CUEDC2

Official Full Name

CUE domain containing 2

Organism

Homo sapiens

GeneID

79004

Background

Predicted to enable ubiquitin binding activity. Acts upstream of or within negative regulation of cytokine production involved in inflammatory response and negative regulation of macrophage cytokine production. Located in cytosol; nuclear membrane; and nucleoplasm. [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

C10orf66; bA18I14.5;

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Detailed Information

Recent Research Progress

CUEDC2 is a CUE domain containing protein, a small ubiquitin-binding motif with approximately 40 amino acid residues in many eukaryotic proteins. It has a dual role in the recognition of monoubiquitin and polyubiquitin, as well as infacilitating intramolecular monoubiquitination. Recent studies have shown that CUEDC2 played a key role in many biological processes such as cell cycle, inflammation and tumorigenesis.

CUEDC2 and I/R

The irreversible loss of cardiomyocytes due to oxidative stress is a major cause of cardiac dysfunction after ischemia/reperfusion (I/R) injury and aging-induced cardiomyopathy. It was reported that CUEDC2 played a key role in oxidative stress-induced heart injury. CUEDC2-/- cardiomyocytes exhibited greater resistance to oxidative stress-induced cell death. Deletion of CUEDC2 enhanced the antioxidant capacity of cardiomyocytes, promoted the clearance of reactive oxygen species (ROS), and subsequently inhibited the redox-dependent activation of signaling pathways. Notably, CUEDC2 promoted the E3 ubiquitin ligase triplet motif-containing 33 (TRIM33)-mediated antioxidant enzyme, glutathione peroxidase 1 (GPX1) ubiquitination and proteasome-dependent degradation. Strikingly, in vivo, the infarct size of CUEDC2-/- heart was significantly decreased after I/R injury, and older CUEDC2-/- mice retained better cardiac function because their overall ROS levels in the heart were significantly lower. These results demonstrated a novel role for CUEDC2 in the regulation of cardiomyocyte death. Manipulation of CUEDC2 levels might be an attractive therapeutic strategy to promoting oxidative stress-induced myocardial cell survival following cardiac injury.

CUEDC2 and glioblastoma

Recent studies have shown that CUEDC2 expression was lower in glioma tissues and glioma cell lines than in normal tissues and astrocytes. Down-regulation of endogenous CUEDC2 in glioma U251 cell line by RNA interference (RNAi) promoted the tumor cell proliferation, migration, invasion and glioma formation, whereas overexpression of CUEDC2 shows the opposite effect. Further studies indicated that overexpression of CUEDC2 inhibited the activation and nuclear translocation of phosphorylated-STAT3 (p-STAT3) but the level of p-STAT3 increased after interfering with the expression of CUEDC2. Furthermore, CUEDC2 expression has an inhibitory effect on the activation of NF-κB. Thus, decreased expression of CUEDC2 in gliomas leads to activation of the transcription factors STAT3 and NF-κB signaling pathways, which may be related to the tumorigenicity of gliomas.

CUEDC2 and lung adenocarcinoma

Lung adenocarcinoma is a type of lung cancer and belongs to non-small cell carcinoma. The study found that CUEDC2 was lower in both lung adenocarcinoma cell lines and lung adenocarcinoma tissues at mRNA and protein levels. Low levels of CUEDC2 were associated with shorter survival times in patients with lung adenocarcinoma. CUEDC2 expression was correlated with tumor T classification of clinical stage and tumor size. Multivariate analysis showed that CUEDC2 expression was an independent prognostic indicator for patients with lung adenocarcinoma. Ectopic expression of CUEDC2 reduced cell proliferation in vitro and inhibited tumor growth in nude mice in vivo. Knockdown of endogenous CUEDC2 by short hairpin RNA (shRNA) increased tumor growth. Inhibition of proliferation by CUEDC2 was associated with inactivation of the PI3K/Akt pathway, induction of p21 and down-regulation of cyclin D1. In conclusion, current findings suggest that decreased expression of CUEDC2 contributes to tumor growth in lung adenocarcinoma.

CUEDC2 and Ovarian carcinoma

Ovarian cancer is the most deadly gynecological malignancy that causes death, with 140,000 deaths worldwide each year. Ovarian serous carcinoma is the most common subtype of epithelial ovarian cancer, accounting for about 45% of all ovarian cancer. Current data showed that overexpression of CUEDC2 was observed in 59.4% of ovarian serous carcinoma tissue samples and associated with histopathological grade, patient age at diagnosis, FIGO stage and relapse. Overall, the results suggested that CUEDC2 may be a promising biomarker for assessing the progression of serous ovarian cancer and predicting possible recurrence of ovarian serous carcinoma.

CUEDC2 and CRC

According to the latest World Health Organization cancer statistics, colorectal cancer (CRC) has become the third most common malignant tumor in men, second only to female breast cancer. About 50% of patients with colorectal cancer will have liver metastases, and the prevalence of simultaneous and metachronous liver metastases is 25%. Recent large studies have shown that CUEDC2 is highly expressed in colorectal cancer tissues and colorectal cancer cell lines with high invasion and migration ability, and CUEDC2 can play a role in promoting invasion and metastasis of colorectal cancer through nuclear and cytoplasmic activities.

Taken together, these findings indicate that CUEDC2 has dual functions, both in tumor promotion and tumor suppression. However, it is important to emphasize that the function of CUEDC2 appears to be different in different types of cancer. Further research is needed to elucidate the molecular mechanisms by which CUEDC2 exerts these diverse effects in different cancers.

References:

Zhong Xiuying, et al. CUE domain-containing protein 2 promotes the Warburg effect and tumorigenesis. EMBO Reports, 2017, 18: 809–825
Zhao Jian, et al. CUEDC2 modulates cardiomyocyte oxidative capacity by regulating GPX1 stability. EMBO Molecular Medicine, 2016, 8: 813–829
Li Feng, et al. CUEDC2 suppresses glioma tumorigenicity by inhibiting the activation of STAT3 and NF-κB signaling pathway. International Journal Of Oncology, 2017, 51: 115-127
Sun Longhua, et al. CUEDC2 down-regulation is associated with tumor growth and poor prognosis in lung adenocarcinoma. Oncotarget, 2015, 6: 24
Wang Aichun, et al. Overexpression of CUEDC2 Predicts Poor Prognosis in Ovarian Serous Carcinomas. Journal of Cancer, 2015, 6(6): 542-547
Hu Shidong, et al. Expression of CUEDC2 in colorectal cancer with different invasion and migration abilities. Journal of International Medical Research, 2019, 47(2): 905–914
Wang Shaoxin, et al. CUEDC2 Protects Against Experimental Colitis and Suppresses Excessive Proliferation of Intestinal Mucosa. Dig Dis Sci, 2015, 60:3603–3609

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