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1.
IUBMB Life ; 75(7): 595-608, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36773333

RESUMO

WW domain containing E3 ubiquitin protein ligase 2 (WWP2) is a member of the NEDD4 E3 ubiquitin ligase family. WWP2 ligase activity is regulated by the 2, 3-linker auto-inhibition. Tyrosine phosphorylation of the 2, 3-linker was identified as an activating means for releasing the auto-inhibition of WWP2. However, the tyrosine kinase (TK) for the phosphorylation and activation remains unknown. In this report, we have found that non-receptor TK ACK1 binds to the WW3 domain of WWP2 and phosphorylates WWP2. ACK1 phosphorylates WWP2 at the 2, 3-linker and partially activates the ubiquitination ligase activity. Unexpectedly, tyrosine phosphorylation of the 2, 3-linker seems not a major mode for activation of WWP2, as ACK1 causes much higher activation of the 2, 3-linker tyrosine phosphorylation defective mutants of WWP2 than that of wild-type WWP2. Furthermore, epidermal growth factor (EGF) stimulates tyrosine phosphorylation of WWP2 and this EGF-stimulated phosphorylation of WWP2 is mediated by ACK1. Finally, knockdown of WWP2 by shWWP2 inhibits the EGF-dependent cell proliferation of lung cancer A549 cells, suggesting that WWP2 may function in the EGFR signaling in lung cancer progression. Taken together, our findings have revealed a novel mechanism underlying activation of WWP2.


Assuntos
Neoplasias Pulmonares , Ubiquitina-Proteína Ligases , Humanos , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Fator de Crescimento Epidérmico/farmacologia , Proteínas Tirosina Quinases/metabolismo , Tirosina/genética
2.
J Cell Sci ; 130(22): 3839-3850, 2017 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-29021346

RESUMO

Our previous studies have shown that the HECT E3 ubiquitin ligase NEDD4 interacts with LC3 and is required for starvation and rapamycin-induced activation of autophagy. Here, we report that NEDD4 directly binds to SQSTM1 via its HECT domain and polyubiquitylates SQSTM1. This ubiquitylation is through K63 conjugation and is not involved in proteasomal degradation. Mutational analysis indicates that NEDD4 interacts with and ubiquitylates the PB1 domain of SQSTM1. Depletion of NEDD4 or overexpression of the ligase-defective mutant of NEDD4 induced accumulation of aberrant enlarged SQSTM1-positive inclusion bodies that are co-localized with the endoplasmic reticulum (ER) marker CANX, suggesting that the ubiquitylation functions in the SQSTM1-mediated biogenic process in inclusion body autophagosomes. Taken together, our studies show that NEDD4 is an autophagic E3 ubiquitin ligase that ubiquitylates SQSTM1, facilitating SQSTM1-mediated inclusion body autophagy.


Assuntos
Autofagia , Ubiquitina-Proteína Ligases Nedd4/fisiologia , Proteína Sequestossoma-1/metabolismo , Ubiquitinação , Células A549 , Células HEK293 , Humanos , Corpos de Inclusão/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular , Complexo de Endopeptidases do Proteassoma/metabolismo , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Mapas de Interação de Proteínas , Proteínas/metabolismo , Proteólise
3.
Cancer Cell Int ; 19: 74, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30976198

