USP44 suppresses proliferation and enhances apoptosis in colorectal cancer cells by inactivating the Wnt/β‐catenin pathway via Axin1 deubiquitination

Huang, Tong; Zhang, Qingquan; Ren, Wei; Yan, Bing; Liang, Yi; Tang, Tielun; Lin, Hai; Yong-jiu, Zhang

doi:10.1002/cbin.11358

Cited by 33 publications

(31 citation statements)

References 22 publications

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“…Experimental studies have found that the expression level of USP44 is significantly reduced in CRC and enhances the apoptosis of CRC cells, indicating that USP44 is a cancer suppressor of CRC. The results showed that USP44 overexpression increased Axin1 protein while reducing β-catenin, c-myc and cyclin D1 protein, indicating that USP44 inhibited the activation of Wnt/β-catenin pathway mediated CRC cell apoptosis [ 41 ]. The 2A-containing V-set and transmembrane domain (VSTM2A) is a top-down secreted protein that negatively regulates the Wnt single-selection pathway in colorectal cancer (CRC).…”

Section: Wnt Pathway-related Biochemical Processmentioning

confidence: 99%

Wnt signaling in colorectal cancer: pathogenic role and therapeutic target

et al. 2022

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Background The Wnt signaling pathway is a complex network of protein interactions that functions most commonly in embryonic development and cancer, but is also involved in normal physiological processes in adults. The canonical Wnt signaling pathway regulates cell pluripotency and determines the differentiation fate of cells during development. The canonical Wnt signaling pathway (also known as the Wnt/β-catenin signaling pathway) is a recognized driver of colon cancer and one of the most representative signaling pathways. As a functional effector molecule of Wnt signaling, the modification and degradation of β-catenin are key events in the Wnt signaling pathway and the development and progression of colon cancer. Therefore, the Wnt signaling pathway plays an important role in the pathogenesis of diseases, especially the pathogenesis of colorectal cancer (CRC). Objective Inhibit the Wnt signaling pathway to explore the therapeutic targets of colorectal cancer. Methods Based on studying the Wnt pathway, master the biochemical processes related to the Wnt pathway, and analyze the relevant targets when drugs or inhibitors act on the Wnt pathway, to clarify the medication ideas of drugs or inhibitors for the treatment of diseases, especially colorectal cancer. Results Wnt signaling pathways include: Wnt/β-catenin or canonical Wnt signaling pathway, planar cell polarity (Wnt-PCP) pathway and Wnt-Ca2+ signaling pathway. The Wnt signaling pathway is closely related to cancer cell proliferation, stemness, apoptosis, autophagy, metabolism, inflammation and immunization, microenvironment, resistance, ion channel, heterogeneity, EMT/migration/invasion/metastasis. Drugs/phytochemicals and molecular preparations for the Wnt pathway of CRC treatment have now been developed. Wnt inhibitors are also commonly used clinically for the treatment of CRC. Conclusion The development of drugs/phytochemicals and molecular inhibitors targeting the Wnt pathway can effectively treat colorectal cancer clinically.

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Section: Wnt Pathway-related Biochemical Processmentioning

confidence: 99%

Wnt signaling in colorectal cancer: pathogenic role and therapeutic target

et al. 2022

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“…Several studies have shown that Axin1 protein expression is frequently regulated by proteasomal degradation and that inhibition of Axin1 results in the activation of the Wnt/ β-catenin pathway [36,37]. Moreover, it has been reported that TRIM11 is involved in the activation of the β-catenin pathway via the ubiquitination and degradation of Axin1 in lymphomas [29] and that it promotes cell growth and epithelial-mesenchymal transition in gastric cancer by activating β-catenin signaling [22].…”

Section: Discussionmentioning

confidence: 99%

The E3 Ubiquitin Ligase TRIM11 Facilitates Gastric Cancer Progression by Activating the Wnt/β-Catenin Pathway via Destabilizing Axin1 Protein

