E3 ubiquitin ligase UBR5 promotes pancreatic cancer growth and aerobic glycolysis by downregulating FBP1 via destabilization of C/EBPα

Chen, Leifeng; Yuan, Rongfa; Wen, Chongyu; Liu, Tiande; Feng, Qian; Deng, Xueqiang; Du, Yunyan; Peng, Xiaogang

doi:10.1038/s41388-020-01527-1

Cited by 52 publications

(30 citation statements)

References 34 publications

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“…Nevertheless, its role in pancreatic cancer was rarely studied. A recent study indicated the growth-promoting effect of UBR5 on pancreatic cancer cells (29). Here, we extended the understanding of its function to the regulation of pancreatic cancer metastasis.…”

Section: Discussionmentioning

confidence: 83%

E3 Ubiquitin Ligase UBR5 Promotes the Metastasis of Pancreatic Cancer via Destabilizing F-Actin Capping Protein CAPZA1

Zhang

Gao

et al. 2021

Front. Oncol.

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The ubiquitin-proteasome system (UPS) is a regulated mechanism of intracellular protein degradation and turnover, and its dysfunction is associated with various diseases including cancer. UBR5, an E3 ubiquitin ligase, is emerging as an important regulator of the UPS in cancers, but its role in pancreatic cancer is poorly understood. Here, we show that UBR5 is significantly upregulated in pancreatic cancer tissues. High UBR5 expression is correlated with increased lymph node metastasis and poor survival of patients. The loss-of-function and gain-of-function studies demonstrated that UBR5 substantially enhanced the in vitro migratory and invasive ability of pancreatic cancer cells. UBR5 knockdown also markedly inhibited in vivo cancer metastasis in the liver metastatic model of pancreatic cancer in nude mice, suggesting UBR5 as a potent metastatic promoter in pancreatic cancer. Furthermore, using co-immunoprecipitation combined with mass spectrometry analyses, CAPZA1, a member of F-actin capping protein α subunit family, was identified as a novel substrate of UBR5. UBR5 overexpression could promote the degradation of CAPZA1 via the UPS and induce the accumulation of F-actin, which has been described as an essential molecular event during the process of CAPZA1 deficiency-induced cancer cells migration and invasion. UBR5 knockdown significantly increased the intracellular level of CAPZA1 and CAPZA1 downregulation largely reversed the UBR5 knockdown-induced suppression of cell migration and invasion in pancreatic cancer cells. Collectively, our findings unveil UBR5 as a novel and critical regulator of pancreatic cancer metastasis and highlight the potential for UBR5-CAPZA1 axis as a therapeutic target for preventing metastasis in pancreatic cancer patients, especially in those with increased UBR5 expression.

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Section: Discussionmentioning

confidence: 83%

E3 Ubiquitin Ligase UBR5 Promotes the Metastasis of Pancreatic Cancer via Destabilizing F-Actin Capping Protein CAPZA1

Zhang

Gao

et al. 2021

Front. Oncol.

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“…In breast cancer, UBR5 is coampli ed with MYC, thereby limiting MYC-dependent apoptosis of cancer cells [12] . In pancreatic cancer, UBR5 downregulates FBP1 by downregulating the expression of C/EBPa, thereby promoting the growth of cancer cells [13] . In gallbladder cancer, UBR5 can promote tumor growth by affecting the PTEN/PI3K/Akt signaling pathway [26] .…”

Section: Discussionmentioning

confidence: 99%

“…Data from the TCGA database shows that UBR5 is abnormally expressed in many types of cancers and is closely involved in various cellular functions, such as DNA damage repair, immune response, transcription regulation, and the cell cycle [8][9][10][11] . UBR5 is also related to chemotherapy sensitivity and the prognosis of various cancers, such as prostate cancer and ovarian cancer [12][13][14] . However, little is known about the expression levels of UBR5 in patients with TNBC.…”

Section: Introductionmentioning

confidence: 99%

Correlation of sTILs Infiltration and UBR5 Expression on the Efficacy of Neoadjuvant Chemotherapy Efficacy and Prognosis in Early Triple Negative Breast Cancer