RESUMO

BACKGROUND: Gastric cardia adenocarcinoma (GCA) is an aggressive subtype of gastric cancer with a high metastatic rate. However, the metastatic biomarker of GCA has not been established. METHODS: To search for the biomarker for GCA metastasis, we here examined expression of the Hippo signaling effector WWTR1 (WW domain containing transcription regulator 1, commonly listed as TAZ) in tumor tissue samples from 214 GCA cases using the tissue microarray assay (TMA), and statistically analyzed association of the WWTR1 expression with metastasis-related pathological outcomes and cumulative survival of the GCA patients. Furthermore, shRNA knockdown was used to determine the role of WWTR1 in promoting cell migration in gastric cancer cells. RESULTS: The results have shown that WWTR1 is overexpressed in 66.4% of the GCA tumor samples. Expression of WWTR1 has a significant inverse correlation with cumulative survival of GCA patients (p < 0.01). WWTR1 positive patients had a mean survival of 56.9 ± 4.4 months, comparing to WWTR1 negative mean survival of 77.3 ± 5.9 months. More importantly, expression of WWTR1 significantly associated with tumor invasion and metastasis (in T stage, p = 0.031; N stage, p < 0.01; and TNM stage, p < 0.001). Furthermore, knockdown of WWTR1 impaired migration of gastric cancer AGS cells. CONCLUSIONS: Our studies have identified WWTR1 as a metastatic biomarker of GCA for poor prognosis, defined a role of WWTR1 in driving metastasis of gastric cancer, and suggested WWTR1 as a potential target for anti-metastatic therapy of GCA.

4.
Microsc Microanal ; 25(3): 625-629, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30869060

RESUMO

The fluorescence effect induced by Kß photons is usually so small that it can be neglected. However, in the Fe-Mn system, omitting Kß fluorescence correction will lead to the overestimation of the Mn content especially when Mn is the minor alloy element. In this study, the error in the Mn concentration induced by Kß fluorescence was investigated by both Monte Carlo simulation, using the pyPENELOPE program, and systematic electron probe measurements on the Fe-0.53% Mn alloy standard by the aid of CalcZAF software. It is shown that the error caused by Kß fluorescence exceeds 4% for the Fe-0.53% Mn alloy. The problem can be overcome by utilizing CalcZAF in which ß-line fluorescence has been included, or by employing a similar standard Fe-0.85% Mn for Mn in the absence of ß-line fluorescence correction. In addition, a modified calibration curve method, using k-values instead of X-ray intensity as a variable, is presented and used to measure the Mn concentration. The accuracy of this method is as good as or better than that of the conventional matrix correction method. Compared with conventional calibration curve methods, it is time-saving because the k-value is not sensitive to instrument fluctuations and the established curve remains valid for a long period.

5.
Mol Cancer ; 17(1): 24, 2018 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-29455656

RESUMO

BACKGROUND: EGFR-dependent cell migration plays an important role in lung cancer progression. Our previous study observed that the HECT E3 ubiquitin ligase NEDD4 is significantly correlated with tumor metastasis and required for migration and invasion signaling of EGFR in gastric cancer cells. However, how NEDD4 promotes the EGFR-dependent lung cancer cell migration is unknown. This study is to elucidate the mechanism by which NEDD4 mediates the EGFR lung cancer migration signaling. METHODS: Lentiviral vector-loaded NEDD4 shRNA was used to deplete endogenous NEDD4 in lung cancer cell lines. Effects of the NEDD4 knockdown on the EGFR-dependent or independent lung cancer cell migration were determined using the wound-healing and transwell assays. Association of NEDD4 with activated EGFR was assayed by co-immunoprecipitation. Co-expression of NEDD4 with EGFR or PTEN was determined by immunohistochemical (IHC) staining in 63 lung adenocarcinoma tissue samples. Effects of NEDD4 ectopic expression or knockdown on PTEN ubiquitination and down-regulation, AKT activation and lysosomal secretion were examined using the GST-Uba pulldown assay, immunoblotting, immunofluorescent staining and a human cathepsin B ELISA assay respectively. The specific cathepsin B inhibitor CA-074Me was used for assessing the role of cathepsin B in lung cancer cell migration. RESULTS: Knockdown of NEDD4 significantly reduced EGF-stimulated cell migration in non-small cell lung carcinoma (NSCLC) cells. Co-immunoprecipitation assay found that NEDD4 is associated with EGFR complex upon EGF stimulation, and IHC staining indicates that NEDD4 is co-expressed with EGFR in lung adenocarcinoma tumor tissues, suggesting that NEDD4 might mediate lung cancer cell migration by interaction with the EGFR signaling complex. Interestingly, NEDD4 promotes the EGF-induced cathepsin B secretion, possibly through lysosomal exocytosis, as overexpression of the ligase-dead mutant of NEDD4 impedes lysosomal secretion, and knockdown of NEDD4 significantly reduced extracellular amount of cathepsin B induced by EGF. Consistent with the role of NEDD4, cathepsin B is pivotal for both basal and the EGF-stimulated lung cancer cell migration. Our studies propose a novel mechanism underlying the EGFR-promoted lung cancer cell migration that is mediated by NEDD4 through regulation of cathepsin B secretion. CONCLUSION: NEDD4 mediates the EGFR lung cancer cell migration signaling through promoting lysosomal secretion of cathepsin B.