Zhou

Wang

Zhong

et al. 2022

Journal of Oncology

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Background. Aberrant expression of tripartite motif 11 (TRIM11) and the Wnt/β-catenin pathway are essential for facilitating tumorigenesis and progression in multiple types of cancer. Aim. To investigate the molecular changes linking the dysregulation of TRIM11 and Wnt/β-catenin pathway activation in gastric cancer (GC) progression. Methods. The expression levels of TRIM11 were detected in GC tissues and cells by immunohistochemistry and western blotting. The role of TRIM11 in the growth, proliferation, and invasion of gastric cancer cells was observed by a series of cell functional experiments and further verified in vivo. Co-immunoprecipitation (Co-IP), immunofluorescence, cycloheximide, and western blotting assays and other experiments were conducted to explore the mechanisms of TRIM11 underlying the regulation of the Wnt/β-catenin pathway. For further verification, rescue experiments were performed by cotransfection of TRIM11 and Axin1 siRNA in GC cells. Results. Using Co-IP assays, we identified TRIM11 as a potent binding partner of Axin1 in GC cells. Elevated TRIM11 levels were significantly correlated with unfavorable clinical outcomes and poor survival in patients with GC. In addition, TRIM11 promoted the cell proliferation and invasion capacities of GC cells in vitro and tumor growth in vivo. Mechanistic investigations revealed that TRIM11 destabilized Axin1 protein by interacting with Axin1, thus inducing the activation of the Wnt/β-catenin pathway. Moreover, we found that the oncogenic effects of TRIM11 on GC cells were partly mediated by suppression of Axin1. Furthermore, the protein expression of TRIM11 and Axin1 was negatively correlated in GC tissues. Conclusion. Collectively, our findings not only establish a pivotal TRIM11-Axin1-β-catenin axis in driving GC progression but also indicate that TRIM11 serves as a valuable therapeutic target for the treatment of GC patients.

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“…It is well established that most genetic mutations in CRC are involved in the deregulation of Wnt/β-catenin signaling ( 31 ). The deregulation of Wnt/β-catenin signaling is associated with apoptosis inhibition, EMT, and an altered tumor microenvironment ( 32 - 34 ), leading to further drug resistance in cancer. Therefore, based on these studies, the hypothesis that UBE2M induces drug resistance in CRC cells by activating Wnt/β-catenin signaling pathways is established.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of UBE2M through Wnt/β-Catenin signaling is associated with poor prognosis and chemotherapy resistance in colorectal cancer

Xu¹,

Lv²,

Xu³

et al. 2020

Transl Cancer Res TCR

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Background: The expression of ubiquitin-conjugating enzyme E2 M (UBE2M) is elevated in colorectal carcinoma (CRC). However, the underlying mechanisms and effects of UBE2M on the prognosis and drug resistance in CRC have not been investigated.Methods: CRC specimens and adjacent normal tissues were collected from 74 patients. The expression of UBE2M was measured by quantitative real-time polymerase chain reaction (PCR) and immunohistochemistry. Multivariable cox regression analysis was used to analyze the risk factors for overall survival in clinical CRC patients. Human colorectal cancer cell lines HCT116 and SW480 were transfected with specific UBE2M small interfering ribonucleic acid (siRNA) or plasmid to either suppress or increase the expression of UBE2M for in vitro experiments. Also, chemotherapy-resistant HCT116 and SW480 cells were established by being treated with increasingly higher concentrations of fluorouracil (5-FU) or oxaliplatin. XAV-939 was used as a wingless/integrated-beta-catenin (Wnt/β-catenin) signaling inhibitor.Results: According to quantitative real-time PCR and immunohistochemistry, the expression of UBE2M was elevated in CRC tissues compared to normal tissues. Based on cox regression analysis, the overexpression of UBE2M was a risk factor for overall survival of CRC patients. The expression of UBE2M was notably high in 5-FU-and oxaliplatin-resistant cells in in vitro experiments. Also, cells transfected with specific UBE2M siRNA or plasmid induced lower resistance to 5-FU and higher resistance to oxaliplatin. Finally, the expression of β-catenin was correlated with the expression of UBE2M in transfected cells and treatment with XAV939 decreased the degree of drug resistance in chemotherapy-resistant HCT116 cells.Conclusions: Overexpression of UBE2M in CRC specimens contributes to a decreased overall survival of patients and mediates 5-FU and oxaliplatin resistance in CRC cells via the Wnt/β-catenin signaling pathway.

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USP44 suppresses proliferation and enhances apoptosis in colorectal cancer cells by inactivating the Wnt/β‐catenin pathway via Axin1 deubiquitination

Cited by 33 publications

References 22 publications

Wnt signaling in colorectal cancer: pathogenic role and therapeutic target

Wnt signaling in colorectal cancer: pathogenic role and therapeutic target

The E3 Ubiquitin Ligase TRIM11 Facilitates Gastric Cancer Progression by Activating the Wnt/β-Catenin Pathway via Destabilizing Axin1 Protein

Overexpression of UBE2M through Wnt/β-Catenin signaling is associated with poor prognosis and chemotherapy resistance in colorectal cancer

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