@article {226, title = {Elevated expression of UBE2T exhibits oncogenic properties in human prostate cancer.}, journal = {Oncotarget}, volume = {6}, year = {2015}, month = {2015 Sep 22}, pages = {25226-39}, abstract = {

Increased expression of ubiquitin-conjugating enzyme E2T (UBE2T) is reported in human prostate cancer. However, whether UBE2T plays any functional role in prostate cancer development remains unknown. We here report the first functional characterization of UBE2T in prostate carcinogenesis. Prostate cancer tissue array analysis confirmed upregulation of UBE2T in prostate cancer, especially these with distant metastasis. Moreover, higher level of UBE2T expression is associated with poorer prognosis of prostate cancer patients. Ectopic expression of UBE2T significantly promotes prostate cancer cell proliferation, motility and invasion, while UBE2T depletion by shRNA significantly inhibits these abilities of prostate cancer cells. Xenograft mouse model studies showed that overexpression of UBE2T promotes whereas UBE2T depletion inhibits tumor formation and metastasis significantly. Collectively, we identify critical roles of UBE2T in prostate cancer development and progression. These findings may serve as a framework for future investigations designed to more comprehensive determination of UBE2T as a potential therapeutic target.

}, keywords = {Cell Line, Tumor, Cell Movement, Cell Proliferation, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Heterografts, Humans, Kaplan-Meier Estimate, Male, Neoplasm Invasiveness, Neoplasm Transplantation, Prognosis, Prostatic Neoplasms, RNA Interference, Signal Transduction, Time Factors, Transfection, Ubiquitin-Conjugating Enzymes, Up-Regulation}, issn = {1949-2553}, doi = {10.18632/oncotarget.4712}, author = {Wen, Mingxin and Kwon, Yongwon and Wang, Yongsheng and Jiang-Hua Mao and Wei, Guangwei} } @article {224, title = {FBXW7 negatively regulates ENO1 expression and function in colorectal cancer.}, journal = {Lab Invest}, volume = {95}, year = {2015}, month = {2015 Sep}, pages = {995-1004}, abstract = {

FBXW7 (F-box and WD40 domain protein 7) is a tumor suppressor frequently inactivated in human cancers. The precise molecular mechanisms by which FBXW7 exerts antitumor activity remain under intensive investigation and are thought to relate in part to FBXW7-mediated destruction of key cancer-relevant proteins. Enolase 1 (ENO1) possesses oncogenic activity and is often overexpressed in various human cancers, besides its critical role in glycolysis. However, the detailed regulatory mechanisms of ENO1 expression remain unclear. Here we show that the elevated expression of ENO1 was identified in FBXW7-depletion HCT116 cells through two-dimensional protein electrophoresis and mass spectrometry assays (2DE-MS). Subsequent western blotting and immunohistochemical assays confirmed that ENO1 expression reversely correlates with FBXW7 expression in several cells and colon cancer tissues. Furthermore, we show that FBXW7 physically binds to ENO1 and targets ENO1 for ubiquitin-mediated degradation. Functionally, we found that FBXW7 suppresses the ENO1-induced gene expression, lactate production, cell proliferation and migration. These findings suggest that ENO1 is a novel substrate of FBXW7, and its activity can be negatively regulated by FBXW7 at the posttranslational level. Our work provides a novel molecular insight into FBXW7-directed tumor suppression through regulation of ENO1.