Assuntos
Neoplasias Pulmonares/metabolismo , Ubiquitina-Proteína Ligases Nedd4/metabolismo , Transdução de Sinais , Catepsina B/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Fator de Crescimento Epidérmico/genética , Fator de Crescimento Epidérmico/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/genética , Lisossomos/metabolismo , Modelos Biológicos , Ubiquitina-Proteína Ligases Nedd4/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo
6.
Cancer Cell Int ; 16: 25, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27034618

RESUMO

BACKGROUND: Epidermal growth factor receptor (EGFR) is an important oncogenic protein in multiple types of cancer. Endocytosis and degradation of epidermal growth factor receptor (EGFR) are two key steps for down-regulation of cell surface level of EGFR and modulation of EGFR signaling. Stress conditions induce ligand-independent endocytosis and degradation of EGFR. However, it is not clear whether stress-induced endocytosis and degradation are consequential or two independent events. METHODS: Endocytosis and degradation of EGFR in response to stress treatment and effects of the p38 inhibitor, the Caspase-3 inhibitor and the proteasomal inhibitor in cervical cancer HeLa cells were determined using immunoblotting and immunofluorescent staining assays. RESULTS: Stress conditions, such as protein biosynthesis inhibition, UV light irradiation, and hyper-osmosis, induced both ligand-independent endocytosis and degradation of EGFR. Stress-induced endocytosis of EGFR relies on p38 kinase activity, while stress-induced degradation of EGFR is catalyzed by Caspase-3 activity. Inhibiting p38 kinase impairs only the endocytosis but not the degradation, while inhibiting Caspase-3 results in the opposite effect to inhibiting p38. Furthermore, proteasomal activity is required for stress-induced degradation of EGFR and cell death, but not for endocytosis. CONCLUSIONS: The results indicate that stress-induced endocytosis and degradation are two independent events and suggest stress signaling may utilize a double-secure mechanism to down-regulate cell surface EGFR in cancer cells.

7.
Cancer Cell Int ; 15: 27, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25745361

RESUMO

PDZ binding-kinase (PBK) (also named T-lymphokine-activated killer cell-originated protein kinase (TOPK)), a serine/threonine kinase, is tightly controlled in normal tissues but elevated in many tumors, and functions in tumorigenesis and metastasis. However, the signaling that regulates expression of PBK in cancer cells remains elusive. Here we show that atorvastatin (Lipitor), an inhibitor of hydroxymethylglutaryl co-enzyme A (HMG-CoA) reductase that is a rate-limiting enzyme of mevalonate pathway, down-regulates expression of PBK by impairing protein geranylgeranylation. The shRNA knockdown demonstrated that Yes-associated protein (YAP) mediates geranylgeranylation-regulated expression of PBK. Importantly, atorvastatin or the geranylgeranyltransferase I inhibitor GGTI-298 inhibited breast cancer cell proliferation through inactivation of YAP signaling and down-regulation of PBK. These findings have defined a new signaling pathway that regulated expression of PBK and identified PBK as a downstream target of the Hippo-YAP signaling, uncoverd a mechanism underlying the anti-cancer effect by inhibition of mevalonate pathway and geranylgeranylation, and provided a potential target for breast cancer targeted therapy.

