The let-7 target gene mouse lin-41 is a stem cell specific E3 ubiquitin ligase for the miRNA pathway protein Ago2

Wnt signaling plays key roles in embryonic development and adult stem cell homeostasis and is altered in human cancer. We explore β-catenin transfer from the destruction complex to the E3 ligase, and test models suggesting Dishevelled and APC2 compete for association with Axin.

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The Hh pathway promotes cell apoptosis through Ci-Rdx-Diap1 axis

Cell Death Discovery ◽

10.1038/s41420-021-00653-3 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Bin Liu ◽

Yan Ding ◽

Bing Sun ◽

Qingxin Liu ◽

Zizhang Zhou ◽

...

Keyword(s):

Birth Defects ◽

Ubiquitin Ligase ◽

Cell Apoptosis ◽

Target Gene ◽

Regulatory Mechanism ◽

E3 Ubiquitin Ligase ◽

Human Diseases ◽

Induced Apoptosis ◽

Tumor Drugs ◽

Transcriptional Target

AbstractApoptosis is a strictly coordinated process to eliminate superfluous or damaged cells, and its deregulation leads to birth defects and various human diseases. The regulatory mechanism underlying apoptosis still remains incompletely understood. To identify novel components in apoptosis, we carry out a modifier screen and find that the Hh pathway aggravates Hid-induced apoptosis. In addition, we reveal that the Hh pathway triggers apoptosis through its transcriptional target gene rdx, which encodes an E3 ubiquitin ligase. Rdx physically binds Diap1 to promote its K63-linked polyubiquitination, culminating in attenuating Diap1−Dronc interaction without affecting Diap1 stability. Taken together, our findings unexpectedly uncover the oncogenic Hh pathway is able to promote apoptosis through Ci-Rdx-Diap1 module, raising a concern to choose Hh pathway inhibitors as anti-tumor drugs.

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TRIM25 Regulates Oxaliplatin Resistance in Colorectal Cancer by Promoting EZH2 Stability

10.21203/rs.3.rs-60545/v1 ◽

2020 ◽

Author(s):

Sha Zhou ◽

Jianhong Peng ◽

Liuniu Xiao ◽

Caixia Zhou ◽

Yujing Fang ◽

...

Keyword(s):

Colorectal Cancer ◽

Stem Cell ◽

Ubiquitin Ligase ◽

E3 Ubiquitin Ligase ◽

Disease Free Survival ◽

Annexin V ◽

Vital Role ◽

Kaplan Meier

Abstract Background Resistance to chemotherapy remains the major cause of treatment failure in patients with colorectal cancer (CRC). TRIM25, an E3-ubiquitin ligase, has been reported to play a vital role in tumorigenesis. This project aims to explore the function and mechanism of TRIM25 in regulating oxaliplatin resistance in colorectal cancer.Methods The expression of TRIM25 in colorectal cancer tissues were examined by publicly available dataset, Immunohistochemistry and western blot. Further survival analysis was conducted using Kaplan-Meier method. CCK8 assay, colony-formation assay, Annexin V-FITC /PI staining and xenograft tumor models were used for evaluating sensitivity of CRC cells to oxaliplatin. Sphere-formation assay, RT-PCR and limiting dilution assay were used to evaluate the influence of TRIM25 on stem cell properties of CRC cells. Co-immunoprecipitation, polyubiquitination assay and western bolt elucidate the mechanism by which TRIM25 regulates EZH2.Results Patients with high expression of TRIM25 have significantly higher recurrence rate (28.9% vs. 15.0%, P = 0.012) and worse disease-free survival (P = 0.006) than those with low TRIM25 expression. Downregulation of TRIM25 dramatically inhibited while TRIM25 overexpression enhanced CRC cells survival after oxaliplatin treatment. In addition, TRIM25 promotes stem cell properties of CRC cells both in vitro and in vivo (8 mice per group). Importantly, we demonstrated that TRIM25 inhibits the binding of E3-ubiquitin ligase TRAF6 to EZH2, thus stabilizing and upregulating EZH2 and promoting oxaliplatin resistance. Conclusions Our study provides evidence that TRIM25 is a novel epigenetic regulator of oxaliplatin resistance. Targeting TRIM25 might be a promising strategy for CRC treatment.

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pVHL regulates protein stability of TCF/LEF transcription factor family via ubiquitin-independent proteasomal degradation

10.1101/2021.10.14.464355 ◽

2021 ◽

Author(s):