Pang

Zhou

Liao

et al. 2021

Preprint

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Neoadjuvant chemotherapy (NAC) is widely used in patients with TNBC, but there are significant differences in the efficacy of chemotherapy in different patients. Stromal tumor infiltrating lymphocytes (sTILs) have been widely studied as biomarkers reflecting the therapeutic effect of NAC. As a tumor-associated gene, UBR5 has been found to be associated with chemotherapy sensitivity and prognosis of many cancers. This is the first time that we have combined UBR5 and sTILs to evaluate the chemotherapy efficacy of patients with TNBC treated with NAC and to study the correlation between sTILs and UBR5. MethodsSPSS was used to analyze the correlation between UBR5 and sTILs and clinicopathological data. Then doxorubicin and mitoxantrone treated mouse breast cancer cells to explore the relationship between UBR5 expression and chemotherapeutic drug sensitivity. Finally, R language analyzes the relationship between UBR5 and immune-related genes and immune score.ResultsIn patients with TNBC treated with NAC, the expression level of UBR5 and the degree of infiltration of sTILs are independent factors that affect whether the patient can achieve PCR and the expression between the two is negatively correlated. UBR5 expression can cause mouse breast cancer cells to develop resistance to doxorubicin and mitoxantrone. At the same time, UBR5 is also highly correlated with a variety of immune-related genes and immune scores.ConclusionUBR5 and sTILs can jointly predict the efficacy of NAC in patients with TNBC. At the same time, the expression of UBR5 is also an important reason for chemotherapy resistance in patients with TNBC.

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“…Mounting evidence has revealed that the levels of ubiquitin protein ligase E3 component n‐recognin 5 (UBR5, also known as EDD1), as a key regulator of the UPS, has strongly associated with malignant phenotypes and shorter survival in many cancers. Overexpression of UBR5 is an independent forecast of poor prognosis in patients with cancer 12–14 . Interestingly, it has been identified that there is a negative regulatory relationship between C2orf40 andUBR5 in colorectal cancer 15 .…”

Section: Introductionmentioning

confidence: 99%

C2orf40 inhibits hepatocellular carcinoma through interaction with UBR5

Qin

et al. 2021

J of Gastro and Hepatol

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Background and Aim Hepatocellular carcinoma (HCC) urgently needs a marker for early diagnosis and targeted treatment. C2orf40 has been identified as a tumor suppressor gene in many cancers. However, the precise role and regulatory mechanism by C2orf40 contribute to HCC remain elusive and merit exploration. Methods Reverse‐transcription PCR, quantitative real‐time PCR, and methylation‐specific PCR were used to detect expression and methylation of C2orf40 in HCC cell lines or tissues. The effects of C2orf40 in liver cancer cells were examined via colony formation, CCK8, transwell, and flow cytometric assays. The effect of C2orf40 on tumorigenesis in vivo was determined by xenografts and immunohistochemical analysis. Western blot, indirect immunofluorescence, Co‐IP, and cycloheximide (CHX) were used to further investigate the potential mechanism of C2orf40. Results The down‐regulation of C2orf40 in hepatocellular cancer tissue samples is often related to the degree of methylation of its promoter CpG. The recovery of C2orf40 expression in HCC cell lines can induce G0/G1 phase arrest and apoptosis and also inhibit cell migration and invasion by reversing the epithelial–mesenchymal transition (EMT) process, both in vivo and in vitro. In addition, C2orf40 can increase the expression of p21 through interaction with UBR5. Conclusions Low expression levels of C2orf40 are related to the hypermethylation of its promoter. C2orf40 can inhibit HCC through UBR5‐dependent or p53‐independent mechanisms. C2orf40 may be a diagnostic biomarker and a potential therapeutic target in HCC.

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E3 ubiquitin ligase UBR5 promotes pancreatic cancer growth and aerobic glycolysis by downregulating FBP1 via destabilization of C/EBPα

Cited by 52 publications

References 34 publications

E3 Ubiquitin Ligase UBR5 Promotes the Metastasis of Pancreatic Cancer via Destabilizing F-Actin Capping Protein CAPZA1

E3 Ubiquitin Ligase UBR5 Promotes the Metastasis of Pancreatic Cancer via Destabilizing F-Actin Capping Protein CAPZA1

Correlation of sTILs Infiltration and UBR5 Expression on the Efficacy of Neoadjuvant Chemotherapy Efficacy and Prognosis in Early Triple Negative Breast Cancer

C2orf40 inhibits hepatocellular carcinoma through interaction with UBR5

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