8.
Mol Cancer ; 13: 248, 2014 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-25395181

RESUMO

BACKGROUND: Gastric cardia adenocarcinoma (GCA) is the most aggressive subtype of gastric carcinoma. New molecular markers and therapeutic targets are needed for diagnosis, prognosis and treatment of GCA. This study is to establish the E3 ubiquitin ligase Nedd4-1 as a prognostic biomarker to predict the survival and guide the treatment of GCA patients. METHODS: Expression of Nedd4-1 in 214 GCA tumor samples was detected by immunohistochemistry staining (IHC) using tissue microarray assay (TMA). Association of Nedd4-1 with cumulative survival of the TNM stages I-III patients and clinicopathological characteristics was statistically analyzed. The role of Nedd4-1 in gastric cancer cell migration and invasion were determined by transwell and wound healing assays. RESULTS: Nedd4-1 is overexpressed in 83% of the GCA tumors. The 5-year survival rate in Nedd4-1 negative GCA patients is as high as 96%. Log-rank analysis indicated that overexpression of Nedd4-1 is inversely correlated with cumulative survival (χ(2) = 21.885, p <0.001). Multivariate logistic regression analysis showed that overexpression of Nedd4-1 is associated with an extremely low GCA survival rate with a hazard ratio (HR) = 0.068 (p = 0.008) in TNM stages I-III patients. Statistical analysis of association of Nedd4-1 overexpression with clinicopathological characteristics revealed that overexpression of Nedd4-1 is tightly associated with TNM stage (p < 0.001). Knockdown of Nedd4-1 in gastric cancer cell lines AGS and N87 dramatically inhibited the gastric cancer cell migration and invasion. CONCLUSIONS: Our results indicate that Nedd4-1 is an exceptional prognostic biomarker for GCA and suggest that Nedd4-1 may play an essential role in GCA metastasis.


Assuntos
Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Metástase Neoplásica/genética , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética , Ubiquitina-Proteína Ligases/genética , Adenocarcinoma/patologia , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Células HEK293 , Humanos , Masculino , Pessoa de Meia-Idade , Ubiquitina-Proteína Ligases Nedd4 , Metástase Neoplásica/patologia , Estadiamento de Neoplasias/métodos , Prognóstico , Neoplasias Gástricas/patologia , Taxa de Sobrevida
9.
World J Diabetes ; 15(3): 475-487, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38591085

RESUMO

BACKGROUND: Dietary fiber (DF) intake may have a protective effect against type 2 diabetes (T2D); however, its relationship with diabetic kidney disease (DKD) remains unclear. AIM: To investigate the potential association between DF intake and the prevalence of DKD in individuals diagnosed with T2D. METHODS: This cross-sectional study used data from the National Health and Nutrition Examination Survey collected between 2005 and 2018. DF intake was assessed through 24-h dietary recall interviews, and DKD diagnosis in individuals with T2D was based on predefined criteria, including albuminuria, impaired glomerular filtration rate, or a combination of both. Logistic regression analysis was used to assess the association between DF intake and DKD, and comprehensive subgroup and sensitivity analyses were performed. RESULTS: Among the 6032 participants, 38.4% had DKD. With lower DF intake-T1 (≤ 6.4 g/1000 kcal/day)-as a reference, the adjusted odds ratio for DF and DKD for levels T2 (6.5-10.0 g/1000 kcal/day) and T3 (≥ 10.1 g/1000 kcal/day) were 0.97 (95%CI: 0.84-1.12, P = 0.674) and 0.79 (95%CI: 0.68-0.92, P = 0.002), respectively. The subgroup analysis yielded consistent results across various demographic and health-related subgroups, with no statistically significant interactions (all P > 0.05). CONCLUSION: In United States adults with T2D, increased DF intake may be related to reduced DKD incidence. Further research is required to confirm these findings.

10.
Biomedicines ; 11(2)2023 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-36831013

RESUMO

Colorectal cancer (CRC) is estimated to rank as the second reason for cancer-related deaths, and the prognosis of CRC patients remains unsatisfactory. Numerous studies on gastrointestinal cell biology have shown that the E3 ligase-mediated ubiquitination exerts key functions in the pathogenesis of CRC. The homologous to E6-associated protein C-terminus (HECT) family E3 ligases are a major group of E3 enzymes, featured with the presence of a catalytic HECT domain, which participate in multiple cellular processes; thus, alterations in HECT E3 ligases in function or expression are closely related to the occurrence and development of many human malignancies, including-but not limited to-CRC. In this review, we summarize the potential role of HECT E3 ligases in colorectal carcinogenesis and the related underlying molecular mechanism to expand our understanding of their pathological functions. Exploiting specific inhibitors targeting HECT E3 ligases could be a potential therapeutic strategy for CRC therapy in the future.

