Cullin-5 (CUL5) as a potential prognostic marker in a pan-cancer analysis of human tumors

Li, Zian; Hu, Nan; Dai, Lirui; Hou, Xuelei; Hu, Weihua; Liang, Wulong; Wang, Xinjun

doi:10.1080/21655979.2021.1940042

Cited by 9 publications

(28 citation statements)

References 36 publications

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“…Knockdown of RBX1 has also been correlated with decreases in the growth of HCC xenografts and the induction of cell cycle arrest and senescence in HCC cells ( Yang et al, 2013 ). RBX1, ELOB, and ELOC can also interact with CUL5 and WSB1, both of which are overexpressed in HCC, to form the CRL5 WSB1 complex ( Okumura et al, 2012 ; Xu et al, 2020 ; Li et al, 2021 ). This E3 ligase complex has a number of targets, including HIPK2, whose loss downregulates apoptosis, and pVHL ( Okumura et al, 2012 ; Kim et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Genetic and Epigenetic Mechanisms Deregulate the CRL2pVHL Complex in Hepatocellular Carcinoma

Minatel¹,

Cohn²,

Pewarchuk³

et al. 2022

Front. Genet.

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Dysregulation of ubiquitin-proteasome pathway genes through copy number alteration, promoter hypomethylation, and miRNA deregulation is involved in cancer development and progression. Further characterizing alterations in these genes may uncover novel drug targets across a range of diseases in which druggable alterations are uncommon, including hepatocellular carcinoma (HCC). We analyzed 377 HCC and 59 adjacent non-malignant liver tissue samples, focusing on alterations to component genes of the widely studied CRL2pVHL E3 ubiquitin ligase complex. mRNA upregulation of the component genes was common, and was correlated with DNA hypomethylation and copy number increase, but many tumours displayed overexpression that was not explained by either mechanism. Interestingly, we found 66 miRNAs, including 39 previously unannotated miRNAs, that were downregulated in HCC and predicted to target one or more CRL2pVHL components. Several miRNAs, including hsa-miR-101-3p and hsa-miR-139-5p, were negatively correlated with multiple component genes, suggesting that miRNA deregulation may contribute to CRL2pVHL overexpression. Combining miRNA and mRNA expression, DNA copy number, and methylation status into one multidimensional survival analysis, we found a significant association between greater numbers of alterations and poorer overall survival for multiple component genes. While the intricacies of CRL2pVHL complex gene regulation require additional research, it is evident that multiple causes for the deregulation of these genes must be considered in HCC, including non-traditional mechanisms.

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Section: Discussionmentioning

confidence: 99%

Genetic and Epigenetic Mechanisms Deregulate the CRL2pVHL Complex in Hepatocellular Carcinoma

Minatel¹,

Cohn²,

Pewarchuk³

et al. 2022

Front. Genet.

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“…We visited the functional protein association networks’ (STRING) web server ( https://string-db.org/ ) ( Szklarczyk et al, 2015 ) with the basic parameters defined as follows: minimum required interaction score (“low confidence 0.150”), maximum number of interactors to display (“no more than 50 interactors” in the first shell), meaning of the network edges (“evidence”), and active interaction sources (“experiments”), as previously stated ( Li et al, 2021 ). Finally, we acquired the top 50 KDM6B-related proteins with experimental evidence.…”

Section: Methodsmentioning

confidence: 99%

A Pan-Cancer Analysis Revealing the Dual Roles of Lysine (K)-Specific Demethylase 6B in Tumorigenesis and Immunity

Ding

et al. 2022

Front. Genet.