}, keywords = {Biomarkers, Tumor, Blotting, Western, Cell Cycle Proteins, Colorectal Neoplasms, DNA Primers, DNA-Binding Proteins, Electrophoresis, Gel, Two-Dimensional, F-Box Proteins, Gene Expression Regulation, Neoplastic, HCT116 Cells, Humans, Immunohistochemistry, Mass Spectrometry, Phosphopyruvate Hydratase, Real-Time Polymerase Chain Reaction, Regression Analysis, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases}, issn = {1530-0307}, doi = {10.1038/labinvest.2015.71}, author = {Zhan, Panpan and Wang, Yuli and Zhao, Shihu and Liu, Chunyan and Wang, Yunshan and Wen, Mingxin and Jiang-Hua Mao and Wei, Guangwei and Zhang, Pengju} } @article {206, title = {CUL4A induces epithelial-mesenchymal transition and promotes cancer metastasis by regulating ZEB1 expression.}, journal = {Cancer Res}, volume = {74}, year = {2014}, month = {2014 Jan 15}, pages = {520-31}, abstract = {

The ubiquitin ligase CUL4A has been implicated in tumorigenesis, but its contributions to progression and metastasis have not been evaluated. Here, we show that CUL4A is elevated in breast cancer as well as in ovarian, gastric, and colorectal tumors in which its expression level correlates positively with distant metastasis. CUL4A overexpression in normal or malignant human mammary epithelial cells increased their neoplastic properties in vitro and in vivo, markedly increasing epithelial-mesenchymal transition (EMT) and the metastatic capacity of malignant cells. In contrast, silencing CUL4A in aggressive breast cancer cells inhibited these processes. Mechanistically, we found that CUL4A modulated histone H3K4me3 at the promoter of the EMT regulatory gene ZEB1 in a manner associated with its transcription. ZEB1 silencing blocked CUL4A-driven proliferation, EMT, tumorigenesis, and metastasis. Furthermore, in human breast cancers, ZEB1 expression correlated positively with CUL4A expression and distant metastasis. Taken together, our findings reveal a pivotal role of CUL4A in regulating the metastatic behavior of breast cancer cells.

}, keywords = {Animals, Breast, Breast Neoplasms, Cell Line, Tumor, Cell Proliferation, Cullin Proteins, Epithelial-Mesenchymal Transition, Female, Gene Expression Regulation, Neoplastic, Histones, Homeodomain Proteins, Humans, Kruppel-Like Transcription Factors, Mammary Neoplasms, Experimental, Mice, Mice, Nude, Neoplasm Metastasis, Neoplasm Transplantation, Promoter Regions, Genetic, Signal Transduction, Transcription Factors}, issn = {1538-7445}, doi = {10.1158/0008-5472.CAN-13-2182}, author = {Wang, Yunshan and Wen, Mingxin and Kwon, Yongwon and Xu, Yangyang and Liu, Yueyong and Zhang, Pengju and He, Xiuquan and Wang, Qin and Huang, Yurong and Jen, Kuang-Yu and LaBarge, Mark A and You, Liang and Kogan, Scott C and Gray, Joe W and Jiang-Hua Mao and Wei, Guangwei} } @article {211, title = {CUL4A overexpression enhances lung tumor growth and sensitizes lung cancer cells to erlotinib via transcriptional regulation of EGFR.}, journal = {Mol Cancer}, volume = {13}, year = {2014}, month = {2014}, pages = {252}, abstract = {

BACKGROUND: CUL4A has been proposed as oncogene in several types of human cancer, but its clinical significance and functional role in human non-small cell lung cancer (NSCLC) remain unclear.

METHODS: Expression level of CUL4A was examined by RT-PCR and Western blot. Forced expression of CUL4A was mediated by retroviruses, and CUL4A silencing by shRNAs expressing lentiviruses. Growth capacity of lung cancer cells was measured by MTT in vitro and tumorigenesis in vivo, respectively.

RESULTS: We found that CUL4A was highly expressed in human lung cancer tissues and lung cancer cell lines, and this elevated expression positively correlated with disease progression and prognosis. Overexpression of CUL4A in human lung cancer cell lines increased cell proliferation, inhibited apoptosis, and subsequently conferred resistance to chemotherapy. On other hand, silencing CUL4A expression in NSCLC cells reduced proliferation, promoted apoptosis and resulted in tumor growth inhibition in cancer xenograft model. Mechanistically, we revealed CUL4A regulated EGFR transcriptional expression and activation, and subsequently activated AKT. Targeted inhibition of EGFR activity blocked these CUL4A induced oncogenic activities.

