Overexpression of UbcH10 alternates the cell cycle profile and accelerate the tumor proliferation in colon cancer

Fujita, Takeo; Ikeda, Hirokuni; Taira, Naruto; Hatoh, Shinji; Naito, Makoto; Doihara, Hiroyoshi

doi:10.1186/1471-2407-9-87

Cited by 64 publications

(76 citation statements)

References 38 publications

(55 reference statements)

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“…Our study demonstrated that siRNA-mediated suppression of UBE2C expression inhibited the growth rate of CRC cells with accumulation of cyclins A and B1, which was consistent with earlier reports. 13,16 Interestingly, we found that down-regulation of UBE2C expression caused inhibition of cell viability by arresting cells in the G2/M phase followed by induction of apoptosis in CRC cells. UBE2C expression in CRC cell lines was found to be inversely associated with cyclin A and B1 in concordance with the mechanistic model of UBE2C function.…”

Section: Discussionmentioning

confidence: 87%

“…This is in agreement with earlier studies in which UBE2C expression was significantly higher in a wide variety of cancer from colon, esophagus, ovary, breast, and lung compared with their healthy counterparts. 12, 16 Lin et al 10 demonstrated a higher expression of UBE2C at the protein and mRNA levels in esophageal carcinoma and dysplastic lesions compared with metaplastic lesions. In concordance with earlier studies, UBE2C gene amplification was associated with distant metastasis (pM1), 15 and UBE2C alteration was significantly associated with Ki-67 (a proliferative marker), accumulation of cyclin A and B1, and a poor overall survival.…”

Section: Discussionmentioning

confidence: 98%

“…In concordance with earlier studies, UBE2C gene amplification was associated with distant metastasis (pM1), 15 and UBE2C alteration was significantly associated with Ki-67 (a proliferative marker), accumulation of cyclin A and B1, and a poor overall survival. 16 UBE2C expression was associated with a poor overall survival in all CRC patients, and, interestingly, in We performed various in vitro and in vivo assays to demonstrate the oncogenic role of UBE2C and the effect of modulating UBE2C expression by gene silencing and with the proteasome inhibitor bortezomib. The function of the UBE2C gene product is closely linked to cell cycle progression and the destruction of mitotic cyclins.…”

Section: Discussionmentioning

confidence: 99%

“…In a recent study 16 using CRC cell lines, depletion of UBE2C resulted in suppression of cellular growth, whereas overexpression of UBE2C promoted cell proliferation and oncogenic cellular growth. Although no specific UBE2C inhibitors are currently available for clinical use, proteasome inhibitors form a novel class of chemotherapeutic agents that lead to cell cycle arrest and cell death.…”

mentioning

confidence: 97%

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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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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 97%

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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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“…Therefore, regulation of UbcH10 expression might also be an essential step for proper function of the checkpoint. Indeed, UbcH10 expression is found to be up-regulated in a number of cancer tissues of different origins, and this up-regulation is related with poor prognosis in some cancer types (21)(22)(23)(24)(25). The UBCH10 gene encoding locus 20q13.1 is also reported to be amplified in several tumors (26).…”

mentioning

confidence: 99%

Spindle Assembly Checkpoint Protein Cdc20 Transcriptionally Activates Expression of Ubiquitin Carrier Protein UbcH10

Nath¹,

Banerjee²,

Sen

et al. 2011

Journal of Biological Chemistry

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The spindle assembly checkpoint (SAC) ensures accurate segregation of chromosomes by monitoring kinetochore attachment of spindles during mitosis. Proper progression of mitosis depends on orderly ubiquitination and subsequent degradation of various mitotic inhibitors. At the molecular level, upon removal of SAC, Cdc20 activates E3 ubiquitin ligase anaphasepromoting complex/cyclosome that, along with E2 ubiquitinconjugating enzyme UbcH10, executes this function. Both Cdc20 and UbcH10 are overexpressed in many cancer types and are associated with defective SAC function leading to chromosomal instability. The precise mechanism of correlated overexpression of these two proteins remains elusive. We show that Cdc20 transcriptionally up-regulates UbcH10 expression. The WD40 domain of Cdc20 is required for this activity. Physical interaction between Cdc20 and anaphase-promoting complex/ cyclosome-CBP/p300 complex and its subsequent recruitment to the UBCH10 promoter are involved in this transactivation process. This transcriptional regulatory function of Cdc20 was observed to be cell cycle-specific. We hypothesize that this coregulated overexpression of both proteins contributes to chromosomal instability.

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Modulation of the ubiquitin‐proteasome system by phytochemicals: Therapeutic implications in malignancies with an emphasis on brain tumors

et al. 2023

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Regarding the multimechanistic nature of cancers, current chemo‐ or radiotherapies often fail to eradicate disease pathology, and frequent relapses or resistance to therapies occur. Brain malignancies, particularly glioblastomas, are difficult‐to‐treat cancers due to their highly malignant and multidimensional biology. Unfortunately, patients suffering from malignant tumors often experience poor prognoses and short survival periods. Thus far, significant efforts have been conducted to discover novel and more effective modalities. To that end, modulation of the ubiquitin‐proteasome system (UPS) has attracted tremendous interest since it affects the homeostasis of proteins critically engaged in various cell functions, for example, cell metabolism, survival, proliferation, and differentiation. With their safe and multimodal actions, phytochemicals are among the promising therapeutic tools capable of turning the operation of various UPS elements. The present review, along with an updated outline of the role of UPS dysregulation in multiple cancers, provided a detailed discussion on the impact of phytochemicals on the UPS function in malignancies, especially brain tumors.

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Overexpression of UbcH10 alternates the cell cycle profile and accelerate the tumor proliferation in colon cancer

Cited by 64 publications

References 38 publications

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

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

Spindle Assembly Checkpoint Protein Cdc20 Transcriptionally Activates Expression of Ubiquitin Carrier Protein UbcH10

Modulation of the ubiquitin‐proteasome system by phytochemicals: Therapeutic implications in malignancies with an emphasis on brain tumors

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