UbcH10 is overexpressed in malignant breast carcinomas

Berlingieri, Maria Teresa; Pallante, Pierlorenzo; Sboner, Andrea; Barbareschi, Mattia; Bianco, Mimma; Ferraro, Angelo; Mansueto, Gelsomina; Borbone, Eleonora; Guerriero, Eliana; Troncone, Giancarlo; Fusco, Alfredo

doi:10.1016/j.ejca.2007.09.003

Cited by 65 publications

(65 citation statements)

References 14 publications

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“…Our result is in contradiction with Berlingieri et al (2007) who evaluated prognostic informativity of UBE2C and found no relation between this protein and the rates of overall and relapsefree survival. According to the following points, we strongly believe that UBE2C is a prognostic marker of breast cancer.…”

Section: Discussioncontrasting

confidence: 56%

Validation of UBE2C protein as a prognostic marker in node-positive breast cancer

et al. 2009

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BACKGROUND:We recently identified and validated UBE2C RNA as a prognostic marker in 252 node-positive (N þ ) breast cancers by means of a microarray study. The aim of this study was to validate UBE2C protein as a prognostic marker in N þ breast cancer by immunohistochemistry (IHC). METHODS: To this end, 92 paraffin-embedded blocks were used. The impact of UBE2C IHC value on metastasis-free survival (MFS) and overall survival (OS) was evaluated and compared with Ki-67 and Nottingham prognostic index (NPI) performances. RESULTS: In accordance with genomic data, UBE2C IHC had a significant impact both on MFS and OS (hazard ratio ¼ 6.79 -P ¼ 0.002; hazard ratio ¼ 7.14 -P ¼ 0.009, respectively). Akaike information criterion proved that the prognostic power of UBE2C IHC was stronger than that of Ki-67 (and close to that of NPI). Furthermore, multivariate analyses with NPI showed that, contrary to Ki-67 IHC, UBE2C IHC remained an independent factor, both for MFS (adjusted P ¼ 0.02) and OS (adjusted P ¼ 0.04). CONCLUSION: We confirmed that UBE2C protein measured by IHC could be used as a prognostic marker in N þ breast cancer. The potential predictive interest of UBE2C as a marker of proteasome activity needs further investigations.

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Section: Discussioncontrasting

confidence: 56%

Validation of UBE2C protein as a prognostic marker in node-positive breast cancer

et al. 2009

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“…We believe it is more likely that even low levels of UbcH10 support initiation of short chains, which could then be extended by Ube2S. In support of this notion, mutation of UbcH10 in flies or its efficient depletion in several human cell lines lead to cyclin B stabilization and a delay in mitosis (21,23,26,(35)(36)(37), while incomplete depletion of UbcH10 does not produce these phenotypes (38). Consistent with their close cooperation in modifying APC/C substrates, UbcH10 and Ube2S are tightly co-regulated in cells.…”

Section: Discussionsupporting

confidence: 51%

Identification of a physiological E2 module for the human anaphase-promoting complex

Williamson

Wickliffe

Mellone

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Ubiquitination by the anaphase-promoting complex (APC/C) is essential for proliferation in all eukaryotes. The human APC/C promotes the degradation of mitotic regulators by assembling K11-linked ubiquitin chains, the formation of which is initiated by its E2 UbcH10. Here, we identify the conserved Ube2S as a K11-specific chain elongating E2 for human and Drosophila APC/C. Ube2S depends on the cell cycledependent association with the APC/C activators Cdc20 and Cdh1 for its activity. While depletion of Ube2S already inhibits APC/C in cells, the loss of the complete UbcH10/Ube2S-module leads to dramatic stabilization of APC/C substrates, severe spindle defects, and a strong mitotic delay. Ube2S and UbcH10 are tightly co-regulated in the cell cycle by APC/C-dependent degradation. We conclude that UbcH10 and Ube2S constitute a physiological E2-module for APC/C, the activity of which is required for spindle assembly and cell division.K11-linked chain ͉ proteasome ͉ ubiquitin