11.
Pathol Oncol Res ; 29: 1610931, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36825281

RESUMO

Gastric cancer (GC) is one of the most pernicious gastrointestinal tumors with extraordinarily high incidence and mortality. Ubiquitination modification of cellular signaling proteins has been shown to play important roles in GC tumorigenesis, progression, and prognosis. The E3 ubiquitin ligase is the crucial enzyme in the ubiquitination reaction and determines the specificity of ubiquitination substrates, and thus, the cellular effects. The HECT E3 ligases are the second largest E3 ubiquitin ligase family characterized by containing a HECT domain that has E3 ubiquitin ligase activity. The HECT E3 ubiquitin ligases have been found to engage in GC progression. However, whether HECT E3 ligases function as tumor promoters or tumor suppressors in GC remains controversial. In this review, we will focus on recent discoveries about the role of the HECT E3 ubiquitin ligases, especially members of the NEDD4 and other HECT E3 ligase subfamilies, in GC.


Assuntos
Neoplasias Gástricas , Ubiquitina-Proteína Ligases , Humanos , Ubiquitina-Proteína Ligases/genética , Ubiquitinação , Carcinogênese , Ubiquitinas , Ubiquitina-Proteína Ligases Nedd4/química , Ubiquitina-Proteína Ligases Nedd4/genética , Ubiquitina-Proteína Ligases Nedd4/metabolismo
12.
Biochem Pharmacol ; 214: 115641, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37307883

RESUMO

Accumulating evidence has demonstrated that NEDD4 E3 ubiquitin ligase family plays a pivotal oncogenic role in a variety of malignancies via mediating ubiquitin dependent degradation processes. Moreover, aberrant expression of NEDD4 E3 ubiquitin ligases is often indicative of cancer progression and correlated with poor prognosis. In this review, we are going to address association of expression of NEDD4 E3 ubiquitin ligases with cancers, the signaling pathways and the molecular mechanisms by which the NEDD4 E3 ubiquitin ligases regulate oncogenesis and progression, and the therapies targeting the NEDD4 E3 ubiquitin ligases. This review provides the systematic and comprehensive summary of the latest research status of E3 ubiquitin ligases in the NEDD4 subfamily, and proposes that NEDD4 family E3 ubiquitin ligases are promising anti-cancer drug targets, aiming to provide research direction for clinical targeting of NEDD4 E3 ubiquitin ligase therapy.


Assuntos
Complexos Endossomais de Distribuição Requeridos para Transporte , Neoplasias , Humanos , Ubiquitinação , Ubiquitina-Proteína Ligases Nedd4/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Neoplasias/tratamento farmacológico , Ubiquitina/metabolismo
13.
Front Endocrinol (Lausanne) ; 14: 1089527, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36875494

RESUMO

SET domain-containing 5 (SETD5) is an uncharacterized member of the protein lysine methyltransferase family and is best known for its transcription machinery by methylating histone H3 on lysine 36 (H3K36). These well-characterized functions of SETD5 are transcription regulation, euchromatin formation, and RNA elongation and splicing. SETD5 is frequently mutated and hyperactive in both human neurodevelopmental disorders and cancer, and could be down-regulated by degradation through the ubiquitin-proteasome pathway, but the biochemical mechanisms underlying such dysregulation are rarely understood. Herein, we provide an update on the particularities of SETD5 enzymatic activity and substrate specificity concerning its biological importance, as well as its molecular and cellular impact on normal physiology and disease, with potential therapeutic options.