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Introduction: Epigenetic-targeted therapy has been increasingly applied in the treatment of cancers. Lysine (K)-specific demethylase 6B (KDM6B) is an epigenetic enzyme involved in the coordinated control between cellular intrinsic regulators and the tissue microenvironment whereas the pan-cancer analysis of KDM6B remains unavailable.Methods: The dual role of KDM6B in 33 cancers was investigated based on the GEO (Gene Expression Omnibus) and TCGA (The Cancer Genome Atlas) databases. TIMER2 and GEPIA2 were applied to investigate the KDM6B levels in different subtypes or stages of tumors. Besides, the Human Protein Atlas database allowed us to conduct a pan-cancer study of the KDM6B protein levels. GEPIA2 and Kaplan–Meier plotter were used for the prognosis analysis in different cancers. Characterization of genetic modifications of the KDM6B gene was analyzed by the cBioPortal. DNA methylation levels of different KDM6B probes in different TCGA tumors were analyzed by MEXPRESS. TIMER2 was applied to determine the association of the KDM6B expression and immune infiltration and DNA methyltransferases. Spearman correlation analysis was used to assess the association of the KDM6B expression with TMB (tumor mutation burden) and MSI (microsatellite instability). The KEGG (Kyoto encyclopedia of genes and genomes) pathway analysis and GO (Gene ontology) enrichment analysis were used to further investigate the potential mechanism of KDM6B in tumor pathophysiology.Results: KDM6B was downregulated in 11 cancer types and upregulated across five types. In KIRC (kidney renal clear cell carcinoma) and OV (ovarian serous cystadenocarcinoma), the KDM6B level was significantly associated with the pathological stage. A high level of KDM6B was related to poor OS (overall survival) outcomes for THCA (thyroid carcinoma), while a low level was correlated with poor OS and DFS (disease-free survival) prognosis of KIRC. The KDM6B expression level was associated with TMB, MSI, and immune cell infiltration, particularly cancer-associated fibroblasts, across various cancer types with different correlations. Furthermore, the enrichment analysis revealed the relationship between H3K4 and H3K27 methylation and KDM6B function.Conclusion: Dysregulation of the DNA methyltransferase activity and methylation levels of H3K4 and H3K27 may involve in the dual role of KDM6B in tumorigenesis and development. Our study offered a relatively comprehensive understanding of KDM6B’s dual role in cancer development and response to immunotherapy.

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“…An ATP-driven chaperone cycle controlled by various cochaperones is required for the HSP90-mediated activation and stability of customer proteins. This is accomplished via an ATP-driven chaperone cycle . The deprivation of HSP90 mediated by Cul5 is not based on the function of either the elongin B or C as indicated by directing elongin C, which can fix Cul5 but not the SOCS box inside substrate receptors that affect ErbB2 denaturation .…”

Section: Some Common Substrates Of Cul5mentioning

confidence: 99%

“…Xu and his team have shown that the neddylation and ubiquitination complexes of UBE2F–Cul5–RBX2 and UBE2M–Parkin/DJ-1 enzymes regulate apoptosis from NOXA turnover . First, UBE2F, one of two neddylators of the ubiquitin-conjugated enzyme (E2), collaborates with RBX2 serving as the E3 neddylator, which initiates Cul5 neddylation around the triplet of a lysine residue (Lys724) . Cul5 activity depends on the presence of this enzyme.…”

Section: Some Common Substrates Of Cul5mentioning

confidence: 99%

“…Each receptor molecule can target multiple protein molecules for the ubiquitination reaction. The CRL subfamilies are controlled via an active covalent alteration through a ubiquitin-like protein called neural precursor cell expressed developmentally down-regulated 8 (Nedd8), which produces many conformational variations in the structures of CRLs and leads to their activation by enabling them to bind with Skp1F box molecules . In the absence of Nedd8 modification, the Cul-associated and neddylation-dissociated 1 (CAND1) molecule, which is a CRL inhibitor, binds with Cul1-Rbx1, causing the formation of an inactive complex that lacks the Skp1F box structure .…”

Section: Introductionmentioning

confidence: 99%

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A Comprehensive Review of Biological Roles and Interactions of Cullin-5 Protein

et al. 2022

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Ubiquitination is a modification of proteins that has a powerful impact on protein function along with other cellular functions. This reaction is regulated through major enzymes, including E3 ligase as a chief enzyme. The Cullin-5 ubiquitin ligase (Cul5) possesses a variety of substrates that maintain the process of ubiquitination as well as proteasomal degradation. It regulates cell development, proliferation, and other physiological tasks in the human body. Moreover, it has been discovered that the expression of Cul5 plays a significant role in specific cancer cells while affecting the progression of tumor cells. This review is based on current knowledge about Cul5 and its expression, signaling pathways, regulation, virus-related responses, and inhibitors for therapeutic strategies.

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Cullin-5 (CUL5) as a potential prognostic marker in a pan-cancer analysis of human tumors

Cited by 9 publications

References 36 publications

Genetic and Epigenetic Mechanisms Deregulate the CRL2pVHL Complex in Hepatocellular Carcinoma

Genetic and Epigenetic Mechanisms Deregulate the CRL2pVHL Complex in Hepatocellular Carcinoma

A Pan-Cancer Analysis Revealing the Dual Roles of Lysine (K)-Specific Demethylase 6B in Tumorigenesis and Immunity

A Comprehensive Review of Biological Roles and Interactions of Cullin-5 Protein

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