positively regulating MITF.

OBJECTIVE: CSE1L (human chromosomal segregation 1-like) is reported to be able to affect cell apoptosis, invasiveness, and migration. The purpose of this study was to uncover the regulatory effects of CSE1L on cell phenotypes of oral cancer and the underlying mechanism. MATERIALS AND METHODS: CSE1L levels in oral cancer cells were determined by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) and Western blot. CSE1L overexpression and knockdown models were constructed in CAL-27 and HN6 cells, respectively. Changes in proliferative and migratory abilities in oral cancer cells affected by CSE1L and microphthalmia-associated transcription factor (MITF) were assessed by cell counting kit-8 (CCK-8), 5-Ethynyl-2'-deoxyuridine (EdU) and wound healing assay. Meanwhile, potential influences of CSE1L and MITF on relative levels of E-cadherin and Vimentin in oral cancer cells were detected. Finally, regulatory effects of CSE1L and MITF on the Akt/mTOR pathway were evaluated by detecting expression levels of p-Akt, Akt, p-mTOR, and mTOR. RESULTS: CSE1L was upregulated in oral cancer cells. Knockdown of CSE1L in HN6 cells attenuated proliferative and migratory abilities, as well as downregulated Vimentin and upregulated E-cadherin. Overexpression of CSE1L in CAL-27 cells yielded the opposite results. MIFT level was positively regulated by CSE1L. Overexpression of MITF partially reversed regulatory effects of CSE1L on proliferative ability of oral cancer cells. Moreover, silence of CSE1L suppressed the Akt/mTOR pathway, which was reversed by overexpression of MITF. CONCLUSIONS: CSE1L promotes the proliferative and migratory abilities in oral cancer cells by positively regulating MITF, thus activating the Akt/mTOR pathway.

Cellular apoptosis susceptibility protein (CAS) suppresses the proliferation of breast cancer cells by upregulated cyp24a1.

Breast cancer is the most common cancer in women. Although several studies demonstrated cellular apoptosis susceptibility protein (CAS) involved in the development of breast cancer, the underlying mechanisms of CAS regulating cell processes in the breast cancer remain elusive. In the present study, we explored the possible mechanism of CAS in contributing to the cell proliferation in the breast cancer cell line MCF-7. Knockdown of CAS led to the reduction of cell viability and proliferation. Furthermore, cell cycle was arrested in G0/G1 phase after knocking down CAS with the decrease of cyclinD1. In addition, RNA-seq analysis for the CAS knockdown cells demonstrated that total eleven genes were significantly altered (Fold changes > 2). Of note, the expression of cyp24a1 was dramatically increased in the shCAS cells compared to that of shNC cells as well as confirmed by quantitative real-time polymerase chain reaction (qPCR). These observations clarified the previous conflicting results on the cell fates of the breast cells regulated by CAS and provide new insight into the role of CAS in the development of breast cancer.

CSE1L silence inhibits the growth and metastasis in gastric cancer by repressing GPNMB via positively regulating transcription factor MITF.

Human chromosomal segregation 1-like (CSE1L) gene functions as a key molecular mediator in cellular proliferation, invasion, and apoptosis. The association of CSE1L with tumor progression has been reported in diverse human cancers. A greater understanding of CSE1L molecular mechanism is beneficial for cancer treatment. In the current study, we show that CSE1L was highly expressed in gastric cancer (GC) cell lines. CSE1L silence promoted apoptosis and inhibited cell proliferation and invasion. Overexpression of glycoprotein nonmetastatic melanoma protein B (GPNMB) reversed the anticancer effect of CSE1L inhibition. CSE1L inhibition decreased GPNMB by microphthalmia-associated transcription factor (MITF). Moreover, GPNMB regulates the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway. Taken together, our study revealed that CSE1L inhibition decreased MITF and suppressed GPNMB expression, thereby activating the PI3K/Akt/mTOR and MEK/ERK signaling pathway, ultimately inhibiting the tumor growth and metastasis in GC.

CSE1L participates in regulating cell mitosis in human seminoma.