CONCLUSIONS: Our results highlight the significance of CUL4A in NSCLC and suggest that CUL4A could be a promising therapy target and a potential biomarker for prognosis and EGFR target therapy in NSCLC patients.

}, keywords = {Apoptosis, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Cell Proliferation, Cullin Proteins, Erlotinib Hydrochloride, Female, Humans, Lung Neoplasms, Male, Middle Aged, Protein Kinase Inhibitors, Quinazolines, Receptor, Epidermal Growth Factor, Transcription, Genetic}, issn = {1476-4598}, doi = {10.1186/1476-4598-13-252}, author = {Wang, Yunshan and Zhang, Pengju and Liu, Ziming and Wang, Qin and Wen, Mingxin and Wang, Yuli and Yuan, Hongtu and Jiang-Hua Mao and Wei, Guangwei} } @article {202, title = {C2ORF40 suppresses breast cancer cell proliferation and invasion through modulating expression of M phase cell cycle genes.}, journal = {Epigenetics}, volume = {8}, year = {2013}, month = {2013 Jun}, pages = {571-83}, abstract = {

Recently, it has been suggested that C2ORF40 is a candidate tumor suppressor gene in breast cancer. However, the mechanism for reduced expression of C2ORF40 and its functional role in breast cancers remain unclear. Here we show that C2ORF40 is frequently silenced in human primary breast cancers and cell lines through promoter hypermethylation. C2ORF40 mRNA level is significantly associated with patient disease-free survival and distant cancer metastasis. Overexpression of C2ORF4 0 inhibits breast cancer cell proliferation, migration and invasion. By contrast, silencing C2ORF40 expression promotes these biological phenotypes. Bioinformatics and FACS analysis reveal C2ORF40 functions at G2/M phase by downregulation of mitotic genes expression, including UBE2C. Our results suggest that C2ORF40 acts as a tumor suppressor gene in breast cancer pathogenesis and progression and is a candidate prognostic marker for this disease.

}, keywords = {Breast Neoplasms, Cell Line, Tumor, Cell Proliferation, DNA Methylation, Female, Gene Expression Regulation, Neoplastic, Genes, cdc, Genes, Tumor Suppressor, Humans, Mitosis, Neoplasm Invasiveness, Neoplasm Proteins, Prognosis}, issn = {1559-2308}, doi = {10.4161/epi.24626}, author = {Lu, Jing and Wen, Mingxin and Huang, Yurong and He, Xiuquan and Wang, Yunshan and Wu, Qi and Li, Zengchun and Castellanos-Mart{\'\i}n, Andr{\'e}s and Abad, Mar and Cruz-Hernandez, Juan J and Rodriguez, Cesar A and Perez-Losada, Jesus and Jiang-Hua Mao and Wei, Guangwei} } @article {205, title = {FAM83D promotes cell proliferation and motility by downregulating tumor suppressor gene FBXW7.}, journal = {Oncotarget}, volume = {4}, year = {2013}, month = {2013 Dec}, pages = {2476-86}, abstract = {

Amplification of chromosome 20q is frequently found in various types of human cancers, including breast cancer. The list of candidate oncogenes in 20q has expanded over the past decade. Here, we investigate whether FAM83D (family with sequence similarity 83, member D) on chromosome 20q plays any role in breast cancer development. The expression level of FAM83D is significantly elevated in breast cancer cell lines and primary human breast cancers. High expression levels of FAM83D are significantly associated with poor clinical outcome and distant metastasis in breast cancer patients. We show that ectopic expression of FAM83D in human mammary epithelial cells promotes cell proliferation, migration and invasion along with epithelial-mesenchymal transition (EMT). Ablation of FAM83D in breast cancer cells induces apoptosis and consequently inhibits cell proliferation and colony formation. Mechanistic studies reveal that overexpression of FAM83D downregulates FBXW7 expression levels through a physical interaction, which results in elevated protein levels of oncogenic substrates downstream to FBXW7, such as mTOR, whose inhibition by rapamycin can suppress FAM83D-induced cell migration and invasion. The results demonstrate that FAM83D has prognostic value for breast cancer patients and is a novel oncogene in breast cancer development that at least in part acts through mTOR hyper-activation by inhibiting FBXW7.