Assuntos
Metiltransferases , Transtornos do Neurodesenvolvimento , Humanos , Histonas , Lisina , Metiltransferases/química , Metiltransferases/genética
14.
Curr Oncol ; 29(10): 6922-6932, 2022 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-36290821

RESUMO

SCYL1 is a pseudokinase and plays roles in cell division and gene transcription, nuclear/cytoplasmic shuttling of tRNA, protein glycosylation, and Golgi morphology. However, the role of SCYL1 in human breast cancer progression remains largely unknown. In this study, we determined expression of SCYL1 in breast cancer by searching the Cancer Genome Atlas (TCGA) and Tumor Immunoassay Resource (TIMER) databases. Meanwhile, we collected breast tumor tissue samples from 247 cases and detected expression of SCYL1 in the tumors using the tissue microarray assay (TMA). Association of SCYL1 with prognosis of breast cancer was determined based on the PrognoScan database. The results have shown that SCYL1 is overexpressed in breast cancer, and the expression of SCYL1 is associated with poor clinical outcomes of breast cancer patients. Furthermore, knockdown of SCYL1 by shRNAs significantly inhibited the proliferation and migration of breast cancer cells. Taken together, our data suggest that SCYL1 is a biomarker for poor prognosis of breast cancer, has a promoting role in breast cancer progression, and is a potential target for breast cancer therapy.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/genética , Prognóstico , RNA de Transferência , Proteínas de Ligação a DNA , Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/metabolismo
15.
Cancers (Basel) ; 15(1)2022 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-36612163

RESUMO

CXC chemokines are small chemotactic and secreted cytokines. Studies have shown that CXC chemokines are dysregulated in multiple types of cancer and are closely correlated with tumor progression. The CXC chemokine family has a dual function in tumor development, either tumor-promoting or tumor-suppressive depending on the context of cellular signaling. Recent evidence highlights the pro-tumorigenic properties of CXC chemokines in most human cancers. CXC chemokines were found to play pivotal roles in promoting angiogenesis, stimulating inflammatory responses, and facilitating tumor metastases. Enhanced expression of CXC chemokines is always signatured with inferior survival and prognosis. The levels of CXC chemokines in cancer patients are in dynamic change according to the tumor contexts (e.g., chemotherapy resistance and tumor recurrence after surgery). Thus, CXC chemokines have great potential to be used as diagnostic and prognostic biomarkers and therapeutic targets. Currently, the molecular mechanisms underlying the effect of CXC chemokines on tumor inflammation and metastasis remain unclear and application of antagonists and neutralizing antibodies of CXC chemokines signaling for cancer therapy is still not fully established. This article will review the roles of CXC chemokines in promoting tumorigenesis and progression and address the future research directions of CXC chemokines for cancer treatment.

16.
Am J Cancer Res ; 12(3): 1143-1155, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35411228

RESUMO

Geranylgeranylation signaling plays an important role in cancer cell proliferation. Our previous studies have shown that the YAP is one of the geranylgeranylation signal transducers in breast cancer cells (Mi W, et al., Oncogene. 2015; 34(24): 3095-3106). However, the downstream effectors that mediate the promoting effect of the geranylgeranylation/YAP signal axis on breast cancer cell proliferation remain elusive. In this report, we investigated the pathway that mediates the effect of the geranylgeranylation on breast cancer cell proliferation. The results have shown that inhibition of geranylgeranyl biosynthesis inactivates transcription of a set of kinetochore/centromere genes. Further biochemical and cell biological studies demonstrated that inhibition of geranylgeranyl biosynthesis significantly reduced the level of key kinetochore/centromere proteins, thus caused a defect in mitosis. Knockdown of YAP caused similar inhibitory effects on the kinetochore/centromere gene expression and mitosis to that of inhibition of geranylgeranyl biosynthesis. Furthermore, we found that E2F1, the gene coding for E2F1 that is known to activate expression of cell cycle genes, is a target gene of YAP. Knockdown of E2F1 also reduced expression of the kinetochore/centromere genes, suggesting that the activation effect of YAP on expression of the kinetochore/centromere genes may be mediated by E2F1. Our studies have proposed a novel geranylgeranylation-dependent cancer cell proliferation signaling pathway in which geranylgeranylation signaling promotes cancer cell mitosis via the YAP-activated transcription of kinetochore/centromere genes.