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“…3,6 Overexpression of UBE2C at the mRNA level has been reported in a number of cancer cell lines and primary tumors, whereas only low levels were found in normal tissues. 7 The oncogenic role of UBE2C is also reported in thyroid, 8 ovarian, 9 esopha-geal, 10 breast, 11 lung, 12 liver, 13 and brain 14 tumors. Takahashi et al 15 suggest that overexpression of UBE2C may play an important role in advanced colon cancer with liver metastases and that this overexpression may be a result of chromosomal amplification at the UBE2C locus, 20q13.1.…”

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confidence: 98%

Bortezomib Stabilizes Mitotic Cyclins and Prevents Cell Cycle Progression via Inhibition of UBE2C in Colorectal Carcinoma

Bavi

Uddin

Ahmed

et al. 2011

The American Journal of Pathology

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Substantial evidence implicates the ubiquitin-conjugating enzyme E2C (UBE2C) gene, in several human cancers, including colorectal carcinoma (CRC). We therefore investigated the prognostic value of UBE2C alterations in CRC and UBE2C signaling in CRC cell lines. UBE2C protein expression and UBE2C gene copy number were evaluated on clinical samples by immunohistochemistry and fluorescence in situ hybridization in a TMA format. The effect of the proteasome inhibitor bortezomib and small-interfering RNA knockdown was assessed by apoptotic assays and immunoblotting. UBE2C dysregulation was associated with proliferative marker Ki-67, accumulation of cyclin A and B1, and a poor overall survival. UBE2C expression was an independent prognostic marker in early-stage (I and II) CRC. UBE2C depletion resulted in suppression of cellular growth and accumulation of cyclin A and B1. In vitro, bortezomib treatment of CRC cells caused inhibition of cell viability via down-regulation of UBE2C. UBE2C knockdown by bortezomib or transfection with specific small-interfering RNA against UBE2C also caused cells to be arrested at the G2/M level, leading to accumulation of cyclin A and cyclin B1. In vivo, a significant reduction in tumor volume and weight was noted in mice treated with a combination of subtoxic doses of oxaliplatin and bortezomib compared with treatment with oxaliplatin or bortezomib alone. Altogether, our results suggest that UBE2C and the ubiq- Although colorectal cancer (CRC) is a major cause of mortality and morbidity worldwide, various therapeutic modalities followed in clinical practice are not life saving. More recently, advances in understanding of tumor biology have led to the development of targeted therapies, 1 allowing progress in the treatment of CRC. 2 The ubiquitin proteasome system is important for the orchestration of several important cell cycle events, such as proteolysis of cyclin-dependent kinase and their inhibitors. 3,4 Proper cell cycle progression is orchestrated by the controlled oscillation of a series of cell cycle events. Deregulation of appropriate cell cycle control often results in chromosomal instability, which is a potential trigger for the initiation of cancer. 5 In this system, substrate molecules are regulated for degradation by ubiquitinactivating enzyme (E1), ubiquitin-conjugating enzyme (E2), and E3 ligase. The ubiquitin-conjugating enzyme E2C (UBE2C), also known as UBCH10, along with the E3 ligase of the anaphase-promoting complex catalyze the ubiquitination of mitotic cyclins A and B1, as well as securin. 3,6 UBE2C is essential for cell cycle progression, and mutation of its active site cysteine confers a dominant-negative phenotype. 3,6 Overexpression of UBE2C at the mRNA level has been reported in a number of cancer cell lines and primary tumors, whereas only low levels were found in normal tissues. 7 The oncogenic role of UBE2C is also reported in thyroid, 8 ovarian, 9 esopha-

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UbcH10 is overexpressed in malignant breast carcinomas

Cited by 65 publications

References 14 publications

Validation of UBE2C protein as a prognostic marker in node-positive breast cancer

Validation of UBE2C protein as a prognostic marker in node-positive breast cancer

Identification of a physiological E2 module for the human anaphase-promoting complex

Bortezomib Stabilizes Mitotic Cyclins and Prevents Cell Cycle Progression via Inhibition of UBE2C in Colorectal Carcinoma

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