}, keywords = {Apoptosis, Breast Neoplasms, Cell Cycle Proteins, Cell Growth Processes, Cell Line, Tumor, Chromosomal Proteins, Non-Histone, Down-Regulation, Epithelial-Mesenchymal Transition, F-Box Proteins, Genes, Tumor Suppressor, Humans, Microtubule-Associated Proteins, Prognosis, Transfection, Ubiquitin-Protein Ligases}, issn = {1949-2553}, doi = {10.18632/oncotarget.1581}, author = {Wang, Zeran and Liu, Yueyong and Zhang, Pengju and Zhang, Weiguo and Wang, Weijing and Curr, Kenneth and Wei, Guangwei and Jiang-Hua Mao} } @article {201, title = {Rapamycin inhibits FBXW7 loss-induced epithelial-mesenchymal transition and cancer stem cell-like characteristics in colorectal cancer cells.}, journal = {Biochem Biophys Res Commun}, volume = {434}, year = {2013}, month = {2013 May 3}, pages = {352-6}, abstract = {

Increased cell migration and invasion lead to cancer metastasis and are crucial to cancer prognosis. In this study, we explore whether FBXW7 plays any role in metastatic process. We show that depletion of FBXW7 induces epithelial-mesenchymal transition (EMT) in human colon cancer cells along with the increase in cell migration and invasion. Moreover, FBXW7 deficiency promotes the generation of colon cancer stem-like cells in tumor-sphere culture. mTOR inhibition by rapamycin suppresses FBXW7 loss-driven EMT, invasion and stemness. Our results define the FBXW7/mTOR axis as a novel EMT pathway that mediates cancer invasion.

}, keywords = {Blotting, Western, Cell Cycle Proteins, Cell Movement, Cell Shape, Colorectal Neoplasms, Epithelial-Mesenchymal Transition, F-Box Proteins, Gene Expression Regulation, Neoplastic, HCT116 Cells, Humans, Neoplasm Invasiveness, Neoplastic Stem Cells, Sirolimus, TOR Serine-Threonine Kinases, Ubiquitin-Protein Ligases}, issn = {1090-2104}, doi = {10.1016/j.bbrc.2013.03.077}, author = {Wang, Yuli and Liu, Yueyong and Lu, Jing and Zhang, Pengju and Wang, Yunshan and Xu, Yangyang and Wang, Zeran and Jiang-Hua Mao and Wei, Guangwei} } @article {196, title = {Temporal mTOR inhibition protects Fbxw7-deficient mice from radiation-induced tumor development.}, journal = {Aging (Albany NY)}, volume = {5}, year = {2013}, month = {2013 Feb}, pages = {111-9}, abstract = {

FBXW7 acts as a tumor suppressor in numerous types of human cancers through ubiquitination of different oncoproteins including mTOR. However, how the mutation/loss of Fbxw7 results in tumor development remains largely unknown. Here we report that downregulation of mTOR by radiation is Fbxw7-dependent, and short-term mTOR inhibition by rapamycin after exposure to radiation significantly postpones tumor development in Fbxw7/p53 double heterozygous (Fbxw7+/-p53+/-) mice but not in p53 single heterozygous (p53+/-) mice. Tumor latency of rapamycin treated Fbxw7+/-p53+/- mice is remarkably similar to those of p53+/- mice while placebo treatedFbxw7+/-p53+/- mice develop tumor significantly earlier than placebo treated p53+/- mice. Furthermore, we surprisingly find that, although temporal treatment of rapamycin is given at a young age, the inhibition of mTOR activity sustainably remains in tumors. These results indicate that inhibition of mTOR signaling pathway suppresses the contribution of Fbxw7 loss toward tumor development.