17.
Am J Cancer Res ; 12(11): 5074-5084, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36504910

RESUMO

E26 transcription factor-1 (ETS1) is involved in extracellular matrix remodeling, migratory infiltration and angiogenesis in tumors and known to play an important role in tumor progression. However, the mechanism by which ETS1 promotes tumor progression remains elusive. In this report, we show that ETS1 is highly expressed in breast tumor tissues and specifically associated with the tumor metastasis and poor survival in triple negative breast cancer (TNBC) tumors, upon analysis by immunohistochemical (IHC) staining of tumor samples from 240 breast cancer cases. Depletion of ETS1 in TNBC cells by shETS1 significantly inhibited the cell proliferation and migration. Mechanistically, knockdown of ETS1 in TNBC cells dramatically reduced expression of YAP and the YAP target genes, and overexpression of YAP in the ETS1 knockdown cells restored the cell proliferation and migration. These data indicate that YAP is a downstream effector mediating the ETS1-promoted TNBC cell proliferation and migration. Taken together, our results suggest that ETS1 promotes TNBC progression through the YAP signaling.

18.
Oncol Lett ; 22(3): 638, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34386060

RESUMO

Autophagy serves an important role in cancer cell survival and drug resistance. In the present study, the prostate cancer DU145 cell line was used, which lacks autophagy related 5 (ATG5) expression and is defective in induction of ATG5-dependent autophagy. The aim of the study was to examine the effects of the restoration of autophagy on cell proliferation and migration, and to assess the cytotoxicity caused by chemotherapeutic drugs, using microscopic, wound-healing, western blot and apoptotic assays. The restoration of the autophagic activity in DU145 cells by the overexpression of ATG5 enhanced the cell proliferation and migration rates. Notably, restoration of the ATG5-dependent autophagy in DU145 cells significantly increased the cytotoxic effects of the chemotherapeutic drugs, docetaxel and valproic acid, and the endoplasmic reticulum stress inducers, brefeldin A, tunicamycin and thapsigargin. The present study provides a novel perspective on the role of ATG5-dependent autophagy in drug resistance and chemotherapy.

19.
Life (Basel) ; 11(11)2021 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-34833029

RESUMO

Our previous studies have shown that the HECT E3 ubiquitin ligase NEDD4 and kinase MEKK5 both play an essential role in lung cancer migration. A report predicts that MEKK5 may be ubiquitinated by NEDD4; however, interaction of MEKK5 with NEDD4 and ubiquitination of MEKK5 by NEDD4 have not been characterized. In this report, we show that NEDD4 interacts with MEKK5 through a conserved WW3 domain by the co-immunoprecipitation and the GST-pulldown assays. The ubiquitination assay indicates that MEKK5 is not a ubiquitination substrate of NEDD4, but negatively regulates NEDD4-mediated ubiquitination. Furthermore, overexpression of MEKK5 significantly reduced the NEDD4-promoted lung cancer cell migration. Taken together, our studies have defined an inhibitory role of MEKK5 in regulation of NEDD4-mediated ubiquitination.

20.
Oncol Lett ; 21(2): 102, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33376535

RESUMO

Lysine-specific demethylase 1 (LSD1) is a nuclear protein and the first histone demethylase to be identified. LSD1 is an evolutionarily conserved member of the FAD-dependent amine oxidase family and serves an important role in controlling gene expression. LSD1 has been implicated in the tumorigenesis and progression of several types of human cancer; however, to the best of our knowledge, the expression levels and clinical significance of LSD1 in triple-negative breast cancer (TNBC) and non-triple-negative breast cancer (NTNBC) have not been investigated in detail. Therefore, the present study aimed to compare the expression levels of LSD1 in TNBC and NTNBC to determine the prognostic significance of LSD1 in breast cancer. Previous studies have suggested that LSD1 may be involved in the carcinogenesis and progression of breast cancer; however, the findings of the present study indicated that LSD1 may not be a suitable molecular treatment target and auxiliary diagnostic indicator for TNBC and NTNBC.

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