OBJECTIVES: CSE1L has been reported to be highly expressed in various tumours. Testicular germ cell tumours are common among young males, and seminoma is the major type. However, whether CSE1L has functions in the seminoma is unclear. MATERIALS AND METHODS: The expression of CSE1L was detected by immunohistochemistry in seminoma tissues and non-tumour normal testis tissues from patients. CSE1L distribution during cell mitosis was determined by immunofluorescent staining with CSE1L, α-tubulin and γ-tubulin antibodies. The effects of Cse1L knockdown on cell proliferation and cell cycle progression were determined by Cell Counting Kit-8 assay, flow cytometry, PH3 staining and bromodeoxyuridine incorporation assay. RESULTS: CSE1L was significantly enriched in the seminoma tissue compared with the non-tumour normal testis tissue. CSE1L also co-localized with α-tubulin in the cells with a potential to divide. In the seminoma cell line TCam-2, CSE1L was associated with the spindles and the centrosomes during cell division. The knockdown of CSE1L in TCam-2 cells attenuated the cells' proliferative capacity. Cell cycle assay revealed that the CSE1L-deficient cells were mainly arrested in the G0/G1 phase and moderately delayed in the G2/M phase. The proportion of cells with multipolar spindle and abnormal spindle geometry was obviously increased by CSE1L expression silencing in the TCam-2 cells. CONCLUSIONS: Overall, these findings showed that CSE1L plays a pivotal role in maintaining cell proliferation and cell division in seminomas.

LncRNA BANCR promotes tumorigenesis and enhances adriamycin resistance in colorectal cancer.

Colorectal cancer (CRC) is the third most common malignancy in the United States. Chemotherapeutic resistance is a massive obstacle for cancer treatment. The roles and molecular basis of long non-coding RNA BRAF-activated noncoding RNA (BANCR) in CRC progression and adriamycin (ADR) resistance have not been extensively identified. In this study, we found that BANCR and CSE1L expressions were upregulated in CRC tumor tissues. Meanwhile, CSE1L expression was correlated with depth of CRC. BANCR silencing suppressed cell proliferation and invasion capacity, increased apoptotic rate and potentiated cell sensitivity to ADR. CSE1L downregulation triggered a reduction of cell proliferation and invasion ability, and an increase of apoptosis rate and cell sensitivity to ADR. CSE1L overexpression attenuated si-BANCR-mediated anti-proliferation, anti-invasion and pro-apoptosis effects in CRC cells. BANCR acted as a molecular sponge of miR-203 to sequester miR-203 away from CSE1L in CRC cells, resulting in the upregulation of CSE1L expression. CSE1L knockdown inhibited expressions of DNA-repair-related proteins (53BP1 and FEN1) in HCT116 cells. BANCR knockdown also inhibited tumor growth and enhanced ADR sensitivity in CRC mice model. In conclusion, BANCR knockdown suppressed CRC progression and strengthened chemosensitization of CRC cells to ADR possibly by regulating miR-203/CSE1L axis, indicating that BANCR might be a promising target for CRC treatment.

Roles of the CSE1L-mediated nuclear import pathway in epigenetic silencing.

Epigenetic silencing can be mediated by various mechanisms, and many regulators remain to be identified. Here, we report a genome-wide siRNA screening to identify regulators essential for maintaining gene repression of a CMV promoter silenced by DNA methylation. We identified CSE1L (chromosome segregation 1 like) as an essential factor for the silencing of the reporter gene and many endogenous methylated genes. CSE1L depletion did not cause DNA demethylation. On the other hand, the methylated genes derepressed by CSE1L depletion largely overlapped with methylated genes that were also reactivated by treatment with histone deacetylase inhibitors (HDACi). Gene silencing defects observed upon CSE1L depletion were linked to its nuclear import function for certain protein cargos because depletion of other factors involved in the same nuclear import pathway, including KPNAs and KPNB1 proteins, displayed similar derepression profiles at the genome-wide level. Therefore, CSE1L appears to be critical for the nuclear import of certain key repressive proteins. Indeed, NOVA1, HDAC1, HDAC2, and HDAC8, genes known as silencing factors, became delocalized into cytosol upon CSE1L depletion. This study suggests that the cargo specificity of the protein nuclear import system may impact the selectivity of gene silencing.

