E3 ubiquitin ligases and deubiquitinases in bladder cancer tumorigenesis and implications for immunotherapies

Wang, Maoyu; Zhang, Zhensheng; Li, Zhizhou; Zhu, Yasheng; Xu, Chuanliang

doi:10.3389/fimmu.2023.1226057

Cited by 5 publications

(3 citation statements)

References 180 publications

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“…Not unlike most post-translational modification, ubiquitination is also associated with many cell functions, including cell cycle progression, apoptosis, gene transcription, DNA repair, and signal transduction, which regulate cell development and differentiation and tumorigenesis ( 35 , 36 ). Therefore, components in the ubiquitin pathway have been proposed as potential targets for treatment strategies for diseases and cancer ( 37 , 38 ). USP7 is one of the most abundant USPs and plays a multifaceted role in many cellular events, including carcinogenic pathways ( 39 - 42 ).…”

Section: Discussionmentioning

confidence: 99%

TMEM43 promotes the development of hepatocellular carcinoma by activating VDAC1 through USP7 deubiquitination

Zhang,

Wang,

Yang

et al. 2024

Transl Gastroenterol Hepatol

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Background Transmembrane protein 43 ( TMEM43 ), a member of the TMEM subfamily, is encoded by a highly conserved gene and widely expressed in most species from bacteria to humans. In previous studies, TMEM43 has been found to play an important role in a variety of tumors. However, the role of TMEM43 in cancer remains unclear. Methods We utilized the RNA sequencing (RNA-seq) and The Cancer Genome Atlas (TGCA) databases to explore and identify genes that may play an important role in the occurrence and development of hepatocellular carcinoma (HCC), such as TMEM43 . The role of TMEM43 in HCC was explored through Cell Counting Kit-8 (CCK-8) cloning, flow cytometry, and Transwell experiments. The regulatory relationship between TMEM43 and voltage-dependent anion channel 1 ( VDAC1 ) was investigated through coimmunoprecipitation (co-IP) and western blot (WB) experiments. WB was used to study the deubiquitination effect of ubiquitin-specific protease 7 ( USP7 ) on TMEM43 . Results In this study, we utilized the RNA-seq and TGCA databases to mine data and found that TMEM43 is highly expressed in HCC. The absence of TMEM43 in cancer cells was shown to inhibit tumor development. Further research detected an important regulatory relationship between TMEM43 and VDAC1 . In addition, we found that USP7 affected the progression of HCC by regulating the ubiquitination level of TMEM43 through deubiquitination. Conclusions Our study demonstrated that USP7 participates in the growth of HCC tumors through TMEM43/VDAC1 .Our results suggest that USP7/TMEM43/VDAC1 may have predictive value and represent a new treatment strategy for HCC.

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Section: Discussionmentioning

confidence: 99%

TMEM43 promotes the development of hepatocellular carcinoma by activating VDAC1 through USP7 deubiquitination

Zhang,

Wang,

Yang

et al. 2024

Transl Gastroenterol Hepatol

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“…Previous studies had already revealed the abnormal ubiquitination mechanisms of multiple onco-proteins or tumor suppressors during the development and progression of malignant tumors [ 30 – 32 ]. In bladder cancer, a variety of proteins were aberrantly expressed in tumors and functioned as E3 ubiquitin ligases, involved in the regulation of various biological processes including proliferation, invasion, cell cycle, apoptosis, stemness and chemoresistance [ 33 – 36 ]. For instance, the expression of TRIM38 was shown to be low in bladder cancer, and it was inversely associated with overall survival and advanced clinical features.…”

Section: Discussionmentioning

confidence: 99%

BHLHE41 inhibits bladder cancer progression via regulation of PYCR1 stability and thus inactivating PI3K/AKT signaling pathway

