SUMOylation, as a post-translational modification, plays essential roles in various biological functions including cell growth, migration, cellular responses to stress and tumorigenesis. The imbalance of SUMOylation and deSUMOylation has been associated with the occurrence and progression of various diseases. Herein, we summarize and discuss the signal crosstalk between SUMOylation and ubiquitination of proteins, protein SUMOylation relations with several diseases, and the identification approaches for SUMOylation site. With the continuous development of bioinformatics and mass spectrometry, several accurate and high-throughput methods have been implemented to explore small ubiquitin-like modifier-modified substrates and sites, which is helpful for deciphering protein SUMOylation-mediated molecular mechanisms of disease.

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The STC2 protein involves in carcinogenesis and progression of many cancers. It remains unclear how STC2 regulates the epithelial-mesenchymal transition (EMT) process and colorectal cancer (CRC) development. Here we systematically investigated STC2-activated early occurrence of EMT and CRC cell migration in vitro, clinical associations of STC2 with CRC development and patient survival. The secretion and expression level of STC2 were both greatly increased in EMT cells and CRC cells compared with the normal epithelial NCM460 cells. And the conditioned media from EMT cells stimulated epithelia and colon cancer cells to obtain EMT characteristics. STC2 overexpression promoted CRC cell growth and cell migration in vitro, and STC2 enhanced tumor growth in a mouse CRC-xenograft model. Corresponding to EMT marker expression changes, several critical signaling pathway molecules including pERK, pAKT, PI3K and Ras were remarkably increased either in NCM460 cells transfected with STC2 plasmids or in cells induced with exogenous STC2 protein. However blocking AKT-ERK signaling pathways attenuated STC2-activated EMT process. Furthermore the elevated STC2 expressions were also confirmed in 77 clinical tumor tissues and sera from CRC patients, and the increased STC2 in tumor tissues and sera correlated with tumor pathologic stage and poor survival for CRC patients. In conclusion, STC2 promotes CRC tumorigenesis and EMT progression through activating ERK/MEK and PI3K/AKT signaling pathways. STC2 protein is also a potential tumor biomarker for CRC diagnosis and prognosis.

Esophageal squamous cell carcinoma (ESCC) has a multifactorial etiology involving environmental and/or genetic factors. End-binding protein 1 (EB1), which was cloned as an interacting partner of the adenomatous polyposis coli (APC) tumor suppressor protein, was previously found overexpressed in ESCC. However, the precise role of EB1 in the development of this malignancy has not yet been elucidated. In this study, we analysed freshly resected ESCC specimens and demonstrated that EB1 was overexpressed in approximately 63% of tumor samples compared to matched normal tissue. We report that overexpression of EB1 in the ESCC line EC9706 significantly promotes cell growth, whereas suppression of EB1 protein level by RNA interference significantly inhibited growth of esophageal tumor cells. In addition, EB1 overexpression induced nuclear accumulation of b-catenin and promoted the transcriptional activity of b-catenin/T-cell factor (TCF). These effects were partially or completely abolished by coexpression of APC or DN TCF4, respectively. Also, we found that EB1 affected the interaction between b-catenin and APC. Furthermore, EB1 overexpression was correlated with cytoplasmic/ nuclear accumulation of b-catenin in primary human ESCC. Taken together, these results support the novel hypothesis that EB1 overexpression may play a role in the development of ESCC by affecting APC function and activating the b-catenin/TCF pathway. Oncogene (2005) 24, 6637-6645.

In mammals it is unclear if UHRF1-mediated DNA maintenance methylation by DNMT1 is strictly dependent on histone H3K9 methylation. Here we have generated an Uhrf1 knockin (KI) mouse model that specifically abolishes the H3K9me2/3-binding activity of Uhrf1. The homozygous Uhrf1 KI mice are viable and fertile, and exhibit ∼10% reduction of DNA methylation in various tissues. The reduced DNA methylation occurs globally in the genome and does not restrict only to the H3K9me2/3 enriched repetitive sequences. In vitro UHRF1 binds with higher affinity to reconstituted nucleosome with hemi-methylated CpGs than that with H3K9me2/3, although it binds cooperatively to nucleosome with both modifications. We also show that the nucleosome positioning affects the binding of methylated DNA by UHRF1. Thus, while our study supports a role for H3K9 methylation in promoting DNA methylation, it demonstrates for the first time that DNA maintenance methylation in mammals is largely independent of H3K9 methylation.