}, keywords = {Animals, Cell Transformation, Neoplastic, F-Box Proteins, Genes, Tumor Suppressor, Mice, Mutation, Neoplasms, Radiation-Induced, Signal Transduction, Sirolimus, TOR Serine-Threonine Kinases, Ubiquitin-Protein Ligases}, issn = {1945-4589}, doi = {10.18632/aging.100535}, author = {Liu, Yueyong and Huang, Yurong and Wang, Zeran and Huang, Yong and Li, Xiaohua and Louie, Alexander and Wei, Guangwei and Jiang-Hua Mao} } @article {189, title = {Evaluating the prognostic significance of FBXW7 expression level in human breast cancer by a meta-analysis of transcriptional profiles.}, journal = {J Cancer Sci Ther}, volume = {4}, year = {2012}, month = {2012 Aug 31}, pages = {299-305}, abstract = {

The tumor suppressor gene FBXW7 is mutated in numerous types of human cancers leading to loss of its function and/or expression. However the clinic significance of FBXW7 alterations remains largely unknown. Here, we carried out a meta-analysis of 10 gene expression microarray studies for a total 1900 patients of breast cancer with clinic information to evaluate the prognostic impact of FBXW7 mRNA expression. The FBXW7 mRNA levels significantly reduced in breast cancer compared to normal tissues. In addition, significant difference in the FBXW7 mRNA levels was found among molecular subtypes (normal-like, luminal A, luminal B, ERBB2 and basal). ERBB2 and basal tumors had significantly lower average FBXW7 mRNA level than normal-like tumors, whereas luminal A and B tumors have the lowest average FBXW7 mRNA level. The patients with higher FBXW7 mRNA level significantly increased disease-free survival, particularly in the group of patients with ER negative and basal subtype tumors. Moreover, higher FBXW7 mRNA level also significantly increased overall survival in the patients with ER negative tumors. But we strikingly found opposite effect of FBXW7 expression on overall survival in different subtypes. The patients with higher FBXW7 mRNA level significantly decreased overall survival in normal-like subtype while the patients with higher FBXW7 mRNA level significantly increased overall survival in ERBB2 and Basal subtype. Taken together, our results suggest that FBXW7 mRNA levels were a prognostic factor for disease-free and overall survival according to ER status and molecular subtypes.

}, issn = {1948-5956}, doi = {10.4172/1948-5956.1000158}, author = {Wei, Guangwei and Wang, Yunshan and Zhang, Pengju and Lu, Jing and Jiang-Hua Mao} } @article {188, title = {Pten regulates Aurora-A and cooperates with Fbxw7 in modulating radiation-induced tumor development.}, journal = {Mol Cancer Res}, volume = {10}, year = {2012}, month = {2012 Jun}, pages = {834-44}, abstract = {

The Aurora-A kinase gene is frequently amplified and/or overexpressed in a variety of human cancers, leading to major efforts to develop therapeutic agents targeting this pathway. Here, we show that Aurora-A is targeted for ubiquitination and subsequent degradation by the F-box protein FBXW7 in a process that is regulated by GSK3β. Using a series of truncated Aurora-A proteins and site-directed mutagenesis, we identified distinct FBXW7 and GSK3β-binding sites in Aurora-A. Mutation of critical residues in either site substantially disrupts degradation of Aurora-A. Furthermore, we show that loss of Pten results in the stabilization of Aurora-A by attenuating FBXW7-dependent degradation of Aurora-A through the AKT/GSK3β pathway. Moreover, radiation-induced tumor latency is significantly shortened in Fbxw7(+/-)Pten(+/-) mice as compared with either Fbxw7(+/-) or Pten(+/-) mice, indicating that Fbxw7 and Pten appear to cooperate in suppressing tumorigenesis. Our results establish a novel posttranslational regulatory network in which the Pten and Fbxw7 pathways appear to converge on the regulation of Aurora-A level.