Caixia Wang ◽

Xiaozhi Rong ◽

Haifeng Zhang ◽

Bo Wang ◽

Yan Bai ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factors ◽

Protein Stability ◽

Ubiquitin Ligase ◽

Target Gene ◽

E3 Ubiquitin Ligase ◽

Proteasomal Degradation ◽

26S Proteasome ◽

Cell Fate Decisions ◽

Target Gene Expression

The Wnt/β-catenin signaling pathway plays key roles in development and adult tissue homeostasis by controlling cell proliferation and cell fate decisions. In this pathway, transcription factors TCF/LEFs are the key components to repress target gene expression by recruiting co-repressors or to activate target gene expression by recruiting β-catenin when the Wnt signals are absent or present, respectively. While progress has been made in our understanding of Wnt signaling regulation, the underlying mechanism that regulates the protein stability of the TCF/LEF family is far less clear. Here, we show that von Hippel-Lindau protein (pVHL), which is the substrate recognition component in an E3 ubiquitin ligase complex, controls TCF/LEF protein stability. Unexpectedly, pVHL directly binds to TCF/LEFs and promotes their proteasomal degradation independent of E3 ubiquitin ligase activity. Knockout of vhl in zebrafish embryos leads to a reduction of dorsal habenular neurons and this effect is upstream of dorsal habenular neurons phenotype in tcf7l2-null mutants. Our study uncovers a previously unknown mechanism for the protein stability regulation of the TCF/LEF transcription factors and demonstrates that pVHL contains a 26S proteasome binding domain that drives ubiquitin-independent proteasomal degradation. These findings provide new insights into the ubiquitin-independent actions of pVHL and uncover novel mechanistical regulation of Wnt/β-catenin signaling.

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WSB1 Regulates c-Myc Expression Through β-catenin Signaling and Forms a Feedforward Circuit Promoting the Development of Cancer

10.1101/2020.09.25.312678 ◽

2020 ◽

Author(s):

Xiaomeng Gao ◽

Yanling Gong ◽

Jieqiong You ◽

Meng Yuan ◽

Haiying Zhu ◽

...

Keyword(s):

Ubiquitin Ligase ◽

Target Gene ◽

Regulatory Mechanism ◽

Intervention Strategy ◽

E3 Ubiquitin Ligase ◽

Promoting Effect ◽

Direct Target Gene ◽

Direct Target

AbstractThe dysregulation of transcription factors is widely associated with tumorigenesis. As the most well-defined transcription factor in multiple types of cancer, c-Myc can directly transform cells by transactivating various downstream genes. Given that there is no effective way to directly inhibit c-Myc, c-Myc targeting strategies based on its regulatory mechanism hold great potential for cancer therapy. In this study, we found that WSB1, a direct target gene of c-Myc, can positively regulate c-Myc expression, which forms a feedforward circuit promoting cancer development. Luciferase-based promoter activity assays and RNA sequencing results confirmed that WSB1 promoted c-Myc expression through the β-catenin pathway. Mechanistically, WSB1 affected β-catenin destruction complex-PPP2CA assembly and E3 ubiquitin ligase adaptor β-TRCP recruitment, which inhibited the ubiquitination of β-catenin and subsequently transactivated c-Myc. Of interest, the promoting effect of WSB1 on c-Myc was independent of its E3 ligase activity. Moreover, co-expression of WSB1 and c-Myc strongly enhanced the initiation and progression of tumours both in vitro and in vivo. Thus, our findings revealed a novel mechanism involved in tumorigenesis in which the WSB1/c-Myc feedforward circuit played an essential role, highlighting a potential c-Myc intervention strategy in cancer treatment.

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TRIM25 regulates oxaliplatin resistance in colorectal cancer by promoting EZH2 stability

10.21203/rs.3.rs-60545/v2 ◽

2020 ◽

Author(s):

Sha Zhou ◽

Jianhong Peng ◽

Liuniu Xiao ◽

Caixia Zhou ◽

Yujing Fang ◽

...

Keyword(s):

Colorectal Cancer ◽

Stem Cell ◽

Western Blotting ◽

Ubiquitin Ligase ◽

E3 Ubiquitin Ligase ◽

Disease Free Survival ◽

Annexin V ◽

Vital Role

Abstract BackgroundResistance to chemotherapy remains the major cause of treatment failure in patients with colorectal cancer (CRC). Tripartite motif containing 25 (TRIM25), an E3-ubiquitin ligase, has been reported to play a vital role in tumorigenesis. The present study aimed to explore the function and mechanism of TRIM25 in regulating oxaliplatin resistance in colorectal cancer.MethodsThe expression of TRIM25 in colorectal cancer tissues was examined using publicly available datasets, immunohistochemistry, and western blotting. Further survival analysis was conducted using the Kaplan-Meier method. CCK8 assays, colony-formation assays, Annexin V-FITC /PI staining and xenograft tumor models were used to evaluate the sensitivity of CRC cells to oxaliplatin. Sphere-formation assays, RT-PCR and limiting dilution assays were used to evaluate the influence of TRIM25 on the stem cell properties of CRC cells. Co-immunoprecipitation, polyubiquitination assays and western blotting were used to determine the mechanism by which TRIM25 regulates EZH2.ResultsPatients with high expression of TRIM25 had a significantly higher recurrence rate (28.9% vs. 15.0%, P = 0.012) and worse disease-free survival (P = 0.006) than those with low TRIM25 expression. Downregulation of TRIM25 dramatically inhibited, while overexpression of TRIM25 increased, CRC cell survival after oxaliplatin treatment. In addition, TRIM25 promoted the stem cell properties of CRC cells both in vitro and in vivo. Importantly, we demonstrated that TRIM25 inhibited the binding of E3-ubiquitin ligase TRAF6 to EZH2, thus stabilizing and upregulating EZH2, and promoting oxaliplatin resistance.ConclusionsOur study provided evidence that TRIM25 is a novel epigenetic regulator of oxaliplatin resistance. Targeting TRIM25 might be a promising strategy for CRC treatment.

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