Xiao,

Chen,

Wei

et al. 2024

Eur J Med Res

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Background The basic helix-loop-helix family member e41 (BHLHE41) is frequently dysregulated in tumors and plays a crucial role in malignant progression of various cancers. Nevertheless, its specific function and underlying mechanism in bladder cancer (BCa) remain largely unexplored. Methods The expression levels of BHLHE41 in BCa tissues and cells were examined by qRT-PCR and western blot assays. BCa cells stably knocking down or overexpressing BHLHE41 were constructed through lentivirus infection. The changes of cell proliferation, cell cycle distribution, migration, and invasion were detected by CCK-8, flow cytometry, wound healing, transwell invasion assays, respectively. The expression levels of related proteins were detected by western blot assay. The interaction between BHLHE41 and PYCR1 was explored by co-immunoprecipitation analysis. Results In this study, we found that BHLHE41 was lowly expressed in bladder cancer tissues and cell lines, and lower expression of BHLHE41 was associated with poor overall survival in bladder cancer patients. Functionally, by manipulating the expression of BHLHE41, we demonstrated that overexpression of BHLHE41 significantly retarded cell proliferation, migration, invasion, and induced cell cycle arrest in bladder cancer through various in vitro and in vivo experiments, while silence of BHLHE41 caused the opposite effect. Mechanistically, we showed that BHLHE41 directly interacted with PYCR1, decreased its stability and resulted in the ubiquitination and degradation of PYCR1, thus inactivating PI3K/AKT signaling pathway. Rescue experiments showed that the effects induced by BHLHE41 overexpression could be attenuated by further upregulating PYCR1. Conclusion BHLHE41 might be a useful prognostic biomarker and a tumor suppressor in bladder cancer. The BHLHE41/PYCR1/PI3K/AKT axis might be a potential therapeutic target for bladder cancer intervention.

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“…Patients with non-muscle-invasive bladder cancer have a five-year overall survival of nearly 80% but are prone to a high rate of recurrence. Once the cancer has become muscle-invasive, the five-year survival rate drops to less than 40%, and once metastasized (stage T4), to less than 5% [ 2 ]. The treatment armamentarium has considerably grown in the last few years, including immune checkpoint inhibitors, targeted drugs and antibody–drug conjugates.…”

Section: Introductionmentioning

confidence: 99%

Sulforaphane Inhibits Adhesion and Migration of Cisplatin- and Gemcitabine-Resistant Bladder Cancer Cells In Vitro

Xie,

Rutz,

Maxeiner

et al. 2024

Nutrients

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Only 20% of patients with muscle-invasive bladder carcinoma respond to cisplatin-based chemotherapy. Since the natural phytochemical sulforaphane (SFN) exhibits antitumor properties, its influence on the adhesive and migratory properties of cisplatin- and gemcitabine-sensitive and cisplatin- and gemcitabine-resistant RT4, RT112, T24, and TCCSUP bladder cancer cells was evaluated. Mechanisms behind the SFN influence were explored by assessing levels of the integrin adhesion receptors β1 (total and activated) and β4 and their functional relevance. To evaluate cell differentiation processes, E- and N-cadherin, vimentin and cytokeratin (CK) 8/18 expression were examined. SFN down-regulated bladder cancer cell adhesion with cell line and resistance-specific differences. Different responses to SFN were reflected in integrin expression that depended on the cell line and presence of resistance. Chemotactic movement of RT112, T24, and TCCSUP (RT4 did not migrate) was markedly blocked by SFN in both chemo-sensitive and chemo-resistant cells. Integrin-blocking studies indicated β1 and β4 as chemotaxis regulators. N-cadherin was diminished by SFN, particularly in sensitive and resistant T24 and RT112 cells, whereas E-cadherin was increased in RT112 cells (not detectable in RT4 and TCCSup cells). Alterations in vimentin and CK8/18 were also apparent, though not the same in all cell lines. SFN exposure resulted in translocation of E-cadherin (RT112), N-cadherin (RT112, T24), and vimentin (T24). SFN down-regulated adhesion and migration in chemo-sensitive and chemo-resistant bladder cancer cells by acting on integrin β1 and β4 expression and inducing the mesenchymal–epithelial translocation of cadherins and vimentin. SFN does, therefore, possess potential to improve bladder cancer therapy.

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E3 ubiquitin ligases and deubiquitinases in bladder cancer tumorigenesis and implications for immunotherapies

Cited by 5 publications

References 180 publications

TMEM43 promotes the development of hepatocellular carcinoma by activating VDAC1 through USP7 deubiquitination

TMEM43 promotes the development of hepatocellular carcinoma by activating VDAC1 through USP7 deubiquitination

BHLHE41 inhibits bladder cancer progression via regulation of PYCR1 stability and thus inactivating PI3K/AKT signaling pathway

Sulforaphane Inhibits Adhesion and Migration of Cisplatin- and Gemcitabine-Resistant Bladder Cancer Cells In Vitro

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