Overexpression of human pituitary tumor transforming gene (PTTG) is wildly detected in many tumors, including esophageal cancer. Besides overexpression of PTTG in esophageal squamous cell carcinoma (ESCC) tissues and cells, we detected accumulation of cytoplasmic ␤-catenin in ESCC. In our study, a putative TCF4-binding element (TBE) was identified in PTTG promoter region. The activity of PTTG promoter containing the TBE was activated by S37A␤-catenin and inhibited by dominant-negative TCF. Furthermore, the activation by S37A␤-catenin was mostly abrogated among PTTG promoter region without the TBE or with a mutant one. By using biotin-streptavidin pull-down assay, we also found that the TBE among PTTG promoter bound to TCF-4 protein. Moreover, levels of PTTG mRNA and protein were increased by S37A␤-catenin. Finally, it is noticeable that we detected a correlation between ␤-catenin localization and PTTG expression in 69 primary ESCC (p<0.01). In brief, our study shows that overexpression of PTTG in ESCC is likely due to the activation of ␤-catenin/WNT signaling. The human pituitary tumor transforming gene (PTTG), also termed as human securin, was first obtained from fetal liver and identified as an oncogene. 1 The functional mechanism of PTTG in tumorigenesis is still barely understood, but accumulating evidence reveals that PTTG plays crucial roles in cell-cycle progression, appropriate cell division and chromosome stability, in addition to involvement in malignant transformation and tumorigenesis. 2-5 PTTG inhibits sister chromatid separation and is related to cell-cycle control. PTTG expression appears to be cell cycle dependent, reaches peak in mitosis and can be phosphorylated by Cdc2 kinase during mitosis. 6 PTTG, through direct interaction with MEK1, participates in the signaling cascade and can be phosphorylated by MAP kinase. 7 As a cotranscription factor, PTTG interacts with sequence-specific elements in the c-myc promoter and increases cell proliferation, suggesting that PTTG would mediate cellular transformation by activating this oncogene. 8 Moreover, PTTG's interacting with Ku 9 physically and binding to P53 10 suggest that PTTG may take part in DNA-damage-response pathway, DNA repair and apoptosis. 11,12 PTTG induces expression of b-FGF 1 and VEGF, 13 implying that it may play a role in tumor angiogenesis. The expression of PTTG in most normal tissues is very restricted, contrary to that in a number of human tumor tissues, such as pituitary adenomas, 1,14 lung and breast cancers, 14 colorectal tumor 15 and especially in esophageal cancer. 16 Human esophageal cancer is an aggressive tumor with a generally poor prognosis. Esophageal squamous cell carcinoma (ESCC) is the most common subtype of esophageal cancer and has a higher incidence than esophageal adenocarcinomas (EADC) among Chinese population. Although it is widely believed that esophageal cancer arises from multistep genetic and cytogenetic alterations, 17 the mechanisms have yet to be convincingly identified. Molecular studies have revealed f...

Background and AimHepatocellular carcinoma (HCC) is one of the most deadly tumors. Transarterial chemoembolization (TACE) is effective for unresectable HCC. In recent years, miRNAs have been proposed as novel diagnostic and prognostic tools for HCC. This study aimed to identify whether microRNAs (miRNAs) can serve as biomarkers to reliably predict outcome before HCC patients are treated with TACE.MethodsEleven miRNAs (miR-, miR-19a, miR-101-3p, miR-199a-5p, miR-200a, miR-21, miR-214, miR-221, miR-222, miR-223 and miR-, -5p) were quantified by quantitative real-time PCR (qRT-PCR) in 136 HCC patients’ serum before they received TACE therapy. Univariate and multivariate analysis were used to identify the prognostic value of clinical parameters and miRNAs. Area under the receiver operating characteristic curve (AUC) was used to evaluate the prediction potency.ResultsThe levels of some miRNAs were dramatically associated with clinicopathologic features regarding Child-Puge class, AFP, tumor size and satellite nodules. Univariate analysis revealed that miR-200a, miR-21, miR-122 and miR-224-5p were significantly associated with patients’ survival. Multivariate analysis demonstrated that AFP, satellite nodules and miR-200a were the independent prognostic factors associated with survival in this cohort (p = 0.000, 0.001, 0.000, respectively). The probability of the prognostic accuracy of miR-200a was 81.64% (74.47% specificity and 88.76% sensitivity), which was higher than the classifier established by combination of AFP and satellite nodules (76.87% probability, 70.21% specificity and 69.66% sensitivity). Furthermore, the combination of AFP, satellite nodules and miR-200a demonstrated as a classifier for HCC prognosis, yielding a ROC curve area of 88.19% (93.62% specificity and 68.54% sensitivity).ConclusionsOur study indicated that serum miR-200a may prognosticate disease outcome in HCC patients with TACE therapy. Therefore, miR-200a can potentially guide individualized treatment for HCC patients with a high risk of TACE treatment failures.

Global DNA hypomethylation is a most common epigenetic alteration in cancer, but the mechanism remains elusive. Previous studies demonstrate that UHRF1 but not UHRF2 is required for mediating DNA maintenance methylation by DNMT1. Here we report unexpectedly a conserved function for UHRF1 and UHRF2: inhibiting de novo DNA methylation by functioning as E3 ligases promoting DNMT3A degradation. UHRF1/2 are frequently overexpressed in cancers and we present evidence that UHRF1/2 overexpression downregulates DNMT3A proteins and consequently leads to DNA hypomethylation. Abrogating this negative regulation on DNMT3A or overexpression of DNMT3A leads to increased DNA methylation and impaired tumor growth. We propose a working model that UHRF1/2 safeguards the fidelity of DNA methylation and suggests that UHRF1/2 overexpression is likely a causal factor for widespread DNA hypomethylation in cancer via suppressing DNMT3A.