}, keywords = {Animals, Aurora Kinase A, Aurora Kinases, Binding Sites, Blotting, Western, Cell Line, F-Box Proteins, Female, Gamma Rays, Glycogen Synthase Kinase 3, HCT116 Cells, HEK293 Cells, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutation, Neoplasms, Radiation-Induced, NIH 3T3 Cells, Protein Binding, Protein-Serine-Threonine Kinases, PTEN Phosphohydrolase, Time Factors, Ubiquitin, Ubiquitin-Protein Ligases}, issn = {1557-3125}, doi = {10.1158/1541-7786.MCR-12-0025}, author = {Kwon, Yong-Won and Kim, Il-Jin and Wu, Di and Lu, Jing and Stock, William A and Liu, Yueyong and Huang, Yurong and Kang, Hio Chung and DelRosario, Reyno and Jen, Kuang-Yu and Perez-Losada, Jesus and Wei, Guangwei and Balmain, Allan and Jiang-Hua Mao} } @article {159, title = {HIPK2 represses beta-catenin-mediated transcription, epidermal stem cell expansion, and skin tumorigenesis.}, journal = {Proc Natl Acad Sci U S A}, volume = {104}, year = {2007}, month = {2007 Aug 7}, pages = {13040-5}, abstract = {

Transcriptional control by beta-catenin and lymphoid enhancer-binding factor 1 (LEF1)/T cell factor regulates proliferation in stem cells and tumorigenesis. Here we provide evidence that transcriptional co repressor homeodomain interacting protein kinase 2 (HIPK2) controls the number of stem and progenitor cells in the skin and the susceptibility to develop squamous cell carcinoma. Loss of HIPK2 leads to increased proliferative potential, more rapid G1-S transition in cell cycle, and expansion of the epidermal stem cell compartment. Among the critical regulators of G1-S transition in the cell cycle, only cyclin D1 is selectively up-regulated in cells lacking HIPK2. Conversely, overexpression of HIPK2 suppresses LEF1/beta-catenin-mediated transcriptional activation of cyclin D1 expression. However, deletion of the C-terminal YH domain of HIPK2 completely abolishes its ability to recruit another transcriptional corepressor CtBP and suppress LEF1/beta-catenin-mediated transcription. To determine whether loss of HIPK2 leads to increased susceptibility to tumorigenesis, we treat wild-type, Hipk2+/-, andHipk2-/- mice with the two-stage carcinogenesis protocol. Our results indicate that more skin tumors are induced in Hipk2+/- and Hipk2-/- mutants, with most of the tumors showing shortened incubation time and malignant progression. Together, our results indicate that HIPK2 is a tumor suppressor that controls proliferation by antagonizing LEF1/beta-catenin-mediated transcription. Loss of HIPK2 synergizes with activation of H-ras to induce tumorigenesis.

}, keywords = {Animals, beta Catenin, Carrier Proteins, Cell Proliferation, Cells, Cultured, Cyclin D1, Epidermis, Keratinocytes, Lymphoid Enhancer-Binding Factor 1, Mice, Protein-Serine-Threonine Kinases, Repressor Proteins, Skin Neoplasms, Stem Cells, Transcriptional Activation}, issn = {0027-8424}, doi = {10.1073/pnas.0703213104}, author = {Wei, Guangwei and Ku, Stephen and Ma, Gene K and Saito, Shin{\textquoteright}ichi and Tang, Amy A and Zhang, Jiasheng and Jiang-Hua Mao and Appella, Ettore and Balmain, Allan and Huang, Eric J} }