CD147 Induces Epithelial-to-Mesenchymal Transition by Disassembling Cellular Apoptosis Susceptibility Protein/E-Cadherin/ß-Catenin Complex in Human Endometriosis.

Epithelial-to-mesenchymal transition (EMT) is postulated to be a prerequisite for the establishment of endometriosis (EMS), a common reproductive disorder in women. Our previous studies have demonstrated the elevated expression of transmembrane glycoprotein CD147 and its prosurvival effect on abnormal cells in endometriosis. Intriguingly, CD147 is known to promote EMT in cancers. However, the involvement of CD147 in EMT during the establishment of endometriosis remains incompletely understood. We found that CD147 promotes EMT in human endometrial adenocarcinoma cell line Ishikawa. We identified a novel CD147-interacting partner, cellular apoptosis susceptibility protein (CAS), which stabilized the interaction between E-cadherin (E-cad) and ß-catenin (ß-cat) by forming the CAS/E-cad/ß-cat complex. Down-regulation of CAS led to the release and nuclear translocation of ß-cat from E-cad, resulting in the overexpression of the EMT-promoting gene SNAIL. Interestingly, overexpression of CD147 impaired the interaction between CAS and E-cad and triggered the release of ß-cat from the CAS/E-cad/ß-cat complex, which in turn led to EMT. Furthermore, CAS was down-regulated in EMS, with elevated levels of CD147 and nuclear ß-cat. These findings suggest a previously undefined role of CAS in regulating EMT and reveal the involvement of a CD147-induced EMT signaling pathway in pathogenic progression of EMS.

CSE1L interaction with MSH6 promotes osteosarcoma progression and predicts poor patient survival.

To discover tumor-associated proteins in osteosarcoma, a quantitative proteomic analysis was performed to identify proteins that were differentially expressed between osteosarcoma and human osteoblastic cells. Through clinical screening and a functional evaluation, chromosome segregation 1-like (CSE1L) protein was found to be related to the growth of osteosarcoma cells. To date, little is known about the function and underlying mechanism of CSE1L in osteosarcoma. In the present study, we show that knockdown of CSE1L inhibits osteosarcoma growth in vitro and in vivo. By co-immunoprecipitation and RNA-seq analysis, CSE1L was found to interact with mutS homolog 6 (MSH6) and function as a positive regulator of MSH6 protein in osteosarcoma cells. A rescue study showed that decreased growth of osteosarcoma cells by CSE1L knockdown was reversed by MSH6 overexpression, indicating that the activity of CSE1L was an MSH6-dependent function. In addition, depletion of MSH6 hindered cellular proliferation in vitro and in vivo. Notably, CSE1L expression was correlated with MSH6 expression in tumor samples and was associated with poor prognosis in patients with osteosarcoma. Taken together, our results demonstrate that the CSE1L-MSH6 axis has an important role in osteosarcoma progression.

Acid phosphatase 2 (ACP2) is required for membrane fusion during influenza virus entry.

Influenza viruses exploit host factors to successfully replicate in infected cells. Using small interfering RNA (siRNA) technology, we identified six human genes required for influenza A virus (IAV) replication. Here we focused on the role of acid phosphatase 2 (ACP2), as its knockdown showed the greatest inhibition of IAV replication. In IAV-infected cells, depletion of ACP2 resulted in a significant reduction in the expression of viral proteins and mRNA, and led to the attenuation of virus multi-cycle growth. ACP2 knockdown also decreased replication of seasonal influenza A and B viruses and avian IAVs of the H7 subtype. Interestingly, ACP2 depletion had no effect on the replication of Ebola or hepatitis C virus. Because ACP2 is known to be a lysosomal acid phosphatase, we assessed the role of ACP2 in influenza virus entry. While neither binding of the viral particle to the cell surface nor endosomal acidification was affected in ACP2-depleted cells, fusion of the endosomal and viral membranes was impaired. As a result, downstream steps in viral entry were blocked, including nucleocapsid uncoating and nuclear import of viral ribonucleoproteins. Our results established ACP2 as a necessary host factor for regulating the fusion step of influenza virus entry.